PLOS Genetics is open for business!

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PLOS Genetics is online today! The full interview with Neil Risch is up. Snip that might interest readers:

Clinton, for example, when the first draft of the human genome sequence came out, made a statement about how all people in the world, in terms of their genetic makeup, are 99.9% the same. His intent—to reduce conflict among peoples—is noble. People on the left, anthropologists and sociologists, do the same thing. They use the 99.9% figure as an argument for social equality. But the truth is that people do differ by that remaining 0.1% and that people do cluster according to their ancestry. The problem is that others could use that information to create division.

18 Comments

  1. “They use the 99.9% figure as an argument for social equality.” 
     
    That’s my favorite argument to destroy.  
    We’re about 99% Chimpanzee so obviously a fraction of a percent is enough to make a HUGE difference.

  2. The irrelevance of this 99%( based on the level of DNA sequence) for a wide range of behavioural differences is analysed here for dogs and wolves: 
     
    http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T07-4CPDNY7-2&_coverDate=07%2F26%2F2004&_alid=298654379&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4855&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=f90371d9b33f27c5819af5b7a3898958 
     
    ” Despite the relatively recent divergence time between domestic dogs (Canis familiaris) and gray wolves (Canis lupus), the two species show remarkable behavioral differences. Since dogs and wolves are nearly identical at the level of DNA sequence, we hypothesize that the two species may differ in patterns of gene expression 
    … 
    This study indicates that rapid changes in brain gene expression may not be exclusive to the development of human brains. Instead, they may provide a common mechanism for rapid adaptive changes during speciation, particularly in cases that present strong selective pressures on behavioral characters” 
     
    Obviously, the selective pressures on behavioral characters were very strong in the last milennia for the humans beings and probably differents for the differents populations.

  3. “Since dogs and wolves are nearly identical at the level of DNA sequence, we hypothesize that the two species may differ in patterns of gene expression” 
     
    This always strikes me as a somewhat silly argument going all the way back to (likely over-interpretations of) King & Wilson. If we don’t see “smoking guns” at the sequence level, they must be in gene expression, right?  
     
    The only reason that idea is so prevalent is that we just haven’t been able to measure gene expression differences, and so it is easy to image how they will correspond beautifully to phenotypic differences. But gene expression differences come from sequence changes, nothing else. If there aren’t that many sequence changes, there won’t be many gene expression change.  
     
    Enough of this sequence vs. expression nonsense.

  4. sequence changes 
     
    well, there are different types. ie; repeats increasing dosage.

  5. haven’t been able to measure gene expression differences 
     
    Northern blots, RT-PCR, microarrays? or just put the suspect sequences into a heterologous system and measure expression of a reporter 
     
    repeats increasing dosage 
     
    I’ve heard discussion of large to small scale insertions and deletions being very prevalent among humans and largely unaccounted for by methods that look at SNPs

  6. Well Mr. Old School: 
     
    ” gene expression differences come from sequence changes, nothing else” 
     
    Yes, you are right, but you are confounding concepts: 
    In the fascinating world of regulatory genetic networks there is a executive hierarchy of orders, that is, a chain of command for the organization of systems and subsystems. Therefore, a SMALL CHANGE in the concentrations of a transcriptional factor at the top of that chain of command can result in a DRAMATIC CHANGE of pattern expression of the total genome of a cell, or a tissue. 
    For example, the FOXP2 gene is involved in the regulatory control of several subsystems affecting language and sequential motor activities: 
     
    http://www.evolutionpages.com/FOXP2_language.htm 
     
    So, what do you think about these works?? 
     
    http://www.bio.psu.edu/People/Faculty/Nei/Lab/2005-glazko-etal.pdf 
     
    http://www.sciencemag.org/cgi/content/summary/292/5514/44 
     
    http://www.sciencemag.org/cgi/content/abstract/308/5718/107 
     
    http://www.nature.com/ng/journal/v37/n4/abs/ng1529.html 
     
    It is a good stuff for the discussion. 
     
    THanks for your observations.

  7. (Hmmm, Hilde responded before I could. I?ll post my musings and then read through the links Hilde provided.) 
     
    Old School: ?If there aren’t that many sequence changes, there won’t be many gene expression change.? 
     
    I believe scientists will discover there are many sequence differences in the non-coding DNA that are very important. 
     
    There seems to be twice as much non-coding DNA under selection as coding DNA in the human genome. Furthermore, short segments of the DNA (around 14 base pairs) can regulate gene expression. Lot of potential for extensive gene regulation. 
     
    Micro-RNA interference with mRNA and intron control of alternate RNA splicing have only be recognized as significant in the last decade. Other factors such as DNA tertiary structure are also known to play a role. My guess is that scientific modeling of the genome is far from complete. 
     
    I wonder how many scripts our genome could support. 
     
    Consider an insect with several life stages, each stage having a specialized body and behaviors. Or the development of the fetus where genetic scripts generate a sequence of shapes. Or fish changing gender based on environmental signals. 
     
    How robust are the scripts? If a script were seldom triggered would it disappear due to mutation? 
     
    Scripts would be built on top of other scripts. The low-level scripts would be relatively fixed since so many high-level systems depend upon them. (As with coding DNA, regulatory DNA could duplicate and diverge.) So small DNA segments might code for high-level scripts that seldom activate. Since the segments are short, the chance of a mutation is small. So even rarely used scripts might be retained under selection. (Abundant food could trigger early puberty. Other conditions might switch the ratio of male to female births. Different conditions could trigger different mating strategies.)

  8. My point is simply that some folks seem to have been imagining that there will be this huge signal from gene expression differences that will explain “what makes us human”. 
     
    But recent work has found no evidence of “DRAMATIC” gene expression differences between, say, human and chimp either (if you read the papers describing changes in brain expression carefully, you’ll see only detectable in a very small proportion of brain expressed genes). 
     
    In fact, it’s becoming increasingly clear that gene expression differences are by and large behaving like sequence changes (i.e. mostly random and neutral, and accumulating linearly with time): 
     
    http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0020132 
     
    The “important” changes are most likely going to be very subtle differences in dosage and timing during development that may have dramatic impact on the eventual phenotype, but they will be very hard to identify against the background noise. 
     
    At least that’s my gut feeling :)

  9. damn you to hell old school!

  10. Yeah, Kimura and I are throwing a BBQ down there.

  11. Ok, I accept these ” very subtle differences”, but I do not agree with: 
     
    ” …they will be very hard to identify against the background noise.” 
     
    Very subtle differences like a single nucleotide polymorphism explain behavioural differences between humans: 
     
    “The temperamental predisposition of the subjects had a significant correlation with brain activity in the C/C group.” 
     
    http://www.jneurosci.org/cgi/content/abstract/25/27/6460 
     
    ” Geneticists identify ‘master switch’ that causes female flies to behave like males” 
     
    http://hum-molgen.org/NewsGen/06-2005/msg44.html 
     
    This is about complex gene-regulatory pathways: 
     
    http://genomebiology.com/2005/6/7/r62/abstract 
     
    An example of molecular switch for behavioral abnormalities : 
     
    http://www.pnas.org/cgi/content/abstract/98/20/11042 
     
    A good question for all us: How do you harmonize this  
     
    “recent work has found no evidence of DRAMATIC gene expression differences between, say, human and chimp” 
     
    with this: 
     
    “Eighty percent of proteins are different between humans and chimpanzees” ? :-o

  12. “Very subtle differences like a single nucleotide polymorphism explain behavioural differences between humans:” 
     
    You mean ‘correlate’, not ‘explain’. The very hard part is going from the former to the latter.  
     
    Note that I’m not saying that it’s impossible to find the important changes (than I might as well change fields).. just that it’s unlikely that we’ll find an asymmetry in human-chimp molecular divergence that is as striking as the phenotypic divergence. 
     
    As for your last question, I think this is really the discussion the community needs to get away from: 
     
    “Eighty percent of proteins are difference between human and chimp” 
     
    “Wow, that’s a lot” 
     
    “But they differ by only one or two amino acids each” 
     
    “Wow, that’s not very much” 
     
    “And overall we’re 99% chimps” 
     
    “Wow, that’s not very different either” 
     
    “But that translates to almost 40 MILLION sequence difference” 
     
    “WOW, that’s a lot” 
     
    Etc…

  13. http://www.journals.uchicago.edu/AJHG/journal/issues/v77n1/42172/42172.html 
     
    wrt to population differences, they find: 
     
    African-descent populations have higher average CRP levels than do European-descent populations (Wener et al. 2000), although there is broad overlap in the range of levels across ethnic groups. Self-reported ethnicity in the United States is also associated with differences in morbidity and mortality from CVD and metabolic diseases, for a variety of medical, social, behavioral, and economic reasons (Watkins 2004). Thus, the genetic portion of the interethnic variance appeared to be attributable to frequency differences at three CRP SNPs (790, 1440, and 2667), in which the allele associated with lower CRP levels (790A, 1440C, and 2667C) was more frequent in EAs than in AAs. These results confirm recent observations that metabolic factors such as obesity account for a large portion of the variation in CRP levels associated with race/ethnicity (Albert et al. 2004; Anand et al. 2004) and suggest that the majority of the remaining variation in CRP levels associated with race/ethnicity in young adults is accounted for by genetic variants within the CRP locus.

  14. http://dx.doi.org/10.1371/journal.pbio.0030267 
    Multiple Locus Linkage Analysis of Genomewide Expression in Yeast 
     
    We apply the new method to a cross between two strains of the budding yeast Saccharomyces cerevisiae, and estimate that at least 37% of all gene expression traits show two simultaneous linkages, where we have allowed for epistatic interactions. Pairs of jointly linking quantitative trait loci are identified with high confidence for 170 gene expression traits, where it is expected that both loci are true positives for at least 153 traits. In addition, we are able to show that epistatic interactions contribute to gene expression variation for at least 14% of all traits.

  15. Old School: ?The “important” changes are most likely going to be very subtle differences in dosage and timing during development that may have dramatic impact on the eventual phenotype, but they will be very hard to identify against the background noise. 
     
    At least that’s my gut feeling ? 
     
    I think you have a wise gut. 
     
    Interesting link on gene expression evolution being a stochastic process. I wonder if many regulatory processes simultaneously undergoing change through random mutations and filtered by selection could produce a stochastic process?  
     
    Or perhaps there are feedback processes that keep gene expression levels within certain ranges? (I?m envisioning a situation in which increased gene expression in a specific tissue first increases fitness but puts more of a load on the tissue. Eventually regulatory adaptation might lead to other tissues taking on some of the load. The expression level in the stressed tissue might then return to a ?normal? level.) 
     
    I was surprised by the PLOS article, http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0030042, showing that compared to rodents many of the primate regulatory sequences seem to wander randomly.

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  17. “Interesting link on gene expression evolution being a stochastic process. I wonder if many regulatory processes simultaneously undergoing change through random mutations and filtered by selection could produce a stochastic process?” 
     
    Ah, now we’re talking… This reminds me of a fascinating, but apparently largely unknown paper by J.H. Gillespie on ‘genetic draft’. The implication being that strong, sustained selection throughout the geome could potentially create a clock-like and stochastic signature: 
     
    http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T39-42696YM-3&_coverDate=12%2F30%2F2000&_alid=298874273&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4941&_sort=d&view=c&_acct=C000022659&_version=1&_urlVersion=0&_userid=501045&md5=4a37c88ec68fe88749b8baac5389946b

  18. A side note about dogs and wolves: 
    Aren’t there more similarities between dog and wolf pup/juvenile behaviour? The wolf genome doesn’t code for the adult only.

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