The future of personal genomics is bright. 23andMe….

23andMeAs most of you know 23andMe is no longer providing health interpretation services, though they are still providing genealogy (and are unrolling a more advanced ancestry painting right now). You can still download raw data though, so you can find third party providers to calculate health risks. Unfortunately, as some have noted 23andMe actually did a rather good job outlining the probabilities. And, I think this answers the question about what 23andMe’s strategy was when it started courting FDA intervention about a year ago when it began to emphasize their health services (you probably encountered the marketing push somewhere). There doesn’t seem to have been a master strategy with contingencies. I obviously wish the company luck, and am hopeful it will make it through this rough patch, but they need to be on the ball from now on. For the customer base, I think it is fine to order their kits so you can get the raw data and genealogy services.

Evolutionary orthodoxy may be boring, but it is probably true

DarwinOne of the aspects of David Dobbs’ Aeon Magazine piece has been a significant backlash, mostly playing out on Twitter. A biologist who did quite like Dobbs’ article was P. Z. Myers. Ultimately I’m not quite sure that Myers disagrees as much with the people I follow on Twitter as you might think from the cautious and qualified tone of the endorsement, but it is clearly an endorsement (“must read today”). He observes that developmental biologists in particular might welcome Dobbs’ exposition of deviations from standard Mendelism (though this is clearly not the case for Armand Leroi, an evolutionary developmental biologist). Dobbs has clarified the thrust of his article, but the general takeaway by many was that the science has passed Richard Dawkins by, and he’s something of an old-fashioned dinosaur. That might not have been the intent, but that’s basically going to be the implication seen by a lot of non-scientists, and people outside of evolutionary biology. I know this because my whole life I’ve run into people who know the “real deal” about evolutionary biology, and aren’t shy about telling me. When I was 13 years old I remember my science teacher explaining that he didn’t buy into Darwinism. Why? Because he accepted Stephen Jay Gould’s punctuated equilibrium, which was definitely the wave of the future. Twenty years later I don’t think much has changed. Standard evolutionary biology is being modified on the margins and edges, extended and expanded, but in a gradual and incremental fashion. Gould and his acolytes are always a decade away from overturning the established order.

And speaking of Gould, here’s Paul Krugman in 1996:

I am not sure how well this is known. I have tried, in preparation for this talk, to read some evolutionary economics, and was particularly curious about what biologists people reference. What I encountered were quite a few references to Stephen Jay Gould, hardly any to other evolutionary theorists. Now it is not very hard to find out, if you spend a little while reading in evolution, that Gould is the John Kenneth Galbraith of his subject. That is, he is a wonderful writer who is bevolved by literary intellectuals and lionized by the media because he does not use algebra or difficult jargon. Unfortunately, it appears that he avoids these sins not because he has transcended his colleagues but because he does does not seem to understand what they have to say; and his own descriptions of what the field is about – not just the answers, but even the questions – are consistently misleading. His impressive literary and historical erudition makes his work seem profound to most readers, but informed readers eventually conclude that there’s no there there….

This may be harsh, but it gets to the heart of the fact that non-specialists esteem Gould far more than most working within his own purported field (I say purported, because from what I can tell Gould was a fine paleontologist. But he left much to be desired as an evolutionary theorist). An analogy with physics might be the fact that Stephen Hawking has been acclaimed as the “most brilliant mind since Einstein,” mostly due to his elegant and popular series of books for the general public. Hawking is brilliant, but he stands head and shoulders above other prominent physicists (e.g., Ed Witten) in the public mind mostly because of his popular contributions, not his scientific work. This is not necessarily a problem, except when people confuse cultural popularity with intellectual eminence.

Every decade there’s always a new trend which is gaining traction and pushing the edge in terms of what we know about evolutionary biology. In the 1970s there was molecular neutralism, which superseded tired arguments between Fisherian selectionists and Wrightian balancing serlectionists. In the 2000s you had evo-devo. Today it is epigenetics, and what that means for the “Central Dogma.” These are not crankish fads, but, the media often exaggerate the impact they’re having on a given field because that’s news. And at that point the general public gets confused as to the nature of the consensus within a field, because their perception is often filtered through the media (when it comes to cosmology, I’m the general public, so I know whereof I speak). This explains why I regularly get irritated emails and Facebook messages to the effect that my focus on population genetics is totally doing a disservice to my readership, which won’t understand that developmental biology and/or epigenetics has totally changed the game and our understanding of evolutionary genetic process.

Finally, PZ Myers seems to have sarcastically tweeted at me that we should vote on David’s piece after I wondered if any others have supported its thesis (David tells me some others have privately, and also in places like Jerry Coyne’s comment board), alluding to the reality that science isn’t a democracy, but proceeds via a method. Well, that’s the ideal. But as it is practiced science is basically the consensus of specialists. When someone plays up the existence of religious scientists PZ has no problem looking at large samples of data which suggest that conventionally orthodox religious scientists are in a small minority. Similarly, when people skeptical of anthropogenic climate change make their case, others are not shy about noting the consensus among climatologists on that question.

I can accede to the fact that within evolutionary biology the tradition which goes back to the grand triumvirate of theoretical population genetics, R. A. Fisher, Sewall Wright, and J. B. S. Haldane, is not universally accepted as having much important to say. Lynn Margulis comes to mind as someone who was skeptical of this in a vocal manner, and even the ‘orthodox,’ such as Ernst Mayr, have had their qualms with excessively formal model building. But, despite the arguments and attempts of of Margulis, Gould, and yes, Mary Jane West-Eberhard, to sideline this old orthodoxy, I believe it still remains the mainstream view of most practicing evolutionary biologists. That doesn’t mean that the classical Neo-Darwinian tradition is right, but it does mean that the scientific community probably leans toward that position more than any other alternative. And that is an important fact, because many people are confused about this, and unfortunately I’m pretty sure that David’s piece will just magnify that trend.

Addendum: Alwyn Scally suggests much of this is simply dislike of Richard Dawkins’ affect and non-scientific views on the part of those sympathetic to Dobbs’ take (though I don’t think this is David’s motivation, it may be for some of those who are taking succor from its takeaway). That is true. And how unfortunate that we sacrifice science on the alter of personal dislike.

Caveman rules: prepare to be surprised!

250px-Caveman_1By now you may have heard that mitochondrial DNA, passed down the female lineage, has been extracted from a ~400,000 year old human fossil from Spain. If you haven’t heard, I recommend Ewen Callaway and Carl Zimmer’s takes. The paper is at Nature, so gated, A mitochondrial genome sequence of a hominin from Sima de los Huesos. The big surprise is that these proto-Neandertals carry a mtDNA lineage which is closer to that of the Siberian Denisovans than that of later Neandertals. That’s the specific finding, and if you read the reaction it is rather clear that this is confusing researchers who work in this area. But take a step back, imagine what a world without ancient DNA would be like. Yes, the broad conjectures would be supported (e.g., Out of Africa), but many specific details would be off. So praise the data! Sometimes complexity is closer to the truth, and this is one of those cases. These are good problems to have.

NeanderIn the primary figure of the paper you can see that these humans are closest on the mtDNA phylogenetic tree to the Denisovans. But, it is important to note that they’re also hundreds of thousands of years older than any other ancient human DNA. Because mtDNA is only passed down through females it tends to be more strongly subject to genetic drift, which might turn over lineages rather rapidly. It is not that unlikely that over hundreds of thousands of years some populations would lose ancestral mtDNA lines. This is what occurred with “mitochondrial Eve.” She wasn’t the only female alive in Africa at the time, but all the other direct maternal lineages went extinct. There are ‘ghost branches’ within the tree which terminated. All you see are the lines of descent back up to the single last common ancestor on the mitochondrial lineage. This doesn’t mean that the ancestry of these women who did not contribute mtDNA disappeared. It is just that their lines of descent may have passed through sons at a given point (my maternal grandmother’s specific mtDNA almost went extinct, she had six son and one daughter). And of course there are other explanations for this pattern, highlighted in the articles linked. Gene flow between lineages, or from a different lineage altogether. We have to remember that the mtDNA of the Denisovan human was more diverged from Neandertals than the whole genome was later found to be, perhaps indicating complex admixture scenarios. The mtDNA tree falsifies, but I do not think it allows us to draw any robust conclusions.

These results are going to get updated in the next year or so with autosomal DNA from the rest of the genome. Even if they can’t get the whole genome sequenced, even a few tens of thousands of markers should be sufficient to clarify issues. Though all of these findings need to be interpreted cautiously in light of the fact that this is a very old lineage, perhaps closer to the time period of diversification for many Eurasian ‘archaic’ H. sapiens than we may have thought.

There is no revolution in genetics

Credit: Shane Pope

The always fascinating Aeon Magazine has a very interesting piece up by my friend David Dobbs, Die, selfish gene, die. As you can tell it is something of a broadside against Richard Dawkins’ ideas promoted in The Selfish Gene. The subheading is straightforward: “The selfish gene is one of the most successful science metaphors ever invented. Unfortunately, it’s wrong.” As I stated on Twitter the writing here was splendid, but at the end of the day I must disagree with the conclusions on the balance. It is true that the selfish gene is wrong as a metaphor and model, but  all representations of this sort have an element of stylized artifice which does not stand up to scrutiny. John Dalton’s atomic theory is also wrong, but still highly useful in imparting conceptual truth. But across 5,000 words David surveys the landscape and seems to come away with the lesson that evolutionary biology took a wrong turn at some point, and that the calcified old order is now facing a revolt from below. To me this does not seem like an accurate representation of what I know, though to be fair sometimes it was difficult for me to gauge whether David himself is always of one mind on the issue. The piece is wide ranging and expansive, and has so much detail that it is difficult to start at one particular place.

Naturally I have some technical and scientific gripes which may be irrelevant to most readers. As I observed on Twitter the mention of microarrays as a means to understand gene expression makes me wonder if this piece was written in 2005, as the field has moved to RNA-Seq. David admitted that this article was years in the making, so this peculiarity is easily explained then. But there is another section where he characterizes William D. Hamilton as a statistician. I think this misleads somewhat as to the primary thrust of his career. To my knowledge Hamilton’s forte was not detailed analysis of reams of data, extracting patterns from the noise. Rather, he engaged in modeling, extrapolating from the core truths of Mendelian genetics.

But the above are minor gripes, and more matters of style than substance. There are some issues where I think the piece may be substantively incorrect. Going in order of my concern, first David seems to imply that the genius of genetics in relation to Charles Darwin’s theory of natural selection is that it presented a straightforward mechanism by which one could introduce variation through mutation. This seems wrong to me. Rather, the power of genetics in a Mendelian framework is that it is a discrete manner of transmission where variation does not decay every generation. Natural selection needs variation to operate, and previous “blending models” of inheritance were subject to the problem that variation decays very rapidly in this framework. Second, the piece contends that the modern evolutionary synthesis was “all about the maths.” A formal mathematical framework was probably a necessary condition for the synthesis as we understand it, but it seems too much to say that this was overwhelmingly dominant. Two of the major figures in the synthesis, Theodosius Dobzhansky and Ernst Mayr, were definitely not mathematical. Dobzhansky saw particular empirical results, and leaned upon Sewall Wright’s formal models to support them, but he admitted that the mathematics escaped him. Mayr famously inveighed against mathematical genetics in his later years.

Then there’s the description of the origin and development of the theory of inclusive fitness. This just seems totally wrong to me (unless it is simply not clear). Though both R. A. Fisher and J. B. S. Haldane alluded to the broader logic of inclusive fitness at various points, the mathematical framework was developed by William D. Hamilton, John Maynard Smith, and George Price in the 1960s. More precisely, two papers in 1964 by Hamilton titled The Genetical Evolution of Social Behaviour laid the groundwork for the formal exploration of the problem of altruism. If I had read the piece without that knowledge I’d have thought it had been developed decades earlier.

Reading through the article I could almost see areas that I felt had to be edited out, or rewritten to be comprehensible to the broader public. I admire David’s effort and doubt I could have pulled something similar off. This is not an easy topic to tackle, the conceptual and empirical landscape is a minefield for someone to explore. Too many of the scientific assertions in the detail I’m not sure I can respond to, because I’m not totally clear on what’s being said, or implied. Many complex ideas and positions are condensed down to a sentence or two, to the point where they become obscure to me.

But there are a few points I’d like to enter into the record. First, as noted by many ideas like genetic assimilation have been around for a long time. C. H. Waddington is not an obscure figure. Evolutionary genetics has not been in stasis since the modern synthesis, or even the 1970s. Genomics means that there is a surfeit of data, and different theories are going to be useful in explaining particular aspects of the shape of biological variation. The emergence of evo-devo in the 2000s was certainly interesting, though I don’t think it “changed everything,” as some are fond of declaring. The narrative that the modern synthesis is being “overthrown” seems to be a persistent one, and always seems t finds support from the latest hot area of study. In the 1970s it was the molecular theory of neutral evolution, which rebutted excessive adaptationism, in the 2000s it was evo-devo, and now it is epigenetics. Science is not like religion, and heretical sects do not just explode and extinguish. New methods and areas of study add and modify the consensus, but only in rare cases do they “overthrow” a paradigm. The current interest in epigenetic inheritance has spawned forth a craze in neo-Lamarckian headlines. This too shall pass.

Finally, there’s the namecheck of several biologists who are presenting an alternative to ‘selfish gene’ model, Massimo Pigliucci, Eva Jablonka, Stuart Kauffman, Stuart A Newman, Stephen Jay Gould, Gregory Wray and Mary Jane West-Eberhard. To the lay reader some of these are familiar names already. It seems that citing them is a way to bolster the case that it isn’t crazy to think that Richard Dawkins’ ideas may not be right. These aren’t all cranks. But, some of them are notable for being heterodox in their thinking. Which leads me to assert that Richard Dawkins’ views are still closer to the center of opinions among evolutionary biologists than Mary Jane West-Eberhard. That doesn’t mean that Dawkins is right and West-Eberhard is wrong, it just means implicitly ‘gene-centric’ models are still popular. There’s a reason it’s calle ‘genetics,’ and not ‘expressionetics.’

I could say much more, but I won’t. After thrashing David a fair amount I have to admit it was a pleasure to read a popular piece which cited the achievements of greats like Fisher, Haldane, Wright, and Hamilton. Though I’d warn you from taking the assertions as gospel, the article is still worth reading for its detail as a starting point for further exploration.

An introduction

For those readers who don’t know me, I’ve been around, as they say. My interests range from population genetics to the history of Near Eastern antiquity. As such you can expect about a 50/50 distribution of posts of science and non-science, though in this day and age the boundary between the two is not as clear and distinct as it used to be.

History as the flux of populations

Father of Lies
Father of Lies

More often than not the discipline of history seems to swing between the true and trivial (or perhaps more precisely, picayune), and grand narratives which emphasize a nearly fictionalized story. In some ways this is not entirely a problem. When teaching young children the history of the United States a punctilious adherence to fact is essential, but, one can not deny that the selection of topicality can sway and shade the direction of the lessons learned. But far too often this ideological element of the historical narrative determines the central focus, rather than floating along the margins. With erudite command of detail historical scholars can, if they so choose, engage in a game of ideological sophistry, cultural flattery, and underhanded polemic. Both Howard Zinn and David Barton were and are players at this game. But there are still those who engage in the Sisyphean task of perceiving the world as it is, not as we would wish it to be, through the dark glass. Such a colossal enterprise, to ascertain the objective character of an exceedingly complex phenomenon, requires every tool at hand. Historians have traditionally been hunters of musty texts in neglected libraries, but they have on many an occasion received auxiliary data from scholars working in more material domains, such as archaeologists and engineers. Today you must add geneticists to the growing brigade of scholars attempting to excavate the past.

It is known
It is known

In truth the power of genetics is most evident and necessary in areas where history is silent, before written records can build a narrative skeleton in which we can play. Using both modern and ancient DNA samples the geneticists, working with archaeologists, can still make vague inferences where before there was only darkness. But illumination can be had even in time periods when historical records are quite good. Though the public understands evolution to transpire over eons, basic population genetic processes occur over a matter of generations, and so can give us fresh insight into dynamics which played out quite recently in time. A new paper in PLoS GENETICS, Reconstructing the Population Genetic History of the Caribbean, does just this. Obviously we already have a history of the Caribbean. As every schoolboy knows it began in 1492, and proceeded across the centuries as a palimpsest of European colonial powers, and later independent nations, rose and fell. But history is more than just wars, international congresses, and once-in-a-generation discoveries. It is the ebbing and flowing of peoples themselves in their aggregate masses. Conventional textual narratives and coarse archaeological inferences can get us rather far. See Charles C. Mann’s magisterial 1493 for an example. But historical population genetics goes a step further, as it attempts to infer demography through patterns of variation in genes, the most elemental instrumental variable for tracing demographic patterns one might imagine.

journal.pgen.1003925.g004What the above paper does is reiterate, emphasize, and clarify, particular population genetic demographic events which have been suspected. First, the Amerindian populations were not static creatures in equilibrium with nature, but dynamic. There is clear evidence in these results that some groups migrated from South America to Central America, and especially the Caribbean. This is not unreasonable a priori, but far too often our stylized models presume the Amerindian population as a homogeneous, uniform, almost ahistorical substrate upon which European agency and African tragedy can unfold. But on the contrary, the peoples of the New World had their own history, oral as it may be. As you can see the Maya, one of the most iconic of Amerindian peoples, seem to exhibit some southern affinities, perhaps the result of an ancient “back migration.” If the Old World is any guide there may have been many forward and back migrations.

journal.pgen.1003925.g004This ancient legacy is evident in the admixed populations, the Mestizos, Zambos, and Mulattos of the Greater Caribbean region. Looking in particular at the Puerto Rican and Dominican populations you see low, but significant, levels of admixture from specific native groups. One the one hand you may not be surprised, but it must be stated that before the genetic evidence there was much skepticism as to whether any Amerindian genetic heritage persisted in the populations of the Caribbean. A particular style of cultural/humanistic scholar intuited that perhaps an emphasis on indigenous ancestry was a mechanism for people of some African ancestry to deflect attention away from this aspect of their heritage because of the fraught history of slavery. Though the internal logic here seems reasonable, the empirical evidence makes it clear that the legacy of the Amerindians does persist in these islands, among these peoples. Their motive may have been unpalatable, but their argument was right.

Who were these Amerindian people? And how did they become integrated with the synthetic populations which came to dominate these islands? This is where textual history and genetics operate in a complimentary fashion. Both history and ethnography document  mass population collapse in concert with an androcide of the Amerindians. By this, I mean that European males took Amerindian women as concubines, and engaged in de facto polygyny in the New World. Hernan Cortes, conqueror of the Aztecs, illustrates his phenomenon, as he had an illegitimate son, Martin Cortes, with his native translator, and later on a legitimate son, another Martin Cortes, with a Spanish noblewoman. This pattern of sexual liberty and license was common in the early years, and has been extensively documented by historians. It is a reason many anthropologists give for the relatively low rates of legitimacy in much of Latin America. And of course what applied to Amerindian females also applied to African females. What the genetics makes clear is that this asymmetric pattern of cultural power relations was demographically very significant. Populations with a near total lack of Amerindian and African Y chromosomal lineages, passed from father to son, may still have high levels of non-European mtDNA, passed from mother to daughter. In this study they also looked at the X chromosome, which spends 2/3 of its time in females, and did find an enrichment of Amerindian ancestry there as well.

TractBut they didn’t just focus on the nature of admixture today, they inferred its history. The technique is rooted in basic concepts in genetics. When you have chromosomes come together from parents in a child, those are distinct and identical in nature to segments of ancestry one might find in parents. But genetic recombination in the next generation shuffles the segments, so that parental elements become mixed together on the same segment. When parents are from different geographic populations you see alternative segments of “ancestry tracts.” For example a chromosomal segment with alternative regions of European, Amerindian, and African, ancestry. Because there are only 20-30 recombination events per generation per individual the distribution of the length of these tracts is a function of the length of time since admixture. The early years after admixture will be characterized by long blocks of ancestry from one population, alternated with another. As time passes the segments will get smaller, and alternate much more rapidly. What the authors found was that indeed Amerindian segments exhibited the latter pattern, while European and African segments were more diverse in their distribution. The distinction was strongest in the Caribbean populations, but was evident elsewhere. The explanation is the one above. The early years of Iberian settlement were characterized by de facto polygyny and decimation of male Amerindians through enslavement (though there was population collapse more generally due to disease). Amerindian ancestry came in one singular pulse, and slowly dissipated and distributed itself through the population.

Finally, the results here also yield the finding that Latin American European ancestry seems to have diverged from its parent source. A detailed exploration of the technical issues can be found at the Haldane’s Sieve weblog, but I will say I am convinced that the authors have made a good, if not definitive, case for the proposition that the Latin American ancestral component is one which has diverged significantly. Again, the reason was listed above: de facto polygyny. This drives down the effective population, increases the drift, and skews the allele frequency distribution rapidly away from the source population. If this is a true result it shows us the possibilities for how new populations can arise through fission and rapid expansion. In particular, they may be male mediated. For this period, from 1500-1900, we have extensive documentation to corroborate the broad inferences made. But not so for many regions deep into the past. What these sorts of papers illustrate is the fine-grained power of genetics in shedding light on topics and issues which might otherwise have remained off limits. In particular genetics taps into some of the most primal activities of humankind, those that lead to procreation.

Citation: Moreno-Estrada A, Gravel S, Zakharia F, McCauley JL, Byrnes JK, et al. (2013) Reconstructing the Population Genetic History of the Caribbean. PLoS Genet 9(11): e1003925. doi:10.1371/journal.pgen.1003925