Just Spengler (David Goldman) being Spengler, From "Zionism is Racism" to "Judaism is Racism":

Judaism has nothing to do with race-there are Jews of every race-but it does have to do with family. Jews are members of Abraham's family. Not only tradition, but a great deal of DNA evidence support this claim. To insist that Jews adopt the criterion of "belief" for membership is to rule that God must act in accordance with a human court's notion of the permissible range of God's behavior. No wonder the Reform Jews and the British Humanist Association support this.

1) Yes, Jews are genetically distinct.

2) But, they are also the product of genetic admixture.

3) And, it seems more likely that that admixture arrived via maternal lineages, that is, gentile female ancestors (the mtDNA results are somewhat confused, but the Y lineages seem to be relatively strongly Middle Eastern in provenance in comparison to total genome content).

In light of the fact that the debate is over the validity of the criterion of maternal descent as to "Who is a Jew," it seems deceptive to appeal to genetics when that field opens up more questions in regards to Jewish tradition than it closes. Of course, this sort of shell-game is normal behavior for Spengler. Someone should really put a "For Entertainment Purposes Only" sticker on his blog.

Labels: Genetics, Jewish Genetics

If you haven't been following the goings-on via Twitter, Luke Jostins has been posting some tidbits on his blog, Genetic Inference. If you get interested in something, remember you can search abstracts.

Labels: Genetics, Population genetics

Very interesting paper in PLoS Genetics, Inferring the Joint Demographic History of Multiple Populations from Multidimensional SNP Frequency Data. Here's the author summary:

The demographic history of our species is reflected in patterns of genetic variation within and among populations. We developed an efficient method for calculating the expected distribution of genetic variation, given a demographic model including such events as population size changes, population splits and joins, and migration. We applied our approach to publicly available human sequencing data, searching for models that best reproduce the observed patterns. Our joint analysis of data from African, European, and Asian populations yielded new dates for when these populations diverged. In particular, we found that African and Eurasian populations diverged around 100,000 years ago. This is earlier than other genetic studies suggest, because our model includes the effects of migration, which we found to be important for reproducing observed patterns of variation in the data. We also analyzed data from European, Asian, and Mexican populations to model the peopling of the Americas. Here, we find no evidence for recurrent migration after East Asian and Native American populations diverged. Our methods are not limited to studying humans, and we hope that future sequencing projects will offer more insights into the history of both our own species and others.

And from the abstract:

We infer divergence between West African and Eurasian populations 140 thousand years ago (95% confidence interval: 40-270 kya). This is earlier than other genetic studies, in part because we incorporate migration. We estimate the European (CEU) and East Asian (CHB) divergence time to be 23 kya (95% c.i.: 17-43 kya), long after archeological evidence places modern humans in Europe. Finally, we estimate divergence between East Asians (CHB) and Mexican-Americans (MXL) of 22 kya (95% c.i.: 16.3-26.9 kya), and our analysis yields no evidence for subsequent migration.

I would keep in mind these 95% confidence intervals, but I immediately wondered about this European-East Asian divergence time just like Dienekes.

Labels: Genetics, Population genetics

Are Humans Still Evolving? Absolutely, Says A New Analysis Of A Long-term Survey Of Human Health:

"There is this idea that because medicine has been so good at reducing mortality rates, that means that natural selection is no longer operating in humans," said Stephen Stearns of Yale University. A recent analysis by Stearns and colleagues turns this idea on its head....

Taking advantage of data collected as part of a 60-year study of more than 2000 North American women in the Framingham Heart Study, the researchers analyzed a handful of traits important to human health. By measuring the effects of these traits on the number of children the women had over their lifetime, the researchers were able to estimate the strength of selection and make short-term predictions about how each trait might evolve in the future. After adjusting for factors such as education and smoking, their models predict that the descendents of these women will be slightly shorter and heavier, will have lower blood pressure and cholesterol, will have their first child at a younger age, and will reach menopause later in life.

Since large numbers of humans forgo reproduction in an evolutionary sense they might as well have died (excluding some inclusive fitness effects). If reproductive variance and heritable variation in traits correlated with that variance continues then naturally selection will be an operative phenomenon.

The paper is coming out in PNAS, so no guarantee when it'll be online, Byars, S., D. Ewbank, et al. Natural selection in a contemporary human population. Proceedings of the National Academy of Sciences, 106(42) DOI: 10.1073_pnas.0906199106.

Labels: Evolution, Genetics

23andMe performs genome-wide association study on NFL players, fails to find athlete genes:

It's unsurprising that the results of this study are negative (more on this below), but the conclusions they draw from this are fallacious. In fact we know from twin and family studies that many (but not all) traits related to athletic performance are highly heritable; researchers just haven't been able to track down the vast majority of the genetic variants responsible yet, and this study is no exception.

What 23andMe have actually shown here is that the limited subset of genetic variation captured by their genotyping chip (which almost exclusively targets genetic variants with a frequency of greater than 5%) doesn't include any variants with an extremely strong association with NFL prowess.

That shouldn't come as a surprise to anyone who's been following advances in human genetics for the last few years; a genome-wide association study on a highly complex trait with a sample size of 100 has, historically speaking, a vanishingly small chance of yielding any positive results at all. (Yes, there are exceptions, but I don't think a sensible prior expectation would be that athletic performance has a similar genetic architecture to macular degeneration.)

NFL players are taller and heavier than average, in addition to being able to run the 40 in 4.5 seconds. Seems like a lot of these are quantitative traits.

Labels: athletes, Genetics

A new paper is getting a lot of press, Reconstructing Indian population history. I will probably have something up on ScienceBlogs tomorrow (have to read the supplements). But I thought I'd highlight a paragraph in the text:

We warn that 'models' in population genetics should be treated with caution. Although they provide an important framework for testing historical hypotheses, they are oversimplifications. For example, the true ancestral populations of India were probably not homogeneous as we assume in our model, but instead were probably formed by clusters of related groups that mixed at different times. However, modelling them as homogeneous fits the data and seems to capture meaningful features of history.

This caution did not percolate to the level of the press releases from what I can gather. John Hawks has some criticisms up....

Labels: Genetics

I thought I'd point quickly to a really nice paper showing that the RNAi pathway, thought to be absent in budding yeasts, is actually only missing from baker's yeast, Saccharomyces cerevisiae. Remarkably, the authors are able to reconstitute the pathway (which was presumably present in the ancestor of all budding yeasts) in S. cerevisiae with exogenous expression of only two genes. The authors close with a remark about the role of contingency (in particular with regards to the choice of model organism) in research:

While anticipating a productive future for RNAi research in budding yeasts, we note that if in the past S. castellii [a yeast with an endogenous RNAi pathway] rather than S. cerevisiae had been chosen as the model budding yeast, the history of RNAi research would have been dramatically different.

Labels: Genetics

ScienceDaily has an interesting piece, Individual Genetic Data Illuminates How Genes Influence Human Health. Points to two papers, Epistasis and Its Implications for Personal Genetics and Genetic Population Structure Analysis in New Hampshire Reveals Eastern European Ancestry. If you read a weblog like Genetic Future you are probably cognizant of the fact that personal genomics firms are invested in overselling and hyping their current efficacy to serve their economic interests. And yet I was intrigued as to the disjunction between the present day capabilities of personal genomics and the perception of its power in the general media when listening to a recent episode of Plant Money. The hosts spoke as if personal genomics had already rendered health insurance obsolete because science had removed uncertainty from prediction of disease risk. Even when personal genomics does become powerful enough to push itself far beyond the margins when it comes to effecting personal health decisions, randomness is probably going to be a big factor in who becomes ill simply because randomness is a fact of biology.

Labels: Genetics, Personal Genomics

Dienekes is posting more ASHG abstracts. This one is interesting:

A nonsynonymous SNP in EDAR is associated with tooth shoveling

Teeth display variations among individuals in the size and the shape of cusps, ridges, grooves, and roots. In addition, there are certain dental characteristics which are predominant in certain human groups, such as tooth shoveling of upper incisors that is major in Asian populations but rare or absent in African and European populations...Human genome diversity data have revealed that the derived allele of a nonsynonymous single nucleotide polymorphism (SNP), rs3827760 that is also called EDAR T1540C, is predominant in East Asian populations but absent in populations of African and European origins. It has recently been reported that the 1540C allele is associated with Asian-specific hair thickness. The aim of this study is to clarify whether the nonsynonymous polymorphism in EDAR is also associated with dental morphology in humans or not. For this purpose, we measured crown diameters and tooth shoveling grades, genotyped EDAR T1540C, and analyzed the correlations between them in Japanese populations. To comprehend individual patterns of dental morphology, we applied a principal component analysis (PCA) to individual-level metric data, the result of which implies that multiple types of factors affect the tooth size. This study clearly demonstrated that the number of the Asian-specific EDAR 1540C allele is strongly correlated with the tooth shoveling grade.

We've posted on EDAR. Interesting that it seems it is related to another classic "Mongoloid" physical trait, the shovel-shaped incisor, which loomed large back in the day when bones and teeth were the way you identified remains. Of course, other ancient populations had shovel-shaped incisors, so it isn't as if this is totally unique to the peoples of East Asia and the Americas. In any case, this shouldn't be too surprising, EDAR does a lot of things, as evident by the summary in GeneCards:

This gene encodes a member of the tumor necrosis factor receptor family. The encoded transmembrane protein is a receptor for the soluble ligand ectodysplasin A, and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia.

Labels: Genetics

Dienekes posted a bunch of abstracts from the 2009 American Society of Human Genetics meeting. This one is of interest in light of recent posts on this weblog:

Some Y-chromosomal haplotypes have been found at unusually high frequencies in Asian and European human populations. The massive spreadof these lineages has been explained by the impact of social selection i.e.the high reproductive success of some males and their relative/descendants due to their high social status. The most well-known examples are the "Khan haplotype" and the "Manchou haplotype" in Asia, and the U’Neill haplotype in Ireland. But are these frequent haplotypes always associated with recentevents of social selection, or could they be linked to much older processes? To address this question, we have surveyed ~ 3500 males in 97 populationsfrom Turkey to Japan. We have focused on the 12 most frequently represented haplotypes in Eurasia and tested whether their expansions are linked to a specific factor such as language or subsistence methods. Our results show that both recent and ancient processes are responsible for the expansions of these lineages. The recent expansions (2000-3000 years) likely to be linked to social selection are prevalent in Altaic-speaking and pastora lpopulations. This might indicate a recent cultural change in the social organizationof these populations. The ancient expansions (8000-10000 years) are over-represented in Indo-European speaking and sedentary farmer populations,and are likely to be the result of the Neolithic transition.

Asymmetries between male and female lineages are always of interest. For example, diversity of Y and mtDNA correlates well with patrilocality vs. matrilocality. The idea of "super-male" lineages was mooted by Bryan Sykes several years ago in the wake of the "Genghis Khan haplotype", though it benefited from particular preconceptions many have about the nature of male genetic reproductive fitness. But it is likely that these dynamics vary by population due to ecological and/or social parameters. The time window for the expansion of Y lineages among Altaic speakers is very suggestive in light of historical records and archaeological data. It seems that early on (i.e., before 500 BCE) horse-based nomadism was dominated by Indo-Europeans, predominantly Iranians, in Eurasia. In the few centuries before Christ the populations of the eastern steppe, the precursors of Altaic language families, adopted this lifestyle, and to a great extent superseded the Iranian populations across the length and breadth of the non-sedentary zone over the next 1,500 years (the fact that the Ossetians are now a people who reside in the Caucasus is illustrative of the great retreat of Iranian peoples on the steppe). I have suggested that there is a winner-take-all dynamic in regards to steppe polities, and I suspect this will be reflected in the genetics of male lineages as well.

* It is notable that Ireland was to a great extent a pastoralist society during the period of domination by the Ui Neill .

Labels: Genetics, History

Since I see p-ter hasn't posted on this, in Science, Coat Variation in the Domestic Dog Is Governed by Variants in Three Genes:

Coat color and type are essential characteristics of domestic dog breeds. While the genetic basis of coat color has been well characterized, relatively little is known about the genes influencing coat growth pattern, length, and curl. We performed genome-wide association studies of more than 1000 dogs from 80 domestic breeds to identify genes associated with canine fur phenotypes. Taking advantage of both inter- and intrabreed variability, we identified distinct mutations in three genes, RSPO2, FGF5, and KRT71 (encoding R-spondin-2, fibroblast growth factor-5 and keratin-71, respectively), which together account for the majority of coat phenotypes in purebred dogs in the United States. This work illustrates that an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only a few genes.

See ScienceDaily for summary. This will help us cure cancer! OK, probably not, but hopefully perhaps we might get toward understanding hair form beyond EDAR.

Labels: Dog genetics, Genetics, Hair

Nature News headline: Human-chimp interbreeding challenged. Makes it seem like there's a breeding program somewhere, and others are challenging it on ethical grounds....

Labels: Genetics

As most readers of this weblog know most humans as adults cannot digest lactose. The ability to digest lactose via the persistence of the enzyme lactase is differentially distributed. Both inferential methods and a small number of ancient genetic extractions suggest that this ability arose within the last 10,000 years. A new paper, The Origins of Lactase Persistence in Europe:

Most adults worldwide do not produce the enzyme lactase and so are unable to digest the milk sugar lactose. However, most people in Europe and many from other populations continue to produce lactase throughout their life (lactase persistence). In Europe, a single genetic variant, �13,910*T, is strongly associated with lactase persistence and appears to have been favoured by natural selection in the last 10,000 years. Since adult consumption of fresh milk was only possible after the domestication of animals, it is likely that lactase persistence coevolved with the cultural practice of dairying, although it is not known when lactase persistence first arose in Europe or what factors drove its rapid spread. To address these questions, we have developed a simulation model of the spread of lactase persistence, dairying, and farmers in Europe, and have integrated genetic and archaeological data using newly developed statistical approaches. We infer that lactase persistence/dairying coevolution began around 7,500 years ago between the central Balkans and central Europe, probably among people of the Linearbandkeramik culture. We also find that lactase persistence was not more favoured in northern latitudes through an increased requirement for dietary vitamin D. Our results illustrate the possibility of integrating genetic and archaeological data to address important questions on human evolution.

Here's a graphical illustration of their conclusion:

Labels: Genetics, Population genetics

ScienceDaily, Genetic Variations Linked To Brain Size. The write-up seems a bit garbled to me, so probably best to read the paper, A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations, when it is live on the PNAS site.

Labels: Genetics, Neuroscience

Megan McArdle has has been talking about the high heritability of BMI again. I have expressed concern about her putting the high heritability numbers out there when it comes to its relevance for public policy, though I do tend to agree with her general stance that glib assertions about the importance of will-power are probably non-starters. And, rather than point to arguments such as "I have a slow metabolism," it is probably more critical emphasize the complexity of the chain of events and framing of how we make decisions, much of which occurs "under the hood" and outside the purview of conscious explicit control. Interestingly, the reality that choice is highly conditioned by details of our environment combined with innate predispositions, and proximately is driven by many implicit factors, has pushed me in a less libertarian direction.

In any case, the whole discussion got me interested in the topic of obesity & heritability, and I found this review, Human Obesity: A Heritable Neurobehavioral Disorder That Is Highly Sensitive to Environmental Conditions. You can read the full text, it's Open Access now, but this part caught my attention:

...He hypothesizes that random natural variation in "hypothalamic energy balance set points" has occurred over millions of years of primate evolution. Whereas variants that would tend to produce a state of low energy stores would have been systematically selected against, at least in part because of their adverse impact of reproductive success, upward drifts in such set points would have been allowed to persist (rather than being positively selected for, as the “thrifty gene” hypothesis would have it). This upward drift would be particularly prominent because the formation of organized social groups and the discovery of fire, both of which occurred around 2,000,000 years ago, made our ancestors less susceptible to predation. Not particularly emphasized by Speakman, but likely to be important, is the probability that such natural tendencies toward an upward drift in adipose stores may rarely have actually manifested themselves as obesity because of the high energy cost of obtaining food during most of human evolution. It is only in the past 50 years or so, when for the first time in human history the majority of people in the developed and developing world can readily access sufficient daily calories to exceed the calories expended in acquiring them, that those with intrinsically higher set points have manifested their "obesity potential" on a grand scale. Unlike the “thrifty gene” hypothesis, this scenario provides a credible explanation for the fact that even in places where obesity is very common, a substantial proportion of the population remains lean.

This is an old hobby horse of mine: if you see a quantitative trait which can be conceived of as normally distributed with a high degree of heritability, such as body mass index, then its fitness implication can't have been too stark. In other words, if a very heritable trait still has a great deal of extant genetic variation, then it is either in transient, or, more likely the fitness implication of any particular trait value was low or there is balancing dynamics preserving the variance. Like IQ, body weight has been increasing over the past century. Many people think that they know the reason why this is occurring. If the reasons are ever established to a high degree of certitude, is it possible to reverse the slouch toward obesity without coercion?

Labels: Genetics, Origin of obesity

Greg Mayer, filling in for Jerry Coyne, has a post up on a somewhat odd objection to the appointment of Francis Collins as director of NIH: that he's a geneticist. The argument seems to be that diseases are complicated and not entirely genetic, and that Collins isn't hip to non-genetic subtleties. To be frank, this is silly--while it's sometimes a revelation to non-biologists that the "gene for X" way of framing things is inaccurate, Collins is not incompetent. If I had to guess what direction he's planning on taking the NIH, I'd look to what he's actually written.

In the comments to the post, there's the additional worry that Collins represents "big science", which I suppose is considered to be a bad thing (apparently Collins thinks it would be nice to catalogue all the transcripts in a cell, which for whatever reason really pissed off this dude). It's not a bad thing at all; in many cases, big, relatively hypothesis-free science is actually really nice for rationally choosing which "little science" projects to pursue.

Let's take a couple recent examples from genome-wide association studies (these studies over the past few years have exponentially increased our understanding of complex disease; whether that exponential increase is enough for you depends on your prior expectations). First, a little over two years ago, an association was found between a genetic variant in the FTO gene and obsesity in humans. At the time, the gene had unknown function. Now, there's a mouse model and focused biochemical analysis being done on this gene, and we're light years closer to understanding what it does and how nearby variation influence obesity. Would all of this been done without the "hypothesis-free" GWAS? Not anytime soon.

Second, consider the genome-wide association studies in several cancers that all pointed to the same, gene-free region on chromosome 8. In the last few weeks, three separate groups have published their "small-scale" molecular biology work establishing that the associated region appears to be an enhancer important for either proper temporal or spatial gene expression. How does it work? It's not clear, but that's the point--this is an interesting question. Much of "small-scale" molecular biology is done in a few model systems, or on a few "popular" genes. There's a very good reason for this--these systems or genes are already known to be interesting either scientifically or medically. One efficient way to identify novel, potentially interesting systems is through large-scale work.

Labels: Genetics, Genomics

Taller, heavier: the speedy evolution of the fastest people on the planet:

While the average person has gained about five centimetres since 1900, the height of champion runners has increased 16.2 centimetres, say Duke University researchers, Jordan Charles and Adrian Bejan, who studied the heights and weights of 100-metre world record holders.

''The trends revealed by our analysis suggest that speed records will continue to be dominated by heavier and taller athletes,'' said Mr Charles, whose study was published last month in The Journal of Experimental Biology .

...

While Dr Norton dismissed those predictions, he believed that the laws of genetics, thanks to the habit of athletes marrying athletes - and possibly even the creation of athlete sperm banks - meant runners would continue growing taller, more powerful and faster.

Remember the "Little Hercules" with the myostatin mutation? His mother was very muscular, and reportedly there was a family history of mesomorphicity. One way population level quantitative trait mean value can shift through selection beyond the most extreme values of the original population without new mutation being necessary is simply to change the underlying allele frequencies enough so that originally unlikely combinations become common. Assortative mating is another variant of this dynamic, if people several sigmas from the mean mate, then new combinations are likely to emerge.

Labels: Genetics, Sports

Online this week, Nature has published a genome-wide association study for response to treatment for chronic hepatitis C infection-the authors identify a polymorphism in an interleukin gene that is a strong predictor of how well an individual is able to clear the virus. Interestingly, the frequency of the polymorphism in different populations tracks the previously noted population difference in drug response, and the authors claim to explain half the difference in response rate between African- and European-Americans with this single polymorphism.

This paper is also interesting in that it represents one of the first (if not the first?) studies to coordinate a drug trial (in this cases, three different treatments for hepatitis C) with a genome-wide association study. This promises to lead to both important advances--as researchers are able to identify genetic subgroups of individuals who respond (or not) to a drug, even if it is ineffective in the population as a whole--as well as (my cynical side speaks) additional opportunities for misleading post hoc analyses by drug companies to try to salvage and market drugs that don't work. Hopefully, mostly the former--this could be an important step towards legitimizing genetic information in the eyes of MDs, and an ever-so-slight step towards personalized medicine.

Labels: Genetics

A remarkable study published in Science this week identifies a rare mutation in the gene DEC2 which influences the duration of sleep in humans. The authors started with a family where patterns of short sleep (about 6 hours of sleep a night on non-workdays, versus ~8 hours for other people in the family) seemed to follow a Mendelian inheritance pattern. In a candidate gene resequencing study, they identified a mutation in all of two people--a mother and daughter--with the short sleep pattern.

In what can only be described as a ballsy move, the authors then invested what must have been a considerable amount of time and money on following up this mutation. Which, I emphasize again, was found in only two individuals in a single family. In particular, they generated mice carrying both of the human versions of the gene, and were thus able to explicitly compare the two human alleles in an animal model. (This is in contrast to most mouse studies, which completely remove a gene or dramatically up-regulate it). Not wishing to show any mammalian bias, they did the same thing in flies. In all cases, the results were consistent with the human data--the low-sleep allele led to increased activity in both species.

Out of curiosity, is 6 hours of sleep (without an alarm clock) really all that odd for people? It certainly would be for me, but I feel like I know plenty of people who claim to naturally need only about that much.

Labels: Genetics

Altered connections on the road to psychopathy:

... Earlier studies suggested that dysfunction of the amygdala and/or orbitofrontal cortex (OFC) may underpin psychopathy. Nobody, however, has ever studied the white matter connections (such as the uncinate fasciculus (UF)) linking these structures in psychopaths. Therefore, we used in vivo diffusion tensor magnetic resonance imaging (DT-MRI) tractography to analyse the microstructural integrity of the UF in psychopaths (defined by a Psychopathy Checklist Revised (PCL-R) score of 25) with convictions that included attempted murder, manslaughter, multiple rape with strangulation and false imprisonment. We report significantly reduced fractional anisotropy (FA) (P<0.003), an indirect measure of microstructural integrity, in the UF of psychopaths compared with age- and IQ-matched controls. We also found, within psychopaths, a correlation between measures of antisocial behaviour and anatomical differences in the UF. To confirm that these findings were specific to the limbic amygdala–OFC network, we also studied two 'non-limbic' control tracts connecting the posterior visual and auditory areas to the amygdala and the OFC, and found no significant between-group differences. Lastly, to determine that our findings in UF could not be totally explained by non-specific confounds, we carried out a post hoc comparison with a psychiatric control group with a past history of drug abuse and institutionalization. Our findings remained significant. Taken together, these results suggest that abnormalities in a specific amygdala–OFC limbic network underpin the neurobiological basis of psychopathy.

I'm a little skeptical about psychiatry's ability to diagnose distinctive phenotypes in general, but from what I have read genuinely amoral psychopaths are a real phenomenon, and not a politicized constructed pathology. Readers with more neuroscience chops are invited to weight in if this another sexy neuro paper with little substance. Also see ScienceDaily.

Labels: Genetics, Psychology

The NY Times reports on a new paper calling into question the theory that the dog was first domesticated in East Asia.

The evidence for an East Asian origin of dogs came from a study of mitochondrial DNA, which showed that dog populations in East Asia harbored more diversity than their counterparts in other parts of the world (the reasoning is that more diverse populations are likely to be the origin of a species; populations which split off and move about will be less diverse). The authors of the new paper, however, point out that this study included more semi-wild "village dogs" from East Asia than from other parts of the world, and that these village dogs tend to be more diverse than purebreds from the same part of the world.

When African village dogs are included in the analysis, the East Asian dogs no longer stand out as extremely diverse (see right; the fitted line is what would be expected is diversity were equal in all places). Though this places the East Asian origin hypothesis in serious doubt, for now the authors--having only sampled African dogs (Africa does not have the wolf from which dogs are thought to have been domesticated)--do not present an alternative. As more data is collected from dogs around the world, this state of affairs in unlikely to last.

Labels: Genetics

Impact of Selection and Demography on the Diffusion of Lactase Persistence:

The lactase enzyme allows lactose digestion in fresh milk. Its activity strongly decreases after the weaning phase in most humans, but persists at a high frequency in Europe and some nomadic populations. Two hypotheses are usually proposed to explain the particular distribution of the lactase persistence phenotype. The gene-culture coevolution hypothesis supposes a nutritional advantage of lactose digestion in pastoral populations. The calcium assimilation hypothesis suggests that carriers of the lactase persistence allele(s) (LCT*P) are favoured in high-latitude regions, where sunshine is insufficient to allow accurate vitamin-D synthesis. In this work, we test the validity of these two hypotheses on a large worldwide dataset of lactase persistence frequencies by using several complementary approaches.

...

Our results show that gene-culture coevolution is a likely hypothesis in Africa as high LCT*P frequencies are preferentially found in pastoral populations. In Europe, we show that population history played an important role in the diffusion of lactase persistence over the continent. Moreover, selection pressure on lactase persistence has been very high in the North-western part of the continent, by contrast to the South-eastern part where genetic drift alone can explain the observed frequencies. This selection pressure increasing with latitude is highly compatible with the calcium assimilation hypothesis while the gene-culture coevolution hypothesis cannot be ruled out if a positively selected lactase gene was carried at the front of the expansion wave during the Neolithic transition in Europe.

The "calcium hypothesis" idea is of course one of the explanations for light skin in Northern Europe as well. The locus responsible for 1/3 of the skin color difference between Africans and Europeans, SLC24A5, is a relative recent sweep, on the order of the last 10,000 years. The authors do caution to be careful about the assumptions of their model. Point taken to heart, as I don't think they have a good enough grasp on the fine-grained variation in the lactase persistence alleles and how they track ecology within Europe. The Greenland Norse did not raise cattle just because of lack of Vitamin D (which they ended up getting through a shift toward a marine diet in any case), rather, there were ecological constraints in terms of the maximum productivity of grain-based subsistence farming (particularly with wheat in cold damp climates). In the conclusion of the paper it is noted that Iberia is a good test case of the model, and more data needs to be gathered there. If it is gene-culture coevolution than many Iberian peoples should be lactase persistent, but if it is due to Vitamin D, they should not be.

Labels: Genetics

The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry:

Persons of African ancestry, on average, have lower white blood cell (WBC) counts than those of European descent (ethnic leukopenia), but whether this impacts negatively on HIV-1 disease course remains unknown. Here, in a large natural history cohort of HIV-infected subjects we show that although leukopenia...was associated with an accelerated HIV disease course, this effect was more prominent in leukopenic subjects of European than African ancestry. The African-specific -46C/C genotype of Duffy Antigen Receptor for Chemokines (DARC) confers the malaria-resisting, Duffy-null phenotype, and we found that the recently described association of this genotype with ethnic leukopenia extends to HIV-infected African Americans (AA). The association of Duffy-null status with HIV disease course differed according to WBC but not CD4+ T cell counts, such that leukopenic but not non-leukopenic HIV+ AAs with DARC -46C/C had a survival advantage compared with all Duffy-positive subjects. This survival advantage became increasingly pronounced in those with progressively lower WBC counts. These data highlight that the interaction between DARC genotype and the cellular milieu defined by WBC counts may influence HIV disease course, and this may provide a partial explanation of why ethnic leukopenia remains benign in HIV-infected African Americans, despite immunodeficiency.

Duffy status is a highly ancestrally informative trait. This is a case where the relatively low between population variance found among humans does not apply. Rather, it seems that the Duffy null phenotype is a recent adaptation to malaria among West Africans. Because malaria has such a strong fitness implication many independent genetic adaptations have emerged, many of them with other negative side effects. On net individuals with side effects may still have higher fitness in an environment where malaria is endemic. Sometimes the net benefit is most evidence on a population wide scale, sickle-cell anemia is a deleterious homozygote which exists because of the much higher frequency of heteryzogytes vis-a-vis wild type homozygotes. Many malaria adaptations exhibit the large effect dynamic and suboptimal characteristic which one might except from the early stages of natural selection in a Fisherian model. You deal with the adaptive pressures of the present and let the future take care of itself. In this case, the future involved HIV:

The researchers found that leukopenia was generally associated with a faster disease progression from HIV to AIDS, independent of known predictors of AIDS development. "On average, leukopenic European Americans progressed nearly three times faster than their non-leukopenic African or European counterparts," explained Hemant Kulkarni, MD, first author of this study. "However, leukopenic African Americans had a slower disease course than leukopenic European Americans, even though twice as many African Americans in the study had leukopenia."

The investigators found that the DARC variation, not race, explained the differences in WBC counts in African Americans with HIV. Among those who were leukopenic, only those with the DARC variation experienced a significant survival benefit. Additionally, this survival advantage became increasingly pronounced in those with progressively lower WBC counts, suggesting that the interaction between DARC and WBC counts was the primary influence on slowing HIV disease progression in African Americans.

There are no doubt details in the genetic architecture of those with the null genotype worth future investigation.

Labels: Genetics, human biodiversity, Population genetics, race

Partial penetrance facilitates developmental evolution in bacteria:

Development normally occurs similarly in all individuals within an isogenic population, but mutations often affect the fates of individual organisms differently...This phenomenon, known as partial penetrance, has been observed in diverse developmental systems. However, it remains unclear how the underlying genetic network specifies the set of possible alternative fates and how the relative frequencies of these fates evolve...Here we identify a stochastic cell fate determination process that operates in Bacillus subtilis sporulation mutants and show how it allows genetic control of the penetrance of multiple fates. Mutations in an intercompartmental signalling process generate a set of discrete alternative fates not observed in wild-type cells, including rare formation of two viable 'twin' spores, rather than one within a single cell. By genetically modulating chromosome replication and septation, we can systematically tune the penetrance of each mutant fate. Furthermore, signalling and replication perturbations synergize to significantly increase the penetrance of twin sporulation. These results suggest a potential pathway for developmental evolution between monosporulation and twin sporulation through states of intermediate twin penetrance. Furthermore, time-lapse microscopy of twin sporulation in wild-type Clostridium oceanicum shows a strong resemblance to twin sporulation in these B. subtilis mutants...Together the results suggest that noise can facilitate developmental evolution by enabling the initial expression of discrete morphological traits at low penetrance, and allowing their stabilization by gradual adjustment of genetic parameters.

Also, see press release, Caltech-led team shows how evolution can allow for large developmental leaps. A bit grandiose in headline.

Labels: Evolution, Genetics

Evolutionary Dynamics of Human Toll-Like Receptors and Their Different Contributions to Host Defense. Interesting stuff on inter-population variation in the discussion:

Our data show that TLR1, and more specifically the nonsynonymous T1805G variant (I602S), is the genuine target of positive selection detected in the TLR10-TLR1-TLR6 gene cluster in Europeans. First, TLR1 is ~2 times more diverse in non-African than in African populations, a pattern not compatible with the African origin of modern humans...This pattern has been observed only once among the 323 genes (0.3%) sequenced by the Seattle SNP consortium. Thus, the increased diversity observed in TLR1 among non-Africans probably results from ongoing hitchhiking between the selected allele and neutral variation at linked sites. Second, the 1805G (602S) mutation presents the highest level of population differentiation (FST = 0.54) of all SNPs located in this gene cluster...Third, among the three nonsynonymous variants composing the haplotype identified as being under positive selection in Europeans (H34, see Figure S5), only the TLR1 1805G (602S) variant has a remarkable impairment effect on agonist-induced NF-ÎşB activation, showing a decreased signaling by up to 60%...These findings are consistent with previous studies showing that, homozygous, and to a lesser extent heterozygous, individuals for the 1805G allele present impaired TLR1-mediated immune responses after whole blood stimulation ...Taken together, it is tempting to speculate that an attenuated TLR1-mediated signaling, and a consequently reduced inflammatory response, has conferred a selective advantage in Europeans - a scenario that would explain the very high frequency (51%) of the "hypo-responsiveness" T1805G mutation in Europe. This observation raises questions about the possible evolutionary conflict between developing optimal mechanisms of pathogen recognition by TLRs, and more generally PRRs, and avoiding an excessive inflammatory response that can be harmful for the host.

This looks to be the same area fingered earlier in Icelanders.

Labels: Genetics

In recent years, the genetic mechanisms by which humans have generated massive phenotypic diversity in dogs have started to be uncovered. We now know, for example, much about the genetics of pigmentation in dogs, and a major gene controlling body size. This week, another phenotype--the short, stubby legs of some dog breeds (see right)--has been revealed to have a simple, but interesting genetic basis.

The authors mapped the short leg phenotype to a small region on chromosome 18; further analysis revealed that the probable causal mutation is the insertion of a transcriptionally-active processed (ie. intronless) retrotransposed copy of the FGF4 gene. How this change leads to the phenotype itself is unknown, but understanding the mechanism will likely lead to some interesting biology.

Labels: Genetics

Chromosomal Problems Affect Nearly All Human Embryos: Discovery May Explain Low Fertility Rates In Humans:

For the first time, scientists have shown that chromosomal abnormalities are present in more than 90% of IVF embryos, even those produced by young, fertile couples. Ms Evelyne Vanneste, a PhD student in the Centre for Human Genetics and the University Fertility Center, Leuven University, Belgium, told the 25th annual conference of the European Society of Human Reproduction and Embryology on July 1st, that the surprising finding meant that current techniques used in preimplantation genetic screening (PGS), where embryos are screened genetically in order to select the best embryo for transfer, do nothing to improve pregnancy and live birth rates. Indeed, it can lead to potentially viable embryos being discarded, she said.
...
"Although in vitro culture conditions are known to have a limited influence on the rate of chromosomal imbalances in IVF/ICSI embryos, it is probable that the chromosome instability observed in vitro also occurs in spontaneous pregnancies since, at most, 30% of human conceptions result in a live birth and more than 50% of spontaneous abortions carry chromosomal aberrations. The high rate of chromosomal abnormalities is almost certainly responsible for the low fecundity of humans compared with other mammals," she added.

The exact proportion of fertilizations which end in spontaneous abortion (or lack of implantation) seems rather sketchy from what I can tell, but it's very high. In The Cooperative Gene Mark Ridley suggests that the very high rates of spontaneous abortion among humans is one reason he is not particularly worried about increased genetic load, a prime concern of W. D. Hamilton. I assume he believes that the proportion of spontaneous abortions would simply increase for individuals who have a high mutational load. Hamilton worried about the fact that many more humans lived to reproduce than would have in the past, so that natural selection was no longer operative. Ridley is suggesting that actually the power of selection may simply be transferred to the gestational stage.

One interesting idea would be to see if different populations have different rates of spontaneous abortion. How one would get a precise measure of this, I don't know.

Labels: Genetics

Nicholas Wade (guesting posting for John Tierney) points to a set of papers in this week's Nature reporting large genome-wide association studies of schizophrenia. The main upshot of the papers is that variants in the MHC region influences susceptibility to schizophrenia. This region influences susceptibility to a number of autoimmune diseases, so the association is suggestive evidence that schizophrenia as well has an autoimmune component.

Outside of the MHC, however, there are few convincing signals of association. One interpretation of this might be that there are simply no other common polymorphisms that influence risk of developing schizophrenia. One of the groups, however, set out to test whether this was the case. They took thousands of the top associated SNPs--none of them individually showing a strong association with the disease--and assembled them into a genotypic score for predicting whether an individual has schizophrenia. And indeed, using these thousands of markers, they were able to do significantly (in the statistical sense, not really in the practical sense) better than random at classifying individuals as schizophrenic or not from genotype data alone. Thus, the aggregate effect of thousands of polymorphisms impacts the development of this disease.

What is the practical significance of this? In terms of treatment or drug development, there is essentially none. But it does suggest that there will be no "silver bullet"--copy number polymorphism, rare variants, or what have you--that will solve schizophrenia genetics.

Labels: Genetics

A few weeks ago I noticed that the Wikipedia entry for Cape Coloureds has little fleshed out information on their genetics. As a mixed population it seems that people would be interested, but has always been hard to find anything from Google Scholar on this topic. But the recent Tishkoff paper, The Genetic Structure and History of Africans and African Americans, has some data. You can find a full post at my other weblog, but it seems that not only are the Cape Coloureds substantially European, Khoisan and Bantu, but likely they're also substantially Indian, and there is a definite East Asian element, no doubt from slaves brought from Maritime Southeast Asia by the VOC. There's also a lot of variance in this particular sample of Cape Coloureds. Assuming this is representative I would offer that the main reason is that the Coloured population has historically had many people entering it from other groups, and, many leaving to other groups.

Labels: Genetics, History

One of the rationales advanced for the identification of common alleles that confer modest risk to a disease via genome-wide association studies is that these associations will lead to biological insight into the disease. Two papers published today represent an important first step towards this goal for a variant associated with colorectal cancer.

Like many polymorphisms associated with complex diseases, the one investigated in these studies does not fall within a gene--this particular variant falls hundreds of thousands of bases away from the nearest gene. It does, however, fall within a non-coding element that is conserved across millions of years of evolution, suggesting that it is functional. These studies show that, indeed, the SNP falls in a binding site for a transcription factor, and that the two alleles have different binding affinities for that factor. Additionally, one of the studies shows that the genomic region containing the SNP loops over and makes physical contact with the nearest gene (MYC, a known oncogene), supporting the hypothesis that the SNP affects its regulation.

These studies raise more questions than they answer, of course. None of the studies find an association between the SNP itself and steady-state MYC expression in cell lines. My guess is that, like many transcriptional enhancers, developmental-time-point-specific manner. An important direction now is to determine when that important time point is.

Labels: Genetics

So after my wingeing about the quality of genetic associations found through candidate gene studies, it's only appropriate that I point to a fun candidate gene association study published this week in Nature.

The interesting point here is that the organism isn't humans, but rather baboons, and the phenotype is susceptibility to malaria. Briefly, the authors find that a SNP in the promoter of the Duffy locus (recall that a mutation that abolishes the expression of Duffy in humans leads to protection from Plasmodium vivax and is one of the best characterized instances of recent positive selection in our species) appears to lead to protection from a malaria-like disease in baboons. The authors seem to really, really want this polymorphism to also be under selection in baboons (to complete the parallel story to humans), but they can't bring themselves to say the evidence is anything more that "suggestive" (and to be honest, even that may be wishful thinking).

So is the association true? The study suffers from the same problem of candidate gene studies mentioned before, in that it's small and the evidence for an association is fairly weak. If I had to bet, I'd guess no, the association isn't real. But collecting and genotyping a large sample of baboons is simply not feasible at this point (if it ever will be), so this is what's possible, and it's a kind of fun, suggestive study that would be really cool if it ends up being true.

Labels: Genetics

In a recent post, I made a blanket statement that the vast majority of candidate gene association studies published in psychiatric genetics (actually, in nearly all fields of genetics) are wrong. I'm not just being offhandedly dismissive--below, I outline the statistical argument behind that claim. This discussion is cribbed almost verbatim from a discussion of the issue by statisticians at the Welcome Trust.

Let's assume that there are a finite number of loci in genome, and we test some number of those (in a genome-wide association study, this is on the order of 500K-1M; in a candidate gene study it's more likely in the tens. But the actual marker density is irrelevant for what follows) for association with some phenotype of interest. In general, the criterion used to decide if one has discovered a true association is the p-value, or the probability of seeing the data that you have given that there is no association. But that's not really the quantity you're interested in. The real quantity of interest is the probability that there's a true association given the data you see--the inverse of what's being reported.

By Bayes' Law, this probability depends on the prior probability of an association at that marker, the p-value threshold you've chosen to call a finding "significant", and crucially, the power you had to detect the association [1][2]. Thus, the interpretation of a given p-value depends on the power to detect an association, such that the lower your power, the lower the probability that a "significant" association is true [3].

That's where recent evidence from large genome-wide association studies comes into play. For nearly all diseases, reproducible associations have small effect size and are only detectable when one has sample sizes in the thousands or tens of thousands (for many psychiatric phenotypes, even studies with these sample sizes don't seem to find much). The vast majority of candidate gene association studies had sample sizes in the low hundreds, and thus had essentially zero power to detect the true associations. By the argument above, in this situation the probability that a "significant" association is real approaches zero. The problem with candidate gene association studies is not that they were only targeting candidate genes, per se, but rather that they tended to have small sample sizes and were woefully underpowered to detect true associations.



[1] Let D be the data, T be the event that an association is true, t, be the event that an association is not true, and P(T) be the prior probability that an association is true.

P(T|D) = P(D|T)P(T) / [ P(D|T) P(T) + P(D|t) (1-P(T) ]

P(D|T) is the power, and P(D|t) is the p-value. Clearly, both are relevant here.

[2] http://jnci.oxfordjournals.org/cgi/content/full/96/6/434#FD1

[3] As the authors note,

A key point from both perspectives is that interpreting the strength of evidence in an association study depends on the likely number of true associations, and the power to detect them which, in turn, depends on effect sizes and sample size. In a less-well-powered study it would be necessary to adopt more stringent thresholds to control the false-positive rate. Thus, when comparing two studies for a particular disease, with a hit with the same MAF and P value for association, the likelihood that this is a true positive will in general be greater for the study that is better powered, typically the larger study. In practice, smaller studies often employ less stringent P-value thresholds, which is precisely the opposite of what should occur.

Labels: Genetics

In 2003, Avshalom Caspi and colleagues published an influential article (Google Scholar lists it as having almost 2000 citations in 6 years) claiming that genetic variation in the seratonin transposter gene influences how people respond to traumatic events--the particular, in terms of risk of depression. For years, this has been the poster-child example of gene-environment interactions (for whatever reason, finding significant interaction terms like this is the Holy Grail of human genetics for some). Like the more recent dubious breastfeeding-IQ-genetics story (led by the same group, it should be noted), the authors identified a phenotype they wished to study (depression), an environmental factor that plays a role in the phenotype (traumatic events), genotyped a couple markers in a gene they thought might reasonably be expected to play a role in that phenotype (seratonin), and found a "statistically significant" interaction. Voila.

The 2003 article, as I noted, received quite a bit of attention. This led to attempts to replicate it, and this week, a comprehensive meta-analysis was published of those studies. The result: nothing. There is no evidence for an interaction between genotype at the seratonin receptor and trauma on risk of depression. And in retrospect, why should there be? The probability of happening on the proper combination of genotype and environmental exposure when sampling one environmental exposure (out of an infinite number) and a few gene markers (out of millions) is miniscule--the statistical burden of proof should be much higher than a simple p-value cutoff of 0.05.

These sorts of candidate gene association studies were/are used in all fields, but in my mind are lent the most credence in psychiatric genetics (the place where they should probably be given the least credence, IMO). This is just an additional cautionary tale: the vast majority of associations found through small candidate gene studies, even ones with functional work, plausibility, and the status of publication in a high-profile journal--MAOA and social problems, FADS and IQ (actually, any study published to date on IQ), NPY and stress--are likely wrong.

Labels: Genetics

PLoS Genetics has a nice paper identifying copy-number polymorphism in the transcription factor SOX5 as the causal mutation leading to the pea-comb phenotype (the bottom panels on the right) in chickens. The mutation leads to more widespread expression of the gene at a particular developmental time point, which presumably represses comb formation.

Labels: Genetics

Genetic Architecture of Tameness in a Rat Model of Animal Domestication:

A common feature of domestic animals is tameness-i.e., they tolerate and are unafraid of human presence and handling. To gain insight into the genetic basis of tameness and aggression, we studied an intercross between two lines of rats (Rattus norvegicus) selected over >60 generations for increased tameness and increased aggression against humans, respectively. We measured 45 traits, including tameness and aggression, anxiety-related traits, organ weights, and levels of serum components in >700 rats from an intercross population. Using 201 genetic markers, we identified two significant quantitative trait loci (QTL) for tameness. These loci overlap with QTL for adrenal gland weight and for anxiety-related traits and are part of a five-locus epistatic network influencing tameness. An additional QTL influences the occurrence of white coat spots, but shows no significant effect on tameness. The loci described here are important starting points for finding the genes that cause tameness in these rats and potentially in domestic animals in general.

Also see ScienceDaily.

Labels: Genetics, Population genetics

Iceland has long been of some interest because of its peculiar demographic history and their genetic consequences. So a new paper in PLoS Genetics is of interest, The Impact of Divergence Time on the Nature of Population Structure: An Example from Iceland:

The Icelandic population has been sampled in many disease association studies, providing a strong motivation to understand the structure of this population and its ramifications for disease gene mapping. Previous work using 40 microsatellites showed that the Icelandic population is relatively homogeneous, but exhibits subtle population structure that can bias disease association statistics. Here, we show that regional geographic ancestries of individuals from Iceland can be distinguished using 292,289 autosomal single-nucleotide polymorphisms (SNPs). We further show that subpopulation differences are due to genetic drift since the settlement of Iceland 1100 years ago, and not to varying contributions from different ancestral populations. A consequence of the recent origin of Icelandic population structure is that allele frequency differences follow a null distribution devoid of outliers, so that the risk of false positive associations due to stratification is minimal. Our results highlight an important distinction between population differences attributable to recent drift and those arising from more ancient divergence, which has implications both for association studies and for efforts to detect natural selection using population differentiation.

Figure 3 is a PCA map which shows how individuals from different regions of Iceland sort out. The Scottish and Norwegian populations are there two, and they don't vary much along the components of variation which Icelanders sort out along, the conclusion being that the Iceland variation isn't due to different ancestral proportions. They further calculate that if the ancestral Iceland populations were like the modern Scottish and Norwegian ones, Icelanders are ~35% Scottish and ~65% Norwegian. Most of the differences between Icelanders and continental Europeans is no doubt due to drift because of their very small population size, no migration due to their isolation and the a few specific bottleneck events. But a section on natural selection in Icelanders is interesting:

We found eight SNPs, representing two chromosomal regions, for which the evidence of unusual population differentiation was genomewide-significant...Six of the SNPs lie in or near the TLR (toll-like receptor) genes TLR10 and TLR1, while the other two lie inside the NADSYN1 (NAD synthesase 1) gene....

Toll-like receptors were pinpointed in a recent paper as likely possibilities for localized adaptation.

Labels: Genetics, Population genetics

Dan MacArthur reviews 50 Genetics Ideas You Really Need to Know. Gives it "3.5 nucleotides out of 4."

Labels: Genetics

In light of p-ter's post on KITLG and cancer risk, I stumbled onto this today, Earwax, osmidrosis, and breast cancer: why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type?:

One single-nucleotide polymorphism (SNP), 538G>A (Gly180Arg), in the ABCC11 gene determines the type of earwax. The G/G and G/A genotypes correspond to the wet type of earwax, whereas A/A corresponds to the dry type. Wide ethnic differences exist in the frequencies of those alleles, reflecting global migratory waves of the ancestors of humankind. We herein provide the evidence that this genetic polymorphism has an effect on the N-linked glycosylation of ABCC11, intracellular sorting, and proteasomal degradation of the variant protein. Immunohistochemical studies with cerumen gland-containing tissue specimens revealed that the ABCC11 WT protein was localized in intracellular granules and large vacuoles, as well as at the luminal membrane of secretory cells in the cerumen gland, whereas granular or vacuolar localization was not detected for the SNP (Arg180) variant. This SNP variant lacking N-linked glycosylation is recognized as a misfolded protein in the endoplasmic reticulum and readily undergoes ubiquitination and proteasomal degradation, which determines the dry type of earwax as a mendelian trait with a recessive phenotype. For rapid genetic diagnosis of axillary osmidrosis and potential risk of breast cancer, we developed specific primers for the SmartAmp method that enabled us to clinically genotype the ABCC11 gene within 30 min

I blogged a paper on this SNP relating it to earwax form a few years ago. Also see ScienceDaily. The variation in earwax seems to conform pretty closely to that of EDAR.

Labels: Genetics, Population genetics

Look before you leap: Are women pre-disposed to be more risk averse than male adventurers?:

"It's not at all that women are risk averse," says Jody Radtke, program director for the Women's Wilderness Institute in Boulder, Colorado. When men are confronted with challenging situations, they typically produce adrenaline, which is what causes them to run around, hollering like frat boys at a kegger. An adrenaline rush is a good feeling, but when confronted with the same situation, women produce a different chemical, called acetylcholine.

"Pretty much what (acetylcholine) does is it makes you want to vomit," says Jody.

Because women don't have the same positive chemical reward, they tend to be less pumped about confronting stressful situations. This leads them to rely on decision-making. Essentially, they want the whole picture before they go diving in.

Research, Jody says, shows women have more cross-networking between the two hemispheres of the brain, which subconsciously allows them to evaluate different sensory cues, facts and emotions when making decisions. The cause of this difference probably lies somewhere in the debate of nature versus nurture and the history of evolution.

Marvin Zuckerman, professor emeritus at the University of Delaware, has studied risk for decades. He found men are typically more likely to take risks when seeking novel or exciting sensations, and that comes from both genetics and environment.

"What's important seems to be the environment that isn't shared by siblings in the same family," he says.

The above was originally published by Women's Adventure Magazine. The last reference is to the repeated finding that non-shared environment matters a great deal but isn't well accounted for. Obviously both men and women vary in terms of psychological attributes, and there have been plenty of attempts to adduce the variation to different quantities of neurochemicals (the "chemical soup" model is easy to translate into prose).

The content of the piece isn't too surprising, you see it all the time. Suggesting innate differences between men and women is totally acceptable so long as it is perceived to be neutral, or, better yet, casts women in a positive light. Michael Lewis' recent article on the Icelandic financial turmoil hints to sex differences and male psychology as a root problem. He presented a rather conventional stereotype of men as financial cowboys willing to take outsized risks for reward, while women were risk averse socialists. During the run up to the Iraq War and afterward I recall many people, mostly but not always women, calling into Leftish radio shows promoting a sex determinist theory that war was the result of the male nature, and the fact that men are head of states of most nations was the ultimate problem (this argument crops up in science fiction as well).

The interesting point to me is the sort of articles which highlight "different ways of thinking" between the sexes and how they might be rooted in biological differences have implications which point in different directions in terms of positive or negative valuation depending on your perspective and circumstance. As a specific example, the risk taking predispositions of many males can be seen to be folly and lack of prudence, but, risk often entails both an upside and a downside. Decisions which may seem foolish and wrongheaded viewed through a conventional mainstream lens are often lauded in hindsight as visionary. Unfortunately the nature of uncertainty is such that one has little idea which risks will pay off and which will simply extract a downside cost. It is likely that human societies dominated by those who are only risk averse, or those who are only risk accepting, would not be those which we would truly wish to live in. Variation in human personalities is probably beneficial in an aggregate sense when it comes to human progress. There are downsides risks to both the risk averse and risk accepting strategy, so it is probably best to have some of both. In an economic scenario what I'm talking about is straightforward; consider two individuals with degrees in computer science, one who goes to work for IBM and another who founds a start-up. You wouldn't want everyone to aspire to become a corporate employee, where would the innovation which drives productivity growth come from? On the other hand, there are only so many start-ups which succeed and there is a need for individuals who work in less sexy sectors who service older established technologies which are at the heart of the current economy. In other words, you want to be able to squeeze more juice from the oranges you have, as well be funding research which might result in the discovery of jucier varietals.

Addendum: Obviously what I'm saying here isn't too novel. It's rooted in human nature itself: our minds are cobbled together from disparate competencies and subfunctions, and our unitary consciousness is a delusion very successfully promoted by the prefrontal cortex. But even when it comes to concepts and assumptions which are the purview of the prefontal cortex its priority isn't usually to keep its story straight. Rather it seem geared toward generative ad hoc narratives which are only proximately consistent. Yes it can engage in rationality, but most of the time its forte is rationalization. And why not? Rationalizing the contradictory feels good! It was almost certainly highly adaptive in the past, and likely is today, in terms of keeping everyone in the group on the same page.

Labels: Genetics, human biodiversity, sex differences

Genes, Brains and the Perils of Publication:

I have no wish to criticize these findings as such. But the way in which this paper is written is striking. The negative results are passed over as quickly as possible. This despite the fact that they are very clear and easy to interpret - the rs1344706 variant has no effect on cognitive task performance or neural activation. It is not a cognition gene, at least not in healthy volunteers.

By contrast, the genetic association with connectivity is modest (see the graphs above - there is a lot of overlap), and very difficult to interpret, since it is clearly not associated with any kind of actual differences in behaviour.

And yet this positive result got the experiment published in no less a journal than Science! The negative results alone would have struggled to get accepted anywhere, and would probably have ended up either unpublished, or published in some rubbish minor journal and never read. It's no wonder the authors decided to write their paper in the way they did. They were just doing the smart thing. And they are perfectly respectable scientists - Andreas Meyer-Lindenberg, the senior author, has done some excellent work in this and other fields.

Labels: Genetics

Tone Language Is Key To Perfect Pitch:

In a study published in the Journal of the Acoustical Society of America and being presented at the ASA meeting in Portland on May 21, Deutsch and her coauthors find that musicians who speak an East Asian tone language fluently are much more likely to have perfect pitch.

...

In 2004, she found that students at the Central Conservatory of Music in Beijing, China, all of whom spoke Mandarin, were almost nine times more likely to have perfect pitch than students at the Eastman School of Music in New York. That last study, however, left open the question of whether perfect pitch might be a genetic trait - since all the Mandarin speakers were East Asian.

...

The present study looked at 203 students at the University of Southern California's Thornton School of Music, all of whom agreed to take the test in class (so there was no self-selection in the sample). The students listened to the 36 notes that haphazardly spanned three octaves. They attempted to identify the notes, and they self-reported their musical, ethnic and linguistic backgrounds - including whether they were very fluent in an East Asian tone language, fairly fluent or not at all fluent. Deutsch and her colleagues found that students who spoke an East Asian tone language very fluently scored nearly 100 percent on the test, and that students who were only fairly fluent in a tone language scored lower overall. Those students - either Caucasian or East Asian - who were not at all fluent in speaking a tone language scored the worst on average.

The abstract makes it a bit clearer that East Asians who do not speak a tonal language are no better than Europeans.

Labels: Genetics

The Oxytocin Receptor (OXTR) Contributes to Prosocial Fund Allocations in the Dictator Game and the Social Value Orientations Task:

The demonstration that genetic polymorphisms for the OXTR are associated with human prosocial decision making converges with a large body of animal research showing that oxytocin is an important social hormone across vertebrates including Homo sapiens. Individual differences in prosocial behavior have been shown by twin studies to have a substantial genetic basis and the current investigation demonstrates that common variants in the oxytocin receptor gene, an important element of mammalian social circuitry, underlie such individual differences.

Here's a figure from the paper:



And the SNPs from the HGDP (G = C & A = T for the first SNP, or at least the paper and PubMed agree on this):










Related: It's hard out here for a vole. Heritability of the Ultimatum Game. Altruism and Risk-Taking: Kinda Heritable. Can someone put the psychic unity of makind out of its misery? DRD4, politics & friendship.

Labels: Behavior Genetics, Behavioral Economics, Genetics

Many readers have probably heard that the ACLU has sued Myriad Genetics for its patent on genetic testing on BRCA1/2 (these genes account overall for a small fraction of breast cancer cases, but for many of the strongly inherited cases).

Many companies hold gene patents, so why sue Myriad? The answer is simple: in the battle of public opinion, there's no way Myriad can come out of this looking good. A bit of recent history: the BRCA1 gene was famously mapped by a group led by Mary-Claire King, currently at the University of Washington. That group, however, narrowed down the location of the gene only to a relatively large region, and the gene itself was finally isolated months later and patented by Myriad (BRCA2 came later). Myriad did the obvious--they designed a test for a series of mutations in the genes and began to market it. However, the series of mutations they test is not the whole story--other mutations, untested by Myriad, can cause the disease as well. Other labs would be happy to market tests for these mutations, except, of course, that Myriad refuses to license its patent, preferring instead to hold onto their monopoly on the gene. The result: families that would like to be tested for rare mutations in BRCA1 but an environment in which it is illegal for any company to sell them such a test. It's not for nothing that Myriad is considered among the most hated diagnostics companies.

Myriad is probably within their legal rights, but when cases like this get publicity, laws have the funny tendency to change.

Labels: Genetics

Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico. The title says it all, so I won't post the abstract. The article is OA, so you can read the whole thing, but I thought this figure from the supplements was pretty informative:

Sonora is exactly where you would expect Mestizos to be the most European, while Guerrero on the coast has more African ancestry. See the paper for other Mexican provinces. The use of a Northwest European population is of course somewhat imperfect as the white ancestry of Mestizos is Iberian (though European populations really are not very differentiated in the worldwide context). Additionally, the Zapotecs would be imperfect representative of the genetic variation of all the Amerindians of Mexico (some of whom are likely to emigrated from the American Southwest relatively recently).

Labels: Genetics, Population genetics

This is fascinating. De novo establishment of wild-type song culture in the zebra finch. See ScienceDaily, Birds Raised In Complete Isolation Evolve 'Normal' Species Song Over Generations.

Labels: Ethology, Genetics

The New York Times has an interesting little piece on bones, including a description of the unsettling genetic disorder fibrodysplasia ossificans progressiva:

When Harry Eastlack was 5 years old, he broke his left leg while out playing with his sister. The fracture failed to set properly, and soon his hip and knee had stiffened up as well. Examining the boy, doctors found ominous bony growths on the muscles of his thigh. Within a few years, bony deposits had spread throughout Harry's body, infiltrating his chest, neck, back and buttocks. Surgeons tried to cut the excess bone away, only to watch it grow back thicker and more invasive than before.

By his mid-20s, his vertebrae had fused together, his torso been thrust rigidly forward and his back muscles replaced with solid bone. Finally, even his jaw locked up, and he died of pneumonia in 1973, just shy of his 40th birthday.

Fun fact: the gene that causes this disease is ACVR1, which lies in a region of extended haplotype homozygosity and extreme population differentiation suggestive of recent positive selection in non-African populations.

Labels: Genetics, Population genetics

Coat Color Variation at the Beginning of Horse Domestication:

The transformation of wild animals into domestic ones available for human nutrition was a key prerequisite for modern human societies. However, no other domestic species has had such a substantial impact on the warfare, transportation, and communication capabilities of human societies as the horse. Here, we show that the analysis of ancient DNA targeting nuclear genes responsible for coat coloration allows us to shed light on the timing and place of horse domestication.We conclude that it is unlikely that horse domestication substantially predates the occurrence of coat color variation, which was found to begin around the third millennium before the common era.

Also see ScienceDaily.

Related: Horse genetics & color, White horses and blonde humans: a genetic connection?, The Horse, the Wheel, and Language: How Bronze-Age Riders from the Eurasian Steppes Shaped the Modern World and Earliest domestication of horse?

Labels: Genetics, History

Based on the comments on my previous post, I'm going to lay out an argument which I find reasonable for sequencing studies in human disease:

Let's follow Goldstein's back-of-the-envelope calculations: assume there are ~100K polymorphisms (assuming Goldstein isn't making the mistake I attribute to him, this includes polymorphisms both common and rare) that contribute to human height, that we've found the ones that account for the largest fractions of the variance, and that these fractions of variance follow an exponential distribution.

Now, assume you have assembled a cohort of 5000 individuals and done a genome-wide association study using common SNPs. You find some interesting things, but you want more. Now, you have two choices: sequence those 5000 individuals to look for rarer variation, or increase sample size to 20,000 and perform another association study using the same set of common polymorphisms.

As Daniel Macarthur points out, you've not yet sucked every drop of marrow out of those 5000 individuals: there are presumably some (many?) rarer SNPs that have modest effect sizes (in sense 2 from this post), and thus account for measurable (though still small) fractions of the variance in your trait. Those are low-hanging fruit for you to find if you pony up the cash for some sequencing (the price of which keeps dropping). This is especially true if there are more rare variants than common ones that influence the trait, as is likely the case (there's more rare variation than common variation overall). So instead of spending on scaling up your sample size, spend on sequencing, and have impact now.

Is this along the lines the argument Goldstein is making? I don't really think so, but welcome comment. In any case, the choice above is somewhat arbitrary--if you want to look for very rare variation, you need a sample size larger than 5000 anyways, and if you're sequencing, you're obviously not just going to look at the rare variants since the common ones come along for free.

Labels: Genetics

Just over two years ago, I wrote a brief post explaining why I find the "debate" about common variants versus rare variants in human medical genetics to be largely unhelpful. I concluded thusly, after explaining some of the rationale for looking for common variants that affect disease susceptibility:

So am I then arguing in favor of the CDCV [Common Disease-Common Variant] hypothesis? Of course not-- rare variants, aside from being predictive for disease in some individuals, also give important insight into the biology of the disease. But it is possible right now, using genome-wide SNP arrays and databases like the HapMap, to search the entire genome for common variants that contribute to disease. This is an essential step--finding the alleles that contribute disproportionately to the population-level risk for a disease. Eventually, the cost of sequencing will drop to a point where rare variants can also be assayed on a genome-wide, high-throughput scale, but that's not the case yet. Once it is, expect the CDRV [Common Disease-Rare Variant] hypothesis to be trumpeted as right all along.

Well, two years later, the price of sequencing has dropped precipitously. And in this week's New England Journal of Medicine, David Goldstein makes the argument that association studies using common variants have been disappointing and what people really need to be doing is--would you believe it?--searching for rare variants using sequencing.

Your opinion about the current crop of genome-wide association studies depends, of course, on what you were expecting to begin with: if you thought that a few common variants would be discovered for each common disease and fully explain its prevalence, you're likely to think the whole enterprise has been a bust (with a few exceptions, of course--Goldstein mentions exfoliation glaucoma and macular degeneration). If, on the other hand, you thought that genome-wide association studies would have about as much success as the linkage and candidate gene studies that preceded them (Daniel Macarthur characterized the field as a "scientific wasteland" prior to 2005, and that's only mild hyperbole), you're probably astounded by their success.

In any case, the objections to large association studies are/have been numerous, but Goldstein has come up with the most bizarre one yet--that large association studies using common variants might find too many things! The premise is this (and let's take a non-disease trait like height as an example): current association studies have identified many loci of small effect that influence human height. Together, these loci account for ~3% of the population variation in height. Assuming these are the largest effect sizes out there to find, and an exponential distribution on effect sizes (both probably approximately fair assumptions), then a massive number of loci influence height, potentially genes across the entire genome. Thus, "[i]f common variants are responsible for most genetic components of type 2 diabetes, height, and similar traits, then genetics will provide relatively little guidance about the biology of these conditions, because most genes are 'height genes' or 'type 2 diabetes genes.'"

The solution to this problem, Goldstein claims, is to look for rare variants that (he presumes) have larger effects. This claim, though it appears reasonable, is a non sequitur. The reason why is that Goldstein is conflating two definitions of effect size. In definition one, effect size is defined as the proportion of variance in a trait explained by a polymorphism. In definition two, effect size is defined as the difference in mean trait value between two genotype classes. Why is this a problem? Because the proportion of variance in a trait explained by a polymorphism is a function both of its frequency and the impact it has on the trait [1]. To re-use a previous example, imagine smoking cigarettes gives you a 5% chance of developing lung cancer, while working in an asbestos factory gives you a 70% chance. In sense one, smoking has a larger effect size--since so many more people smoke than work in asbestos factories, the number of lung cancer cases due to smoking is much higher than the number due to asbestos. However, under definition two, working in an asbestos factory has the larger effect size--the probability of developing the disease is much higher. Thus, though a rare polymorphism might have a large effect (in sense 2), it will explain a tiny amount of the variance in the trait simply due to the fact it is rare [2].

The contention that the number of loci needed to explain the heritability of a trait will somehow be smaller if one looks at rare variation is simply false.

[1] Assuming additivity, the variance explained by a locus is 2p(1-p)a^2, where p is the allele frequency and a is half the difference between the means of each homozygote. See Figure 4.8 of Lynch and Walsh.

[2] For example, let's use the equation in [1] and assume a polymorphism has a frequency of 0.001%. Then, in order for this polymorphism to account for 0.05% of the variation in height (on the small end of the proportions accounted by common polymorphisms identified to date), a single allele would have to increase height by a whopping 5 standard deviations.

Labels: Genetics

Multiple articles on personal genomics in The New England Journal of Medicine, Genomewide Association Studies and Human Disease, Common Genetic Variation and Human Traits, Genomewide Association Studies - Illuminating Biologic Pathways and Genetic Risk Prediction -Are We There Yet?. Nick Wade has a piece on these articles in The New York Times.

Related: Preparing doctors for the genomic tsunami, Linkage versus association: a mini-primer, A note on the Common Disease-Common Variant debate, Common disease, common variant and Common disease, common variant.

Labels: Genetics, Genomics

Most readers are likely familiar with the classic "taming of the fox" experiment started by Dmitri Belyaev--starting with a wild silver fox, the group was able to quickly breed both a tame and hyper-aggressive line of animals. I was unaware that, concurrently with this experiment, that same group was also performing the same experiment on rats.

Just published is the the first steps in a search for the precise genetic changes underlying the differences between a tame and aggressive line of rats, separated by only 60 generations of breeding. The basic result is that they are able to identify two regions of the genome that very likely carry variation affecting tameness. They are unable to identify particular genes due to the resolution of the study, but one can only assume they're in the process of following this up (since these two lines are only separated by 60 generations, one easy way to search for a causal polymorphism might be to just sequence the two lines--there's likely very few differences between them in the candidate regions).

It was also been noticed, in both the fox and rat experiments, that changes in tameness were associated with changes in pigmentation--in the rat case, the presence of a white patch of fur. This study design allows the authors to determine whether the same locus influencing pigmentation is also involved in tameness. In this case, they're not.

Labels: Genetics

Nature has a nice piece on the uses of alternative model organisms in various parts of biology. The focus is on the medical applications of these models, which I suppose is due to issues with funding. But the real message is that with novel genomics applications (mainly high-throughput sequencing), understanding the genetics of a wide variety of nature's bizarre creatures is possible. Sure, understanding how the Antarctic icefish adapted to sub-zero temperatures might in theory help understanding of some human disease, but let's be honest--that's worth studying just because it's really cool.

Labels: Genetics

There was some talk about Pygmies on the post about Jerry Coyne's weblog. PLoS Genetics has a new paper up on the topic of Pygmy origins and their relationship to non-Pygmy populations. I've blogged it over at ScienceBlogs.

Labels: Evolution, Genetics, Population genetics, Pygmies

Genes may time loss of virginity:

As genetic determinism goes, the new findings are modest. Segal's team found that genes explain a third of the differences in participants' age at first intercourse - which was, on average, a little over 19 years old. By comparison, roughly 80% of variations in height across a population can be explained by genes alone.
...
On the other hand, conservative social mores might delay a teen's first sexual experience, causing scientists to low-ball the effect of genes. Indeed, Segal's team noticed a less pronounced genetic effect among twins born before 1948, compared with those who came of age in the 1960s or later.
...
As for the specific genes involved, another team previously found that a version of a gene encoding a receptor for the neurotransmitter dopamine is associated with age at first intercourse. Others have linked the same version of the gene - called DRD4 - to impulsive, risk-taking behaviour.

The paper is Age at first intercourse in twins reared apart: Genetic influence and life history events.

FuturePundit notes:

The team found a weaker effect from genes with people born before 1948. This supports an argument I've made here previously: the breakdown of old cultural constraints on behavior frees up people to follow genetically driven desires and impulses. We become more genetically driven as external constraints weaken.

When you remove the strength of environmental parameters from the equation it naturally results in a greater salience of heritable ones. Ergo, the logic whereby you can make the case that in a perfect meritocracy there will be much stronger genetic sorting by class (via assortative mating, etc.).

Related: DRD4 and virginity.

Labels: Genetics, Personality

I've written before about a pattern emerging from genome-wide association studies--genes in which mutations cause rare extreme forms of a phenotype often harbor common variation that influence natural, non-disease variation in that same phenotype. A pair of new studies on variation in cardiac repolarization (summarized here) provide an additional example of this pattern.

It's worth noting that this was something of an obvious hypothesis--candidate gene association studies often targeted gene known to cause Mendelian disorders when mutated. In retrospect, the reason these studies were often inconclusive was a simple lack of power.

Labels: Genetics

New paper in Genome Research, Signals of recent positive selection in a worldwide sample of human populations:

Genome-wide scans for recent positive selection in humans have yielded insight into the mechanisms underlying the extensive phenotypic diversity in our species, but have focused on a limited number of populations. Here, we present an analysis of recent selection in a global sample of 53 populations, using genotype data from the Human Genome Diversity-CEPH Panel. We refine the geographic distributions of known selective sweeps, and find extensive overlap between these distributions for populations in the same continental region but limited overlap between populations outside these groupings. We present several examples of previously unrecognized candidate targets of selection, including signals at a number of genes in the NRG-ERBB4 developmental pathway in non-African populations. Analysis of recently identified genes involved in complex diseases suggests that there has been selection on loci involved in susceptibility to type II diabetes. Finally, we search for local adaptation between geographically close populations, and highlight several examples.

I've blogged it at ScienceBlogs, and so has Genetic Future, and John Hawks offers a response. Though there are so many references to the Supplements, which aren't online, I feel like there's on more course remaining....

Labels: Genetics, Population genetics

It was only six short years ago that Greg Barsh wrote an "unsolved mystery" review in PLoS Biology asking, "What Controls Variation in Human Skin Color?"

A recent review provides a nice summary of the developments since then--in short, pigmentation is now probably one of the best understood (at a genetic level) phenotypes in humans. A pretty impressive story.

Labels: Genetics

A number of people have commented on a recent paper showing an increase in heterozygosity in human populations over time, presumably due to increased outbreeding (though Dienekes suggests some of this effect may be due to more homozygous individuals living longer, my feeling is that the results associating homozygosity and lifespan are more likely to be artifacts due to increased outbreeding over time, rather than vice versa).

This is an interesting result, and seems plausible, but the figure in the paper is difficult to judge--I wondered why the authors chose not to show their actual data, but rather only the fitted regression line. The answer is that the data itself looks much less impressive than the pretty lines in the main text (see right).

This isn't to say that the result isn't correct (I assume the authors made sure their results are robust to the few outliers in that plot), but the relationship between homozygosity and time is certainly more noisy than implied by the figure.

Labels: Genetics

The genetics of blue eye color in humans is almost entirely controlled by a single SNP in a conserved non-coding region in an intron of HERC2, as was strikingly demonstrated in a recent study on using genetics to predict eye pigmentation.

Humans are not the only primate to have blue eyes--one notable example is the blue-eyed black lemur (pictured on the right). As it's well-known that convergent evolution in pigmentation has occurred in many taxa via similar genetic mechanisms (eg. MC1R), one obvious question is: have similar genetic changes led to blue eyes in humans and other primates? For blue-eyed lemurs, a new study demonstrates that, well, the answer is no. The authors sequence the region known to be causal for human blue eyes in both blue-eyed black lemurs and a closely-related, non-blue-eyed species, and find no differences.

Though this is a negative result, it's still kind of fun, and establishes a nice example of convergent evolution via separate genetic mechanisms in primates.

Labels: Evolution, Genetics

Genetic Gating of Human Fear Learning and Extinction: Possible Implications for Gene-Environment Interaction in Anxiety Disorder:

Pavlovian fear conditioning is a widely used model of the acquisition and extinction of fear. Neural findings suggest that the amygdala is the core structure for fear acquisition, whereas prefrontal cortical areas are given pivotal roles in fear extinction. Forty-eight volunteers participated in a fear-conditioning experiment, which used fear potentiation of the startle reflex as the primary measure to investigate the effect of two genetic polymorphisms (5-HTTLPR and COMTval158met) on conditioning and extinction of fear. The 5-HTTLPR polymorphism, located in the serotonin transporter gene, is associated with amygdala reactivity and neuroticism, whereas the COMTval158met polymorphism, which is located in the gene coding for catechol-O-methyltransferase (COMT), a dopamine-degrading enzyme, affects prefrontal executive functions. Our results show that only carriers of the 5-HTTLPR s allele exhibited conditioned startle potentiation, whereas carriers of the COMT met/met genotype failed to extinguish conditioned fear. These results may have interesting implications for understanding gene-environment interactions in the development and treatment of anxiety disorders.

Also see ScienceDaily. Here's the COMT SNP in SNPedia. Also, here it is in the HGDP browser. A/A is low activity variant.

Related: Other posts on COMT.

Labels: Behavior Genetics, Genetics

Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood. I blogged it at ScienceBlogs.

Labels: Genetics

It has been noticed in some diseases that common variants which lead to modest increases in risk are located in or near genes that also, when mutated, cause severe monogenic forms of a the same disease (eg. obesity). This naturally leads to the hypothesis that newly identified genes containing modest risk alleles will also contain rarer alleles of strong effect.

A new study tests this hypothesis in type I diabetes: the authors take 10 genes known to be involved in diabetes etiology (note that many of these genes were discovered by genome-wide association studies of common variants) and re-sequence them in a large set of cases and controls.

What do they find? As hypothesized, a number of rare protein-altering changes in one of the genes (IFIH1, a gene involved in response to viral infection) end up being strongly associated with type I diabetes. The effect sizes aren't massive (the risk alleles have odds ratios around 2), but they certainly have stronger effects than the common variants identified (though because of their low frequencies, they explain only a minimal fraction of all the variance in diabetes risk).

This is only a proof-of-principle-- expect many similar studies, including full exome re-sequencing, in the years to come.

Labels: Genetics

Via Dienekes, The Earliest Horse Harnessing and Milking:

Horse domestication revolutionized transport, communications, and warfare in prehistory, yet the identification of early domestication processes has been problematic. Here, we present three independent lines of evidence demonstrating domestication in the Eneolithic Botai Culture of Kazakhstan, dating to about 3500 B.C.E. Metrical analysis of horse metacarpals shows that Botai horses resemble Bronze Age domestic horses rather than Paleolithic wild horses from the same region. Pathological characteristics indicate that some Botai horses were bridled, perhaps ridden. Organic residue analysis, using 13C and D values of fatty acids, reveals processing of mare's milk and carcass products in ceramics, indicating a developed domestic economy encompassing secondary products.

Related: The Horse, the Wheel, and Language: How Bronze-Age Riders from the Eurasian Steppes Shaped the Modern World and lactase persistence.

Labels: Genetics, History

John Hawks points to an article by James F. Crow, Mayr, mathematics and the study of evolution. As John stated this is Open Access assuming you take the time to register. Here is a taste:

In 1959 Ernst Mayr...flung down the gauntlet...at the feet of the three great population geneticists RA Fisher, Sewall Wright and JBS Haldane..."But what, precisely," he said, "has been the contribution of this mathematical school to the evolutionary theory, if I may be permitted to ask such a provocative question?" His skepticism arose in part from the fact that the mathematical theory at the time had little to say about speciation, Mayr's major interest. But his criticism was more broadly addressed to the utility of the entire approach. A particular focus was the simplification that he called "beanbag genetics", in which "Evolutionary genetics was essentially presented as an input or output of genes, as the adding of certain beans to a beanbag and the withdrawing of others."
...
Recent mathematical work has gone well beyond that of the three pioneers. Partly this is due to skilled mathematicians entering the field and bringing new techniques with them; especially noteworthy are stochastic processes. Second, and perhaps more important, is the extensive use of computers. Often you can use a computer to get by without deep mathematical knowledge. An additional influence is the explosive growth of molecular data, which lend themselves to mathematical treatment. In the first half of the twentieth century, population genetics and evolution had a beautiful theory, but there were very limited opportunities to apply it. Now the situation is reversed. Molecular data accumulate too fast to be assimilated.

Crow referred to some of these questions 3 years ago when I interviewed him. Though much of the essay is a restatement of ideas floated elsewhere, it's still awesome that Crow is publishing at the age of 92. Judging by how quickly he replied when I sent him an email he is also still actively corresponding.

As for the general thesis outlined in the article, of course I tend to agree with Crow. From what I know Ernst Mayr's viewpoint in Systematics was overturned by the cladist revolution, which introduced a rigorous hypothetico-deductive framework into the field. It is perhaps just part of a trend of a marginalization of more philosophical biologists who rely on intuition in the realm of theory, and serves as a specific case study of Mayr's own philosophy of science and how it is ceding ground to more moral analytic techniques. Nevertheless, we can thank Mayr for his mentoring of someone like Robert Trivers. I remember talking to a friend of mine who was at OEB in the early 2000s, and she mentioned getting stuck in the elevator with Ernst Mayr, and my first reaction was, "Dude is still alive?!?!"

Labels: Genetics, Philosophy of science

Not news to many readers, I'm sure, but Nicholas Wade has a nice article on epigenetics and gene regulation. Some people in the article complain about the lack of a focused investment by the government in this area. I found this a little odd--isn't quite a bit of large-scale work being done by the ENCODE project?

Labels: Epigenetics, Genetics

In 2007, SNPs in an intron of the gene FTO were reported to be associated with obesity. At the time, essentially nothing was known about the gene. A few months later, a group of biochemists proposed a role for the gene in demethylation of nucleic acids (RNA or DNA). This week, a group of mouse geneticists present an analysis of a knockout of the gene, and show that the knockouts are resistant to weight gain due to increased energy expenditure.

There's still quite a ways to go before the mechanism by which FTO contributes to weight variation in humans is understood (oddly enough, there's some evidence that the mechanism is through increased energy intake rather than expenditure), but people keep chipping away...

Labels: Genetics, Molecular biology

Short article in Conservation and Convergence of Colour Genetics: MC1R Mutations in brown Cavefish:

One of the most striking observations in nature is when similar phenotypes appear independently, such as wings in birds and bats, or melanism in moths and mice. These examples of so-called convergent evolution naturally lead us to ponder the question of genetic repeatability, i.e., the extent to which similar phenotypes that evolved in parallel share the same genetic mechanisms. Cave-dwelling organisms provide an attractive system for studying genetic repeatability, since populations in geographically isolated caves often undergo striking convergent evolution in response to the drastically altered environment, with reduced pigmentation and vision being particularly common phenotypes.

Labels: Genetics

This is a pretty nice little story: a man enters a clinic with leukemia and HIV, gets a bone marrow transplant from a donor homozygous for the CCR5 deletion (these individuals are largely resistant to HIV infection), and ends up no longer needing anti-retroviral therapy.

It's just a single patient, and I somehow doubt this is a viable option for HIV treatment, but still, this is pretty impressive:

In our patient, transplantation led to complete chimerism, and the patient's peripheral-blood monocytes changed from a heterozygous to a homozygous genotype regarding the CCR5 delta32 allele. Although the patient had non–CCR5-tropic X4 variants and HAART was discontinued for more than 20 months, HIV-1 virus could not be detected in peripheral blood, bone marrow, or rectal mucosa, as assessed with RNA and proviral DNA PCR assays. For as long as the viral load continues to be undetectable, this patient will not require antiretroviral therapy.

Labels: Genetics

Molecular and Evolutionary History of Melanism in North American Gray Wolves:

Morphologic diversity within closely related species is an essential aspect of evolution and adaptation. Mutations in the Melanocortin 1 receptor (Mc1r) gene contribute to pigmentary diversity in natural populations of fish, birds, and many mammals. However, melanism in the gray wolf, Canis lupus, is caused by a different melanocortin pathway component, the K locus, that encodes a beta-defensin protein which acts as an alternative ligand for the Mc1r. We show that the melanistic K locus mutation in North American wolves derives from past hybridization with domestic dogs, has risen to high frequency in forested habitats, and exhibits a molecular signature of positive selection. The same mutation also causes melanism in the coyote, Canis latrans, and Italian gray wolves, and hence our results demonstrate how traits selected in domesticated species can influence the morphologic diversity of their wild relatives.

Also see ScienceDaily. The general dynamics should be relatively familiar. Here's the model in a figure:

Labels: Genetics

A few years ago I had a semi-serious post up making fun of Armand Leroi for broaching the topic of neo-eugenics. Now there are reports of elective pre-implantation screenings:

Genes determining sex, hair and eye colour can be identified, alongside any DNA red flags for diseases such as muscular dystrophy, cystic fibrosis and Down's Syndrome.

"Basically any genetic ailment, and there are thousands of them. We find the genetic error responsible for that in the embryo," Dr Steinberg says.

Only those embryos free of problem genetic markers and matching parental wishes, if stated, are then implanted in the mother.
...
"To deny them the ability to do that when the technology is there is to me unethical," Dr Steinberg says.

"You can say eye colour and hair colour are not diseases, no they're not, and there is a cosmetic element to it, but we fix crooked noses all the time.
...
He says he's concerned Australian women are risking their health by undertaking IVF overseas for "frivolous" reasons, using a process that raises the moral issue of "deliberate embryo loss".

"But the main issue is the idea of treating the child as an object, as product for which you are seeking quality control," Dr Tonti-Filippini says.

1) Part of this is publicity, you can get only so much information out of genetic tests right now (see Genetic Future). Take a look at Genetic determinants of hair, eye and skin pigmentation in Europeans, and note how much higher the odds ratio (20-30 vs. ~5) for OCA2 "blue-eye" markers are vs. the ones which might give some information about hair color. The same differences in effect size apply to disease loci. I suspect many people will balk at paying up when confronted with the provisionality of some of the inferences.

2) It isn't as if these fertility technologies aren't without downsides (not to mention the cost).
Note: The link above is to an Australian newspaper. So I don't take everything they report literally...perhaps they spiced up a quote here and there?

Labels: Genetics

The latest disease to be put under the scrutiny of a large genome-wide association study is psoriasis--see articles here, here, and here. These are mostly standard studies, but once again I'm struck by the effect of the MHC (HLA) region (see the figure). It was well-known, of course, that variation in HLA affects all manner of immunity-related phenotypes, but what's becoming clear is that this variation has much larger effects than other loci in the genome. I find this somewhat surprising--associations with MHC variability were identified because typing HLA was feasible many years ago; well before genome-wide association mapping with SNPs was even considered. This could be a case where, in the analogy to the man searching for the lost keys in the dark, looking under the lamppost was actually the best bet.

Labels: Genetics

Over at my other weblog I review a paper on the genetics of Koreans. The title is a shout-out to an old Korean American friend of mine who received a great deal of grief from his female Korean American peers for openly admitting that he was into a Hmong girl. She was very good-looking, but as they said, "But she's Hmong...."

Labels: Genetics, Koreans

Everyone is talking about Steven Pinker's article in the NY Times on his experiences toying with results from personal genomics companies Counsyl and 23andme. The article is, like most of Pinker's writing, entertaining and scientifically legit; well worth a read.

One interesting point to notice is that the different companies involved in this nascent field (I find Razib's analogy to the early computer industry apt) are taking very different angles; there's been something of an adaptive radiation into these new niches (ie. 23andme going for the social networking approach, Counsyl a more medical one, etc.) My impression is this is likely to be overall a good thing for people who, of course, will have varied ideas of the type of data that piques their interest.

Labels: Genetics

One of the established cool examples of convergent evolution (which for my purposes here I'll define loosely here as the evolution of different populations to the same phenotype via different mutations) has been the repeated loss of pigmentation (and eyes) in fish that have adapted to life in light-poor, nutrient-poor caves. In 2006, a group reported that albinism (panel J in the picture) in several of these caves was due to mutations in OCA2 (a SNP in a regulatory region of this gene also causes blue eyes in humans).

Not all cavefish however, are fully albino--in some populations, there also exists a "brown" phenotype (panel "G" in the picture) with reduced pigmentation. In a new paper, the gene underlying this phenotype is shown to be MC1R (this gene, of course influences pigmentation in all sorts of species), and, similarly to OCA2, two different mutations have arisen in different populations.

One might imagine that light pigmentation in cavefish could just be due to simple drift--a random mutation that knocks out pigmentation is no longer selected against in a place where there's little light, and so could drift up to high frequency. But the fact that this phenotype has arisen so many times, and reached high frequency in the presumably short time period that these fish populations have been isolated (I say presumably short because I can't find any numbers on this, but the different populations can interbreed freely) suggests a role for strong positive selection for this phenotype in adaptation to the cave environment.

Labels: Evolution, Genetics

This is a pretty thorough review of biology and evolution of lactase persistence. It's interesting that the precise genetic mechanism underlying the phenotype remains unknown-this seems like a potentially very interesting model phenotype for people interested in the temporal and spatial regulation of gene expression.

Labels: Genetics

A number of papers out this week (summarized here) notice, using various technologies, the presence of extensive transcription off both DNA strands around active promoters. A figure from one of the papers is above--note the peak in transcription from the sense strand just downstream of the transcription start site (TSS), and the peak in anti-sense transcription just upstream of the TSS. This is an interesting observation, and an example of the unexpected things you can see with new technologies, but no one is exactly sure what to make of it--it could just be the transcriptional machinery being a bit sloppy.

Labels: Gene Expression, Genetics

H. Allen Orr (one of the authors of the study I mentioned recently) has a fun article in Scientific American on testing hypotheses about natural selection using genetic data. Orr has been one of the few people to try and formally model adaptation in a population genetics framework (I highly recommend this review article from 2005 for a well-written and accessible discussion of this issue), so his thoughts are worth a read.

And if you're in the mood for a chuckle, check out Larry Moran's thoughts on the article.

Labels: Genetics

RPM points to a couple great papers on the genetics of speciation in Drosophila and mouse. The first is particularly interesting--the gene underlying hybrid incompatibility is also involved in meiotic drive.

What's fun about these sorts of studies is that one can almost start to reconstruct the sequence of population genetic events leading to speciation--like all alleles, one that leads to hybrid infertility has to pass through a phase in which it segregates in the population. This is counterintuitive, of course--any allele causing infertility in some fraction of offspring should be deleterious. One possibility is that divergence at these genes is due to differential selection, and this new paper raises the possibility that sometimes this selection might not be due to external selection pressures, but rather to intragenomic conflict.

Labels: Genetics

In early 2007, a paper on expression differences between populations claimed that something like 25% of all genes are differentially expressed between two population groups (in that case, in cells lines from people of either European or Chinese origin). That paper, though, had a pretty serious flaw--ancestry effect on expression were completely confounded with microarray batch effects, so the precise numbers in the paper were somewhat suspect.

One way to test whether differences between populations in expression levels are real would be to measure expression on admixed individuals--if expression levels correlate with admixure proportions within a sample, that's pretty good evidence that genetic background plays an important role in expression (barring some third factor that correlates with both genetic background and expression of a large number of genes). A population of admixed European-Asian individuals is probably a little hard to come by, but admixed European-African individuals (AKA African-Americans) are less so. A recent paper lays out the results of a study like this in African-Americans.

The results are somewhat surprising--by correlating expression levels with admixture proportions, the authors speculate that nearly all genes have an ancestry effect on expression. The reason this is somewhat surprising is that, given the way the authors did the analysis, it means the expression of a locus depends on a large number of other loci throughout the genome (if the expression levels of a locus were only affected by variation at that same locus, there would be no correlation between total ancestry and expression). Indeed, the authors estimate that only ~12% of heritable variation in expression of a given gene is due to the effects of local (or cis) variation. Other studies have had little success in identifying distant (or trans-acting) effects in humans, this suggests that the reason, as in many other genome-wide association studies, is simply a lack of power.

Labels: Genetics

A report in Science from the annual meeting of the American Society for Human Genetics focuses on copy number variation. Some interesting observations:

Don Conrad and his colleagues at the Sanger Institute have their eyes on smaller common CNVs, as little as 500 base pairs in length. Checking about every 50 base pairs across parts of the genomes of people of African and European ancestry, they uncovered more than 10,000 CNVs--suggesting that other efforts, which have identified about 1500 common ones, are missing most CNVs. Although "there haven't been many" CNVs linked to disease yet, Conrad said in his talk, "there might be quite a few out there." Indeed, he noted that 129 of the 419 genetic-association regions pinpointed in genome-wide association studies hunting for disease DNA contain a common CNV.

Labels: Genetics

From Henry Harpending:

This is from a 1984 paper, citation below the figure. The genetic data were 6 red cell antigens, 9 electrophoretic systems, and HLA and HLB. The context was the authors' effort to set up a big population genetic and demographic database of Mormons, which was criticized because the Mormons were thought to be derived from a small isolated inbred group. They wrote this paper to show that Mormon allele frequencies were generic northern European. Another paper the followed this showed that Amish and Mennonites were indeed off in another dimension, but not Mormons.

This isn't up to current standards but it does show that 25 years ago the correspondence between genetic and geographic distances in Europe was clear.

McLellan T, Jorde LB, Skolnick MH. 1984. Genetic distances between the Utah Mormons and related populations. Am J Hum Genet 36:836-857.

I made a minor modification to the figure, which is courtesy of Lynn Jorde.

Labels: Genetics

In the comments below Susan C asks an interesting question:

I'm still surprised that this works as well as it does, given that there were mass movements of people during the nineteenth and twentieth century.

For Europe prior to 1815, I'd expect it to work. Genealogical records show that people were very often born in the same village that their parents were, or the next village along. I would guess the rate of diffusion to be a few km per generation.

After the Napoleonic Wars, though, it goes nuts. Changing methods of agriculture (e.g. enclosure of land) meant that many rural agricultural labourers were put out of work, and had to move to the major industrial cities. This migration could easily be in the range of 100km in one generation, or even transcontinental - people emigrating to North America or Australia.

Moving forward to the Second World War, many people from central Europe fled the Nazis and came to settle in Britain.

So if you take a British person today, and ask them where their grandmother was born, likely answers range from Aberystwyth to Krakow, even if they answer "white" to an ethnicity question. (Of course there's plenty of evidence of immigration from e.g. India or the Caribbean, too)

An interesting point. Some levels of immigration and movement have always been part of European history. Think about the outflow of Huguenots after the revocation of the Edict of Nantes. The trade and migration between the Low Countries and the eastern shore of Britain. The immigration of Spaniards, Poles and Italians to France in the 19th century. The relocation of Saxons to Romania, Russia, etc.

Some thoughts:

1) Many of the immigrants, like the Huguenots, settled disproportionately in cities and towns (the Volga Russians are an exception obviously). French in Berlin, British Puritans in Amsterdam, Jewish industrial workers in East London, Asian sailors in Cardiff. And cities until recently were powerful relative population sinks. So modern European cities might be affected by past immigration (e.g., in changing the accent on dialects) culturally, but they are far less reshaped genetically than you would expect.

2) Many of the immigrants were from nearby regions. Spanish and Italian immigration to France was far higher than Polish. So the affect would be more to subtly shift the positions and centers of gravity, as opposed to rearranged the expected spatial relationship.

3) Aside from France, there wasn't much migration as a proportion of the population. The ancestors from Aberswyth and Krakow are very salient because of their exoticism. This is just subject to the same dynamics as disappearing English phenomenon.

4) They sampled from only a few locations within each nation, so the clumping is exaggerated, and combined with #3, the migration effect wasn't strong enough to change your impression. Perhaps they also generally don't sample ethnic minorities in these studies; e.g., avoiding Hungarians and Saxons in Romania.

5) Some migrations, like the expulsion of Germans from Eastern Europe after World War II, rolled back the obscuring effects of earlier movements.

I was thinking about following the notes and what not and see where the samples came from, but I'll leave it to enterprising readers. I'm sure that can answer some of these questions.

Labels: Genetics

I pointed to the paper at my other weblog, but since ScienceBlogs has a narrow page width, I've put the important charts below the fold.





Table 4 - Each horizontal line in the table shows the proportions of test samples originating from a given country that were assigned to each possible target country. I made a few edits, see paper for original.

Populations	Spain	France	Belgium	UK	Norway	Sweden	Romania	Germany	Hungary	Slovakia	Czech	Poland	Russia
Spain	0.945	0.055	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000
France	0.085	0.515	0.270	0.105	0.000	0.000	0.004	0.014	0.007	0.000	0.000	0.000	0.000
Belgium	0.000	0.086	0.854	0.059	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000
UK	0.000	0.009	0.027	0.947	0.000	0.000	0.000	0.017	0.000	0.000	0.000	0.000	0.000
Norway	0.000	0.000	0.000	0.000	0.991	0.010	0.000	0.000	0.000	0.000	0.000	0.000	0.000
Sweden	0.000	0.000	0.000	0.000	0.099	0.901	0.000	0.000	0.000	0.000	0.000	0.000	0.000
Romania	0.000	0.000	0.000	0.000	0.000	0.000	0.960	0.000	0.040	0.000	0.000	0.000	0.000
Germany	0.000	0.000	0.102	0.004	0.029	0.022	0.008	0.644	0.003	0.003	0.177	0.008	0.000
Hungary	0.000	0.000	0.000	0.000	0.000	0.000	0.022	0.051	0.546	0.292	0.090	0.000	0.000
Slovakia	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.077	0.220	0.453	0.250	0.000	0.000
Czech	0.000	0.000	0.000	0.000	0.000	0.000	0.038	0.052	0.161	0.205	0.484	0.062	0.000
Poland	0.000	0.000	0.000	0.000	0.000	0.000	0.008	0.002	0.009	0.025	0.021	0.802	0.134
Russia	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.000	0.008	0.008	0.000	0.040	0.944

Labels: Genetics

Two studies published today demonstrate what was immediately evident from genome-wide association studies of many common diseases: the genetic variants identified account for only a small fraction of risk.

In these cases, the authors try to predict whether an individual will get type II diabetes from a number of clinical variables, as well as recently identified genetic risk factors. The genetic factors only marginally improve the prediction of diabetes, likely to a clinically insignificant extent.

This was obvious, of course, from the initial studies themselves--you can't expect variants responsible for a meager fraction of overall disease risk to function as effective predictors of the disease. But somewhat notable nonetheless.

Labels: disease, Genetics

Nature this week has published articles describing the genomes sequences of two individuals--one Nigerian and one Chinese. Both were sequenced using Illumina's short read technology, and the brute force approach of deep sequencing seems to have worked fairly well--they estimate their SNP calling error rate is on the order of 0.6%. Recall that SNPs called from the Venter genome had an order of magnitude more errors.

Dan MacArthur at Genetic Future has more.

Labels: Genetics

Jim Manzi writes that it's plausible that epistatic interactions are central to complex mental phenotypes, and that they might therefore prevent genome-wide association studies from achieving much success. In the comments to a response post by Razib, Jason Malloy does a pretty good job of showing that traits like IQ are primarily additive and that epistasis therefore won't prevent successful GWA with good sample sizes. [UPDATE 06-25-2009: I've read more behavior genetics, and I'm not quite sure that Jason's view is correct. I think it's still an open question, actually.]

With all that in mind, some epistasis does exist, and it is worth uncovering. It will not be uncovered directly by genome-wide searches, though, because of multiple testing issues. Even a two-dimensional search overwhelms foreseeable sample sizes. However, a multi-step approach could work by breaking down the multiple dimensions into individual searches. Say that gene-A and gene-B only have an effect when they appear together. Thus, a GWA should pickup an effect from either gene-A or gene-B (whichever has a higher minor allele frequency, presumably), even if that effect is smaller than the overall effect of having both of them. Now, suppose we identify via GWA that gene-A is contributing to the phenotype. We could then do a second scan for interactions and identify gene-B.

Of course, scientists are not limited solely to association searches. They can also harness biological evidence of epistasis to help identify candidates. Because traits like IQ are primarily additive, epistasis is not the overwhelming bogeyman that it might first appear, and it should be possible to tackle in the years to come.

Reference:
Hirschhorn, J. N., & Daly, M. J. (2005). Genome-wide association studies for common diseases and complex traits. Nature Reviews Genetics, 6, 95-108.

Labels: Genetics

While reading through a Nature Genetics Review article, I came cross a link to this catalog of published genome-wide association studies. Pretty cool stuff.

Labels: Genetics

Why Do Women Get More Cavities Than Men?:

"The role of female-specific factors has been denied by anthropologists, yet they attain considerable importance in the model proposed here, because the adoption of agriculture is associated with increased sedentism and fertility," Lukacs said. "I argue that the rise of agriculture increased demands on women's reproductive systems, contributing to an increase in fertility that intensified the negative impact of dietary change on women's oral health. The combined impacts of increased fertility, dietary changes and division of labor during the move into agricultural societies contributed to the widespread gender differential observed in dental caries rates today."

The original paper is Fertility and Agriculture Accentuate Sex Differences in Dental Caries Rates:

The transition from foraging to farming is associated with a widespread and well-documented decline in oral health, wherein women experience a more rapid and dramatic decline than men. Historically, anthropologists have attributed this difference to behavioral factors such as sexual division of labor and gender-based dietary preferences. However, the clinical and epidemiological literature on caries prevalence reveals a ubiquitous pattern of worse oral heath among women than men. Research on cariogenesis shows that women's higher caries rates are influenced by changes in female sex hormones, the biochemical composition and flow rate of saliva, and food cravings and aversions during pregnancy. Significantly, the adoption of agriculture is associated with increased sedentism and fertility. I argue that the impact of dietary change on women's oral health was intensified by the increased demands on women's reproductive systems, including the increase in fertility, that accompanied the rise of agriculture and that these factors contribute to the observed gender differential in dental caries.

Honestly, my first thought was "maybe women just like sugar more?" In any case, one thing I assume is that the higher "fertility" of agricultural women is going to be due to the fact that they do not space their births. In contrast, hunter-gatherer women typically have a reduced number of pregnancies because ofbehaviors such as extended breastfeeding. Of course, most agricultural societies quickly reached the Malthusian limit (ecological carrying capacity), so the higher fertility was likely balanced out by higher infant mortality. If agricultural women gave birth to more infants a greater proportion of these offspring ended up dying of diseases, etc., than for hunter-gatherers. So at birth any given hunter-gatherer infant is far more likely to reach reproductive age than any given offspring of peasants....

Related: Group lifespan differences? Maybe it's agriculture, Maybe it's agriculture?, Demon rum, Maybe it's agriculture - soft sweep TRPV6, Maybe it's agriculture?, Maybe it's agriculture - skin color edition.... and Tall, to short, to tall (again).

Labels: Genetics

Male-pattern baldness susceptibility locus at 20p11:

We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 10-14 for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 10-15).

ScienceDaily has a somewhat amusing headline, Baldness Gene Discovered: 1 In 7 Men At Risk:

"I would presume male pattern baldness is caused by the same genetic variation in non-caucasians," said Richards, an assistant professor in genetic epidemiology, "but we haven't studied those populations, so we can't say for certain."

Well, the SNP at 20p11 exhibits different frequencies of the alleles across the HapMap populations (Europeans are the outgroup to Africans and Asians, just as they are to a great extent on the phenotype). I was amused at the use of the term "risk," I understand the technical reason, but it seems to make male pattern baldness seems like a much more problematic condition than it really is.

Labels: Genetics

Yann reviews a recent paper, Lactase persistence-related genetic variant: population substructure and health outcomes.

Labels: Genetics, Human Evolution

Over at evolgen, more on the cis vs. trans debate:

...First, there is an excess of trans variation within populations. And, second, cis changes tend to be additive, while trans changes are dominant/recessive. That means recessive trans mutations can segregate in populations without phenotypic effects, while cis changes are exposed to selection from the get go (either purged by purifying selection or fixed by positive selection).

Labels: Genetics

Many recent posts on this site have been dedicated to genome-wide association studies, in which variants across the genome are tested for their association with a phenotype. These studies, if successful, identify a relatively small candidate region that presumably contains some sort of polymorphism that plays a role in the phenotype. Identifying that causal polymorphism is far from trivial.

A recent study on cleft lip provides a glimpse into how these sorts of follow-up might proceed. The authors had earlier shown (through a candidate gene study) that SNPs in IRF6 (a transcription factor) were associated with cleft lip. In particular, a non-synonymous SNP in the gene was repeatedly and reliably associated with the phenotype. In this follow-up study, however, the authors find another, non-coding SNP that shows the strongest association with the phenotype.

The authors are then able to show that this SNP falls in a binding site for another transcription factor, and that the region is an enhancer element that drives expression of IRF6 in the developing face. They don't show that the SNP changes expression patterns, but it's still a pretty impressive piece of work, and exemplifies the extensive experimental work that will be needed to ultimately refine the glut of genome-wide association signals being published.

Labels: Genetics

Leading geneticist Steve Jones says human evolution is over. Steve Jones has an appointment in the Galton laboratory, and has written several books on human genetics (e.g., Y: The Descent of Man and Darwin's Ghost: The Origin of Species Updated). But he says things like this:

"Small populations which are isolated can evolve at random as genes are accidentally lost. World-wide, all populations are becoming connected and the opportunity for random change is dwindling. History is made in bed, but nowadays the beds are getting closer together. We are mixing into a glo-bal mass, and the future is brown."

First, we're nowhere close to panmixia.* Second, there is going to be a large variance around the expectation. Even if you remove new mutations, there are a lot of variants out there for selection to pick up from the extant genetic background I would think. The future will not be brown for the same reason that people in an English village do not all have the same hair color despite there being a lot of intermarriage.

Lots of other things to point to that leave you confused in that piece, but I'll leave it as an exercise for the readers....

* And what about the lack of importance of population size as a parameter effecting substitutions in Neutral Theory? I know there are ways you can object to this, but Jones' quote seems to garble many issues here.

Update: I emailed an academic who I suspected would know if Jones was being quoted out of context or misrepresented. But they say that this is probably an accurate representation of his views (and they also seem to think that his coherency leaves a bit to be desired).

Update II: Here is Chris Stringer's rebuttal to Jones:

But Professor Chris Stringer, research leader in human origins at the Natural History Museum, London, said the idea that evolutionary pressures were no longer taking their toll on humanity was true of only western civilisation.

He said: "The argument that modern life has stemmed the effects of evolution is true in some areas, such as the way in which medicine has improved health and wellbeing, and the fact I am not out in the cold and wet, but sitting in a nice, warm office with heat and clothing. But that is very much something that applies only in developed, western countries. You only need look to Africa to see how HIV/Aids is still having an enormous impact on selection, and I believe that genetics will continue to play a part in our evolution."

*roll eyes* Someone should tell these guys that you don't need to die to not reproduce.

Labels: Genetics, Human Evolution

Nature Genetics this week has published a genome-wide association study of narcolepsy in the Japanese population. The finding in the paper is a variant that confers a modest risk of narcolepsy, but personally, I was blown away by Figure 1, reproduced above. The figure shows the strength of association of each of 500,000 SNPs with narcolespy, and the novel reproducible finding is on chromosome 22 (ie, it doesn't stand out all that impressively in this plot). The major signal, absolutely swamping everything else, is in fact in the MHC region (called HLA in humans).

This region, of course, contains risk factors for type I diabetes, crohn's disease, and most (all?) other autoimmune diseases. A quick google confirms that, indeed, thinking of narcolepsy as an autoimmune disease is not new, but it's definitely new to me, and it's pretty striking to see just how much more important the risk factors in HLA are compared to everything else.

Labels: disease, Genetics

Dienekes posted a bunch of abstracts from a meeting of the American Society of Human Genetics. This one jumped out at me:

Seven selection-nominated candidate genes (COL11A1, LMNA, FGFR1, FGFR2, TRPS, BRAF, FLNA) known to be involved in Mendelian craniofacial dysmorphologies and to have high allele frequency differences between West African and European populations were tested for admixture linkage to normal facial feature traits. The sample consists of 254 subjects (n=131 African Americans, n=123 Brazilians) of West African and European genetic ancestry. Each individual was genotyped at 176 ancestry informative markers (AIMs), which allowed for proportional estimation of genetic ancestry from four parental populations and adjustments for admixture stratification.

3D images of faces were acquired using the 3dMDface imaging system. 3D coordinate data were collected from 22 landmarks placed on each image using the 3dMDPatient software. The 231 possible pairwise landmark distances were scaled to the geometric mean and then analyzed using Euclidean Distance Matrix Analysis.

We used both ANOVA and ADMIXMAP to control for admixture stratification and to test for associations between the 231 pairwise landmark distances and 183 AIMs, using sex, height and BMI as covariates. We used a four-population model (West African, European, East Asian, and Native American).

There is a strong concordance between the ANOVA and ADMIXMAP results. Many landmark distances, particularly on the mouth and nose, were significantly associated with genetic ancestry. Additionally, three of the candidate genes show no effects on pairwise landmark distances while four show distinct patterns of association. For example, FGFR2 is associated primarily with the length of the face. These results represent the first identification of the first genes affecting normal variation in facial features.

A definite new twist possible on DNA forensics.

Labels: Genetics

It's widely accepted that many of the differences between species are due to changes in gene regulation, rather than in protein sequences themselves. It's plausible, however, that changes in the sequences of transcription factors could lead to large-scale changes in gene regulation in a relatively simple manner--just a single nucleotide substitution could alter transcription factor binding across the whole genome.

Is this how evolution has worked? A new study takes advantage of a pretty cool resource--a mouse carrying human chromosome 21--to answer no, it doesn't appear so.

The authors begin by noting that several transcription factors bind different spots in human and mouse livers. With the mouse carrying human chromosome 21, they can pretty definitively test whether this difference in binding is due to changes in the transcription factors themselves or to changes in binding site sequence. Remarkably, it doesn't seem to matter whether the human chromosome is located in a mouse or a human--the same human regulatory sequences are bound. Similarly, the locations of an epigentic mark they test seems to depend almost solely on the species the chromosome belongs to rather than the species in which it's located.

This has enormous implications--as the authors write:

Here we show that each layer of transcriptional regulation within the adult hepatocyte, from the binding of liver master regulators and chromatin remodeling complexes to the output of the transcriptional machinery, is directed primarily by DNA sequence. Although conservation of motifs alone cannot predict transcription factor binding, we show that within the genetic sequence there must be embedded adequate instructions to direct species-specific transcription.

Now it's "just" a question of deciphering those instructions.

Labels: Genetics

Thank god for animals and their resemblance to humans to elucidate general patterns and relationships. Missense Mutation in Exon 2 of SLC36A1 Responsible for Champagne Dilution in Horses:

The purpose of this study was to uncover the molecular basis for the champagne hair color dilution phenotype in horses. Here, we report a DNA base substitution in the second exon of the horse gene SLC36A1 that changes an amino acid in the transmembrane domain of the protein from threonine to arginine. The phenotypic effect of this base change is a diminution of hair and skin color intensity for both red and black pigment in horses, and the resulting dilution has become known as champagne. This is the first genetic variant reported for SLC36A1 and the first evidence for its effect on eye, skin, and hair pigmentation. So far, no other phenotypic effects have been attributed to this gene. This discovery of the base substitution provides a molecular test for horse breeders to test their animals for the Champagne gene (CH).

Is horse color a big deal in terms of value? I wonder what the reason why there are so many horse pigmentation papers as opposed to a cheaper multi-colored animal like dog or cat.

Related: White horses and blonde humans: a genetic connection? KITLG makes you whiter.

Labels: Genetics, Pigmentation

In response to a recent paper detailing how to identify an individual from aggregate allele frequency data, the NIH has removed all such data under its control from the public eye.

This is obviously overkill (to identify an individual from such data, one would have to have genotyped them independently), but it's easier to inconvenience a few scientists than risk a PR backlash. Stories like this make it clear that expectations of privacy in terms of genetic data need a major rethinking; the open consent model of the Personal Genome Project is worth a very close look.

Labels: Genetics

ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry. ScienceDaily has a summary:

Asthma researchers have found that a gene variant known to raise the risk of childhood asthma in European children plays a similar role in white American children, but not in African American children.
...
Researchers from The Children's Hospital of Philadelphia found that variants in the ORMDL3 gene were associated with childhood-onset asthma among U.S. patients of European ancestry. In 2007 a study team based in Europe had identified the ORMDL3 gene, located on chromosome 17, as contributing to childhood asthma among British and German children.

Labels: Genetics

This week's Science has a nice article mapping the hairless phenotype in dogs to a small deletion in a poorly-characterized transcription factor. One of the hairless breeds used in mapping is the Chinese Crested, members of which are perennial contenders in the World's Ugliest Dog Competition. As more dog phenotypes are mapped, one imagines that this competition will be taken over by hideous genetically-modified freaks with the hair/tooth-lessness of the Chinese Crested, the slobber of a Newfoundland, the legs of a Daschund, and the rage of a Springer Spaniel. The horror.

Labels: Genetics