Razib Khan One-stop-shopping for all of my content

November 30, 2013

Endings & beginnings

Filed under: Administration,Farewell post — Razib Khan @ 8:32 pm

Update: Comments enabled now!

Until further notice this is my last post as a blogger at Discover Magazine. This shouldn’t impact regular readers. As always you can follow me by going to:

My feed, http://feeds.feedburner.com/RazibKhansTotalFeed

My Twitter, https://twitter.com/razibkhan

And of course, my website, http://www.razib.com

From December 1st, 2013, I will be blogging at Ron Unz’s new website, The Unz Review, at a familar subdomain http://www.unz.com/gnxp (feed, http://www.unz.com/gnxp/feed/).

I’m excited to explore this new opportunity. Ron is still nailing down the details of look, style, and functionality, so expect some changes on my Gene Expression sub-site. To make a long story short Ron wanted to beef up his science coverage, and I was amenable. At least when it comes to my particular bailiwick. Ron has merged my archives from the old Gene Expression website with the content generated at ScienceBlogs and Discover, so no matter where I go, or if I stop blogging due to other obligations, those archives will remain as a coherent whole.

I want to emphasize that my time at Discover was incredible. I want to give special thanks to Tasha Eichenseher, Amos Zeeberg, and Sheril Kirshenbaum. As it happens none of these individuals are associated with Discover at this point (Tasha is leaving as well), but they were instrumental in allowing me to either be here (in Sheril’s case) or focus on writing (in Tasha and Amos’ case). I assume you’ll be somewhat surprised that I mention Sheril, but I feel like I have to give special thanks to her because I’m 99% sure that it was her “good word” which allowed me to catch the eye of an outfit as respectable as Discover. Unlike a blogger as writerly as Ed Yong, or Sheril herself, I’ve always been more data nerd-cum-verbal pugilist. So this leads me to praise the great management skills of the two web editors I’ve had while being a blogger at Discover. They’ve let “Razib be Razib,” by and large letting me do my thing (though yes, in the interests of professionalism I’ve moved most of the more “direct” verbal volleys to Twitter). I really can’t thank anyone else at Discover because I barely knew they existed, which, in light of recent events, seems like a good thing. Overall I give Discover a good grade in terms of understanding how blogging should be run, with a light hand. This, despite the fact that I often put up posts which rubbed many “right-thinking-people” the wrong way, and scoured the comment threads acidly.

There’s really not much else to say. Aside from a new domain, don’t expect many changes.

The post Endings & beginnings appeared first on Gene Expression.

November 28, 2013

The total information world

Filed under: Personal genomics — Razib Khan @ 1:46 pm

Credit: Cryteria

Credit: Cryteria

Happy Thanksgiving (if you are an American)!

It’s been a busy few days in the world of personal genomics. By coincidence I have a coauthored comment in Genome Biology out, Rumors of the death of consumer genomics are greatly exaggerated (it was written and submitted a while back). If you haven’t, please read the FDA’s letter, and 23andMe’s response, as much as there is one right now. Since Slate ran my piece on Monday a lot of people have offered smart, and more well informed, takes. On the one hand you have someone like Alex Tabarrok, with “Our DNA, Our Selves”, which is close to a libertarian cri de coeur. Then you have cases like Christine Gorman, “FDA Was Right to Block 23andMe”. It will be no surprise that I am much closer to Tabarrok than I am to Gorman (she doesn’t even seem to be aware that 23andMe offers a genotyping, not sequencing, service, though fuzziness on the details doesn’t discourage strong opinions from her). An interesting aspect is that many who are not deeply in the technical weeds of the issue are exhibiting politicized responses. I’ve noticed this on Facebook, where some seem to think that 23andMe and the Tea Party have something to do with each other, and the Obama administration and the FDA are basically stand-ins. In other words, some liberals are seeing this dispute as one of those attempts to evade government regulation, something they support on prior grounds. Though Tabarrok is more well informed than the average person (his wife is a biologist), there are others from the right-wing who are taking 23andMe’s side on normative grounds as well. Ultimately I’m not interested in this this argument, because it’s not going to have any significant lasting power. No one will remember in 20 years. As I implied in my Slate piece 23andMe the company now is less interesting than personal genomics the industry sector in the future. Over the long term I’m optimistic that it will evolve into a field which impacts our lives broadly. Nothing the United States government can do will change that.

Yet tunneling down to the level of 23andMe’s specific issues with the regulatory process, there is the reality that it has to deal with the US government and the FDA, no matter what the details of its science are. It’s a profit-making firm. Matt Herper has a judicious take on this, 23andStupid: Is 23andMe Self-Destructing? I don’t have any “inside” information, so I’m not going to offer the hypothesis that this is part of some grand master plan by Anne Wojcicki. I hope it is, but that’s because I want 23andMe to continue to subsidize genotyping services (I’ve heard that though 23andMe owns the machines, the typing is done by LabCorp. And last I checked the $99 upfront cost is a major loss leader; they’re paying you to get typed). I’m afraid that they goofed here, and miscalculated. As I said above, it won’t make a major difference in the long run, but I have many friends who were waiting until this Christmas to purchase kits from 23andMe.


Then there are “the scientists,” or perhaps more precisely the genoscenti. Matt Herper stated to the effect that the genoscenti have libertarian tendencies, and I objected. In part because I am someone who has conservative and/or libertarian tendencies, and I’m pretty well aware that I’m politically out of step with most individuals deeply involved in genetics, who are at most libertarian-leaning moderate liberals, and more often conventional liberal Democrats. Michael Eisen has a well thought out post, FDA vs. 23andMe: How do we want genetic testing to be regulated? Eisen doesn’t have a political ax to grind, and is probably representative of most working geneticists in the academy (he is on 23andMe’s board, but you should probably know that these things don’t mean that much). I may not know much about the FDA regulatory process, but like many immersed in genomics I’m well aware that many people talking about these issues don’t know much about the cutting edge of the modern science. Talk to any geneticist about conversations with medical doctors and genetic counselors, and they will usually express concern that these “professionals” and “gatekeepers” are often wrong, unclear, or confused, on many of the details. A concrete example, when a friend explained to a veteran genetic counselor how my wife used pedigree information combined with genomic data to infer that my daughter did not have an autosomally dominant condition, the counselor asserted that you can’t know if there were two recombination events within the gene, which might invalidate these inferences. Though my friend was suspicious, they did not say anything, because they were not a professional. As a matter of fact there just aren’t enough recombinations across the genome for an intra-genic event to be a likely occurrence (also, recombination likelihood is not uniformly distributed, and not necessarily independent, insofar as there may be suppression of very close events). And this was a very well informed genetic counselor.

Additionally, there are the two major objections to 23andMe’s service which some on Twitter have been pointing me to. First, they return results which are highly actionable. The FDA explicitly used the example of a woman who goes and gets a mastectomy due to a 23andMe result. I don’t think this is a very strong objection. No doctor would perform a mastectomy based on 23andMe results. So that’s not an issue. Then there are those who allude to psychological harm. This could be a problem, but 23andMe has multiple steps which make it so that you have to proactively find out information on these sorts of diseases. Call me a libertarian if you will, but I object on principle to the idea that medical professionals necessarily have to be involved in the dissemination of information about my own genome as a regulatory matter. Obviously when it comes to a course of treatment they will be consulted, and no doubt there will be replications of any actionable results. But I don’t trust the medical sector to be populated by angels. To illustrate why I don’t trust medical professionals to always behave out of the goodness of their hearts, consider that deaths from hospital infections started dropping sharply when Medicare stopped paying for treating these infections. Workers in the health care sector do care about patients, but even here incentives matter, and the human cognitive budget is such that they can shift the outcomes greatly by reminding nurses and doctors that washing hands is going to impact the bottom line (the reality is that hospitals probably instituted much stricter measures). What does this have to do with personal genomics? You are our own best advocate, and one of the major reasons that those in higher socioeconomic strata have better health outcomes is that they are so much less passive as patients. The more detailed the information you have on your own health, the better you can advocate and be involved in the decision-making process. And the reality is that with dropping prices in sequencing, and the ability to design software to do interpretation, without draconian measures there’s almost nothing the United States government will be able to do to prevent anyone with a moderate amount of motivation from getting this sort of information.

A second objection is that the SNPs returned are of small and very probabilistic effect. This is embedded in issues regarding the “missing heritability” and the reality that most complex diseases are due to many factors. Because of the small effect size, and until recently, small sample sizes, this literature has been littered with false positives, which passed arbitrary statistical thresholds. The argument then boils down to the reality that 23andMe in many cases is not really adding any informative value. If that’s the case though then why the urgency to regulate it? Horoscopes and diet books do not add informative value either. This problem with small effect SNPs is widely known, so bringing it up as if it is revelatory is rather strange to me. Additionally, as Eric Lander and others have pointed out the locus which helped us discover statins is of very small effect. As long as they’re not false positives, small-effect SNPs are likely a good way to go in understanding biological pathways for pharmaceutical products. But that doesn’t speak to the risk prediction models. I think there the possibilities are murkier even in the long run because complex traits are complex. Even if we have massive GWAS with sample sizes in the millions and 100x whole-genome coverage (this will happen), the environmental factors may still be significant enough that researchers may balk at definitive risk predictions.

Ultimately where I think personal genomics is going is alluded to in the Genome Biology piece: as part of a broader suite of information services, probably centralized, filtered, and curated, by a helper artificial intelligence. What cognitive science and behavioral economics are telling us is that individuals operate under mental budget constraints. Dan MacArthur is probably right that personal genomics enthusiasts overestimated how involved the average person on the street was going to want to get in terms of their own interpretations of returned results. The reality is that even genetic counselors can barely keep up. Someday the field will stabilize, but this is not that day. But overall the information overload is going to get worse and worse, not better, and where the real upside, and game-changer, will be is in the domain of computational tools which helps us make decisions with a minimum of effort. A cartoon model of this might be an artificial intelligence which talks to you through an ear-bud all day, and takes your genomic, epigenomic, and biomarker status into account when advising you on whether you should pass on the dessert. But to get from here to there is going to require innovation. The end point is inevitable, barring a collapse of post-industrial civilization. The question is where it is going to happen. Here in the United States we have the technology, but we also have cultural and institutional road-blocks to this sort of future. If those road-blocks are onerous enough it doesn’t take a genius to predict that high-tech lifestyle advisement firms, whose aims are to replace the whole gamut of self-help sectors with rationally designed applications and appliances, will simply decamp to Singapore or Dubai.

Personal genomics is a small piece of that. And 23andMe is a small piece of personal genomics. But they are not trivial pieces.

The post The total information world appeared first on Gene Expression.

November 25, 2013

The FDA and 23andMe

Filed under: Personal genomics — Razib Khan @ 10:30 am

napFirst, download your 23andMe raw results now if you have them. If you don’t know what’s going on, the FDA has finally started to move aggressively against the firm. Unfortunately this is not surprising, as this was foreshadowed years ago. And, 23andMe has been moving aggressively to emphasize its medical, as opposed to genealogical, services over the past year. But this isn’t the story of one firm. This is the story of government response to very important structural shifts occurring in the medical delivery system of the United States. The government could potentially bankrupt 23andMe, but taking a step back that would still be like the RIAA managing to take down Napster. The information is coming, and if there’s one thing that can overpower state planning it is consumer demand. Unless the US government wants to ban their citizens from receiving their own genetic data they’re just putting off the inevitable outsourcing of various interpretation services. Engagement would probably be the better long term bet, but I don’t see that happening.

The post The FDA and 23andMe appeared first on Gene Expression.

November 24, 2013

Open Thread, 11/24/13

Filed under: Blog,Open Thread — Razib Khan @ 2:21 am

23andMe

One of the stranger call-ins on my interview with Kathleen Dunn last month was when a woman who proudly declared that she was a math major in college asserted that 23andMe had told her she wasn’t at risk for many diseases which now in her 60s she had developed. I didn’t want to be too pointed about it, but if you are in your 60s you are at risk for developing many illnesses no matter what your “genetic risk.” This is clear from 23andMe’s statistics, which display high baseline risks for many common diseases. From reading comments on 23andMe discussion forums it seems that perceived false negatives are going to be a much bigger issue than false positives over the long run. If the tests are “wrong” in a direction which leaves you in a better state than predicted you might feel like you’ve dodged a bullet. On other hand if the tests are “wrong” in a direction which gave you false comfort, or add insult to injury when you’ve developed a debilitating disease, then you feel much more burned.

I don’t really recommend blogs too much anymore. But please check out The Stage and Social Evolution Forum.

The post Open Thread, 11/24/13 appeared first on Gene Expression.

Open Thread, 11/24/13

Filed under: Blog,Open Thread — Razib Khan @ 2:21 am

23andMe

One of the stranger call-ins on my interview with Kathleen Dunn last month was when a woman who proudly declared that she was a math major in college asserted that 23andMe had told her she wasn’t at risk for many diseases which now in her 60s she had developed. I didn’t want to be too pointed about it, but if you are in your 60s you are at risk for developing many illnesses no matter what your “genetic risk.” This is clear from 23andMe’s statistics, which display high baseline risks for many common diseases. From reading comments on 23andMe discussion forums it seems that perceived false negatives are going to be a much bigger issue than false positives over the long run. If the tests are “wrong” in a direction which leaves you in a better state than predicted you might feel like you’ve dodged a bullet. On other hand if the tests are “wrong” in a direction which gave you false comfort, or add insult to injury when you’ve developed a debilitating disease, then you feel much more burned.

I don’t really recommend blogs too much anymore. But please check out The Stage and Social Evolution Forum.

The post Open Thread, 11/24/13 appeared first on Gene Expression.

November 20, 2013

Our ancestors are part us…or the other way around?

Filed under: Archaeology,Siberian boy — Razib Khan @ 11:34 am

Keeping a close watch on media representations of the new Nature paper on the ancient Siberian genome. Here’s The New York Times, 24,000-Year-Old Body Is Kin to Both Europeans and American Indians. I don’t have a problem with the title, but the roll-out isn’t totally accurate in what it will connote to the audience in my opinion:

he genome of a young boy buried at Mal’ta near Lake Baikal in eastern Siberia some 24,000 years ago has turned Tout to hold two surprises for anthropologists.

The first is that the boy’s DNA matches that of Western Europeans, showing that during the last Ice Age people from Europe had reached farther east across Eurasia than previously supposed. Though none of the Mal’ta boy’s skin or hair survive, his genes suggest he would have had brown hair, brown eyes and freckled skin.

The second surprise is that his DNA also matches a large proportion — some 25 percent — of the DNA of living Native Americans. The first people to arrive in the Americas have long been assumed to have descended from Siberian populations related to East Asians. It now seems that they may be a mixture between the Western Europeans who had reached Siberia and an East Asian population.

The Mal’ta boy was aged 3 to 4 and was buried under a stone slab wearing an ivory diadem, a bead necklace and a bird-shaped pendant. Elsewhere at the same site some 30 Venus figurines were found of the kind produced by the Upper Paleolithic cultures of Europe. The remains were excavated by Russian archaeologists over a 20-year period ending in 1958 and stored in museums in St. Petersburg.

The issue I have is that modern Europeans are a new population which emerged through admixture processes over the past ~10,000 years. And one of those populations which contributed to their ancestry are the descendants of the Siberian boy! Talking about “Western Europeans” ~20,000 years ago is geographic convenience. They wouldn’t be “Western Europeans” as we understand them genetically. Even if there wasn’t any recent admixture, ~1,000 generations of drift is not trivial. Though the archaeology may clarify, I also don’t think it is definite that the ancient Siberians were from Europe as we’d understand it. Perhaps they all come from a common Central Eurasian stock which diversified?

Not that I have a better solution for terminology.

The post Our ancestors are part us…or the other way around? appeared first on Gene Expression.

The long First Age of mankind

Filed under: Anthroplogy,Archaeology,Siberians — Razib Khan @ 10:22 am

OldSiberian

“What it begins to suggest is that we’re looking at a ‘Lord of the Rings’-type world – that there were many hominid populations,” says Mark Thomas, an evolutionary geneticist at University College London who was at the meeting but was not involved in the work.

- Mark Thomas, as reported by Nature

This is in reference to the ancient DNA meeting where David Reich reported that the Denisovans, an exotic archaic population which contributed ~5-10 percent of the ancestry of Papuans, was itself a synthesis of Neandertals and a mysterious group currently unknown. This is not surprising, as the broad outlines of these results were presented at ASHG 2012, though no doubt they’re moving closer to publication. But for this post I want to shift the focus to a different time and place, after the ancient admixture with archaic lineages, and to the reticulation present within our own.


But first we need to backtrack a bit. Let’s think about what we knew in the early 2000s. If you want a refresher, you might check our Spencer Wells’ The Journey of Man or Stephen Oppeneheimer’s Out of Eden, which focused on Y and mtDNA lineages respectively. These books were capstones to the era of uniparental phylogeographic analysis of the spread and diversification of anatomically modern African hominids ~50-100,000 years ago. Rather than looking at the whole genome (the technology was not there yet) these researchers focused on pieces of DNA passed down via direct maternal or paternal lineages, and reconstructed clean phylogenetic trees using a coalescent framework. Broadly speaking these trees were concordant, and told us that our lineage, all extant humans, derived from a small African population which flourished ~100,000 years ago. These insights suffused the thought of human evolutionary thinkers in other disciplines (see The Dawn of Human Culture). H. sapiens sapiens, veni, vidi, vici.

After that initial “Out of Africa” migration a series of bottlenecks and founder events led to the expansion of our lineage, as it replaced all predecessors. By the Last Glacial Maximum, ~20-25,000 years ago, the rough outlines of human genetic variation were established (with the exception of the expansion into the New World). We know now that this picture is very incomplete at the most innocuous, and highly misleading given the least charitable interpretation.

Reticulation. Graphs. Admixture. These words all point to the reality that rather than being the culmination of deep rooted regional populations which date back to the depths of the Pleistocene, most modern humans are recombinations of ancient lineages. On the grandest scale this is illustrated by the evidence of ‘archaic’ ancestry in modern humans. But even more pervasively we see evidence of widespread admixture between distinct lineages which are major world populations which we think of as archetypes. This is true for Amerindians, South Asians, and Europeans. This is also the case for Ethiopians, and Australian populations. A major problem crops up when we talk about extinct ancient populations which were the founding substituent elements of modern ones: it doesn’t make sense to use modern referents when they are simply recombinations of what they are describing. But language and history being what they weare we can’t change the awkwardness of talking about “Ancestral North Eurasians,” anodyne and somewhat incoherent at the same time (Eurasia is a modern construct with contemporary historical salience).

Into the mix comes another ancient DNA paper which reconstructs the genome of a boy who lived in Siberia, near Lake Baikal, somewhat over 20,000 years ago. It’s titled Upper Palaeolithic Siberian genome reveals dual ancestry of Native Americans. Here’s the topline finding: a substantial minority of the ancestry of modern Native Americans derives from a North Eurasian population which has closer affinities to West Eurasians than East Eurasians. And, this is an old admixture event. In the paper itself they observe that all “First American” populations seem to exhibit the same admixture distance to the Siberian genome. These results are also broadly consistent with the admixture of this population in Western Eurasia, especially northeast Europe. As among Amerindian populations it seems that this element is at substantial minority across Europe as a whole, and perhaps at parity in some populations, such as Finns.

Fig1To the left you see the geographical affinities of the MA-1 Siberian sample. It is shifted toward West Eurasians in the PCA. But on the map with circles representing populations, the definite evidence of admixture between Amerindians and MA-1 is clear in the shading. The statistic used, f-3, looks for complex population history between and outgroup (X) and a putative clade. From this test it is evident Amerindians had some admixture related to MA-1. Because of the dating of Siberian remains it does not seem likely that admixture was from Amerindians to West Eurasian and related populations. Rather, the reverse seems more plausible. You can also see from the map the close affinities with particular European and Central Asian populations of MA-1. This is intriguing, and requires further follow up. Though MA-1 and its kin were closer to West Eurasians than East Eurasians, it still seems likely that there was an early divergence between the populations of north-northeast Eurasia, and those of the southwest. Eventually they came back together in various proportions to produce modern Europeans, but it seems likely that during the Pleistocene these two groups went their own way.

treemixThere are hints of this in the TreeMix plot to the right. Note now drifted MA-1 is in relation to other West Eurasians (the branch is long). I suspect some of this is due to the fact that this individual is nearly 1,000 generations in the past. Not only is it difficult to name ancient populations with those of moderns, I suspect that some of the variation in the ancient populations has been lost, and so they seem exotic and difficult to fit into a broader phylogenetic framework (they had hundreds of thousands of SNPs though). And yet MA-1 can be fitted into the broader framework of populations which went north or west after leaving Africa because of mtDNA and Y chromosome results. Both of these indicate that MA-1 was basal to West Eurasians, with haplogroup U for mtDNA, and R for the Y lineage.

To really understand what’s going on here is going to take a while. A later subfossil, circa ~15,000 years before the present, yielded some genetic material, and exhibited continuity with MA-1. This suggests that Siberia may have had massive population replacement relatively recently. We know this was likely the case elsewhere. Reading Jean Manco’s Ancestral Journeys one possible scenario is that Pleistocene Europeans were MA-1 like, but were replaced by Middle Eastern farmers in the early Neolithic. But later eruptions from Central Asia brought mixed populations (Indo-Europeans?) with substantial MA-1 affinities to the center of European history.

Finally, one must make a note of phenotype. The authors looked at 124 pigmentation related SNPs (see supplemental). The conclusion seems to be that MA-1 was not highly de-pigmented, as is the case with most modern Northern Europeans. This stands to some reason, as substantial ancestry of this sort in Amerindians would result in phenotypic variation which does not seem to be present. Though the authors do suggest that coarse morphological variation among early First Americans (e.g., Kennewick Man) might be due to this population, which had West Eurasian affinities.

Where does this leave us? More questions of course. Though I’m confident the befuddlement will clear up in a few years….

Citation: doi:10.1038/nature12736

Addendum: Please read the supplements. They’re rich enough that you don’t need to read the letter if you don’t have access. Also, can we now finally bury the debate when east and west Eurasians diverged? Obviously it can’t have been that recent if a >20,000 year old individual had closer affinity to western populations.

The post The long First Age of mankind appeared first on Gene Expression.

November 18, 2013

Some of us don’t care if people look like us

Filed under: Identity — Razib Khan @ 1:56 am
Alone in a Room Full of Science Writers: You can never overestimate how empowering it is to see someone who looks like you—only older and more successful. That, much more than well-meaning advice and encouragement, tells you that you can … Continue reading

November 17, 2013

Open Thread, 11/17/2013

Filed under: Administration,Open Thread — Razib Khan @ 5:22 pm

Finished J. P. Mallory’s The Origins of the Irish. Good book, but it was as illuminating as to the origins of the Irish as Danel Dennett’s Consciousness Explained was in explaining consciousness.

The post Open Thread, 11/17/2013 appeared first on Gene Expression.

November 13, 2013

The color of life as a coincidence

Filed under: Anthroplogy,Evolution,Evolutionary Genetics,Genetics of taste,Taste — Razib Khan @ 12:35 am

Credit: Eric Hunt

Credit: Eric Hunt

I do love me some sprouts! Greens, bitters, strong flavors of all sorts. I’ve always been like this. Some of this is surely environment. My family comes from a part of South Asia known for its love of bracing and bold sensation. But perhaps I was born this way? There’s a fair amount of evidence that taste has a substantial genetic component. This does not mean genes determine what one tastes, but it certainly opens the door for passive gene-environment correlations. If you do not find a flavor offensive, you are much more likely to explore it depths, and cultivate your palette.

220px-Durio_kutej_F_070203_ime

Dost thou dare?
Credit: W.A. Djatmiko

And of course I’m not the only one with a deep interest in such questions. With the marginal income available to us many Americans have become “foodies,” searching for flavor bursts and novelties which their ancestors might never have been able to comprehend. More deeply in a philosophical sense the question of qualia reemerges if there is a predictable degree of inter-subjectivity in taste perception (OK, qualia is always there, though scientific sorts tend to view it as intractable in a fundamental sense).


But there’s heritability, and then there’s genes. We know that perception in some ways is heritable, but what is perhaps more interesting is if you can peg a specific genomic location to it. Then the evolutionary story becomes all the richer. And so it is with the locus TAS2R16, where a nonsynonymous mutation at location 516 seems to result in heightened sensitivity to bitter tastes. More specifically, it’s rs846664, and the derived T allele is fixed outside of Africa, while the ancestral G allele still segregates at appreciable fractions within African populations. A new paper in Molecular Biology and Evolution puts this locus under a microscope, though it does not come up with any clear conclusions. Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa presents some interesting findings. First, let’s look at the distribution of the variation in their sample populations at the SNP of most particular interest:

Region Population T516G
Outside of Africa Non-Africans 0.000
Ethiopia Semitic 0.059
Tanzania Sandawe 0.083
Ethiopia Omotic 0.093
Ethiopia Cushitic 0.095
Tanzania Iraqw 0.111
West Central Africa Fulani 0.114
Kenya Niger-Kordofanian 0.133
Ethiopia Nilo-Saharan 0.156
Kenya Afroasiatic 0.162
West Central Africa Niger-Kordofanian 0.214
Kenya Nilo-Saharan 0.225
Kenya Luo 0.250
Central Africa Niger-Kordofanian 0.329
Tanzania Hadza 0.333
Central Africa Bulala 0.361
Central Africa Nilo-Saharan 0.367
West Central Africa Afroasiatic 0.462
West Central Africa Nilo-Saharan 0.500

As you can see T is fixed outside of Africa, and varies across many African populations  Previous work implied this, though coverage within Africa was not good. One thing to observe though is that the frequency of A within Africa can not be explained by recent Eurasian admixture. The frequency is way too high for that to be the sole explanation, and in any case there is no evidence that ~33% of the Hadza’s ancestry is of Eurasian provenance (the Hadza being one of the three major groups of African hunter-gatherers, along with the Bushmen and Pygmies).

Within the paper the authors resequenced ~1,000 base pairs across diverse African populations in an exonic region of this gene (the stuff that codes for amino acids). What they discovered is that of the SNPs segregating, 516 in particular was critical toward effecting phenotyping change. Not only did individuals with the T variant notably exhibit stronger bitter sensitivity, but in vitro expression with a reporter was elevated. Because they had such a dense genomic region they could perform various nucleotide based tests to detect natural selection, and, attempt coalescent models to infer genealogical history.

I’m going to spare you some of the gory details at this point. Here’s what they found. First, it does look like the region is under natural selection in many African populations, in particular, the derived haplotype with T at 516 at the center. But this result is not reproduced across all tests. The coalescent simulations make clear why: the mutation is an old variant with deep roots in the hominin lineage. In other words this variation pre-dates H. sapiens. It looks like the T allele has rapidly increased in frequency relatively recently, though more on the order of ~50,000 years, rather than ~10,000.* Basically around the time of the “Out of Africa” event. Additionally, there’s a tell-tale sign that this is being subject to selection within Africa: the genetic differences across populations at TAS2R16 far exceed the genome-wide values (the Fst at this locus is in the top 1% of loci within the African genome). Finally, one should note that the G allele haplotypes seem to be much more strongly constrained, as if they’re under purifying selection. This means that the switch to T is not all gain.

At this point you may be ready for a story about how some African populations, like Eurasians, underwent a lifestyle change, and diet changes resulted in a shift in sensory perception. That does not seem to be the story. Rather, the authors did not seem to be able to agree upon a neat explanation for what is driving these recent sweeps up from ancient standing genetic variation. They do observe that the variation does tend to cluster geographically, more so than the genome-wide results would imply. There’s likely some adaptation going on, they simply don’t know what. In the introduction and elsewhere you can see that variation at TAS2R16 does correlate with other traits. Not too surprising due to the relatively ubiquity of pleiotropy; one gene with many effects.

Stepping outside of the implications of this specific result, let’s think about what might be a takeaway: something as essential as taste perception might be a side effect of other aspects of evolutionary processes. In other words, we don’t know what the phenotypic target of selection is in this case, but we do have a good handle one of the major side effects, which is sensory perception. How one taste seems like a big deal.** Andthere have been many theories propounded that variation in bitter sensitivity is due to adaptation to poisonous plants and such, but really no one knew, and that was just the most plausible of low hanging fruit. With these results from Africa, where there is more variation in the trait and genes, and good geographic coverage, that seems to be an implausible model to adhere to (one would think the hunter-gatherer Hadza would exhibit the most sensitivity, no?). Many of the traits and tendencies which we humans see as fundamental, essential, and of great import, many actually be side effects of powerful evolutionary forces hammering at the genetic-correlation matrices which define the hidden network of co-dependencies within the genome. So there, I said it. Life is an accident. Enjoy it.

Citation: Campbell, Michael C., et al. “Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa.” Molecular biology and evolution (2013): mst211.

* If it was closer to ~10,000 I think haplotype based tests would come back with something, but they do not.

** Some Epicureans might be accused of reducing the good to taste!

The post The color of life as a coincidence appeared first on Gene Expression.

The color of life as a coincidence

Filed under: Anthroplogy,Evolution,Evolutionary Genetics,Genetics of taste,Taste — Razib Khan @ 12:35 am

Credit: Eric Hunt

Credit: Eric Hunt

I do love me some sprouts! Greens, bitters, strong flavors of all sorts. I’ve always been like this. Some of this is surely environment. My family comes from a part of South Asia known for its love of bracing and bold sensation. But perhaps I was born this way? There’s a fair amount of evidence that taste has a substantial genetic component. This does not mean genes determine what one tastes, but it certainly opens the door for passive gene-environment correlations. If you do not find a flavor offensive, you are much more likely to explore it depths, and cultivate your palette.

220px-Durio_kutej_F_070203_ime

Dost thou dare?
Credit: W.A. Djatmiko

And of course I’m not the only one with a deep interest in such questions. With the marginal income available to us many Americans have become “foodies,” searching for flavor bursts and novelties which their ancestors might never have been able to comprehend. More deeply in a philosophical sense the question of qualia reemerges if there is a predictable degree of inter-subjectivity in taste perception (OK, qualia is always there, though scientific sorts tend to view it as intractable in a fundamental sense).


But there’s heritability, and then there’s genes. We know that perception in some ways is heritable, but what is perhaps more interesting is if you can peg a specific genomic location to it. Then the evolutionary story becomes all the richer. And so it is with the locus TAS2R16, where a nonsynonymous mutation at location 516 seems to result in heightened sensitivity to bitter tastes. More specifically, it’s rs846664, and the derived T allele is fixed outside of Africa, while the ancestral G allele still segregates at appreciable fractions within African populations. A new paper in Molecular Biology and Evolution puts this locus under a microscope, though it does not come up with any clear conclusions. Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa presents some interesting findings. First, let’s look at the distribution of the variation in their sample populations at the SNP of most particular interest:

Region Population T516G
Outside of Africa Non-Africans 0.000
Ethiopia Semitic 0.059
Tanzania Sandawe 0.083
Ethiopia Omotic 0.093
Ethiopia Cushitic 0.095
Tanzania Iraqw 0.111
West Central Africa Fulani 0.114
Kenya Niger-Kordofanian 0.133
Ethiopia Nilo-Saharan 0.156
Kenya Afroasiatic 0.162
West Central Africa Niger-Kordofanian 0.214
Kenya Nilo-Saharan 0.225
Kenya Luo 0.250
Central Africa Niger-Kordofanian 0.329
Tanzania Hadza 0.333
Central Africa Bulala 0.361
Central Africa Nilo-Saharan 0.367
West Central Africa Afroasiatic 0.462
West Central Africa Nilo-Saharan 0.500

As you can see T is fixed outside of Africa, and varies across many African populations  Previous work implied this, though coverage within Africa was not good. One thing to observe though is that the frequency of A within Africa can not be explained by recent Eurasian admixture. The frequency is way too high for that to be the sole explanation, and in any case there is no evidence that ~33% of the Hadza’s ancestry is of Eurasian provenance (the Hadza being one of the three major groups of African hunter-gatherers, along with the Bushmen and Pygmies).

Within the paper the authors resequenced ~1,000 base pairs across diverse African populations in an exonic region of this gene (the stuff that codes for amino acids). What they discovered is that of the SNPs segregating, 516 in particular was critical toward effecting phenotyping change. Not only did individuals with the T variant notably exhibit stronger bitter sensitivity, but in vitro expression with a reporter was elevated. Because they had such a dense genomic region they could perform various nucleotide based tests to detect natural selection, and, attempt coalescent models to infer genealogical history.

I’m going to spare you some of the gory details at this point. Here’s what they found. First, it does look like the region is under natural selection in many African populations, in particular, the derived haplotype with T at 516 at the center. But this result is not reproduced across all tests. The coalescent simulations make clear why: the mutation is an old variant with deep roots in the hominin lineage. In other words this variation pre-dates H. sapiens. It looks like the T allele has rapidly increased in frequency relatively recently, though more on the order of ~50,000 years, rather than ~10,000.* Basically around the time of the “Out of Africa” event. Additionally, there’s a tell-tale sign that this is being subject to selection within Africa: the genetic differences across populations at TAS2R16 far exceed the genome-wide values (the Fst at this locus is in the top 1% of loci within the African genome). Finally, one should note that the G allele haplotypes seem to be much more strongly constrained, as if they’re under purifying selection. This means that the switch to T is not all gain.

At this point you may be ready for a story about how some African populations, like Eurasians, underwent a lifestyle change, and diet changes resulted in a shift in sensory perception. That does not seem to be the story. Rather, the authors did not seem to be able to agree upon a neat explanation for what is driving these recent sweeps up from ancient standing genetic variation. They do observe that the variation does tend to cluster geographically, more so than the genome-wide results would imply. There’s likely some adaptation going on, they simply don’t know what. In the introduction and elsewhere you can see that variation at TAS2R16 does correlate with other traits. Not too surprising due to the relatively ubiquity of pleiotropy; one gene with many effects.

Stepping outside of the implications of this specific result, let’s think about what might be a takeaway: something as essential as taste perception might be a side effect of other aspects of evolutionary processes. In other words, we don’t know what the phenotypic target of selection is in this case, but we do have a good handle one of the major side effects, which is sensory perception. How one taste seems like a big deal.** Andthere have been many theories propounded that variation in bitter sensitivity is due to adaptation to poisonous plants and such, but really no one knew, and that was just the most plausible of low hanging fruit. With these results from Africa, where there is more variation in the trait and genes, and good geographic coverage, that seems to be an implausible model to adhere to (one would think the hunter-gatherer Hadza would exhibit the most sensitivity, no?). Many of the traits and tendencies which we humans see as fundamental, essential, and of great import, many actually be side effects of powerful evolutionary forces hammering at the genetic-correlation matrices which define the hidden network of co-dependencies within the genome. So there, I said it. Life is an accident. Enjoy it.

Citation: Campbell, Michael C., et al. “Origin and Differential Selection of Allelic Variation at TAS2R16 Associated with Salicin Bitter Taste Sensitivity in Africa.” Molecular biology and evolution (2013): mst211.

* If it was closer to ~10,000 I think haplotype based tests would come back with something, but they do not.

** Some Epicureans might be accused of reducing the good to taste!

The post The color of life as a coincidence appeared first on Gene Expression.

November 12, 2013

Is that white supremacist part black?

Filed under: Craig Cobb,race — Razib Khan @ 9:45 am

Goebbels, Nordic superman! Credit: Bundesarchiv, Bild

Goebbels, Nordic superman! 
Credit:, Bundesarchiv, Bild

Many of you probably know about Dave Chappelle’s black white supremacist sketch (NSFW video!), though fewer are aware of Leo Felton, a white supremacist (ex, after he was outed) with a black father (a less tragic outcome than Dan Burros, the Jewish American Nazi). I know, these sound like they’re out of South Park episodes, though the last two are actually not fictional. But now the media is exploding with news that a DNA test has suggested that a notorious white supremacist is 14 percent black. The same one who was recently profiled in The New York Times promoting a separatist racial vision in a small North Dakota town. I’ll be honest and admit that I don’t think that these results will hold up. (though personally I would think it was rich and very funny if they did, just like everyone else).

Credit: ScottH

Credit: ScottH

The reason is the chart to the left. It’s from 23andMe‘s data set. Out of their ~100,000 white American individuals tested, ~5% have any evidence of African ancestry. Of those, you see the distribution of results. If Craig Cobb, the white supremacist, is ~14% Sub-Saharan African, he’s in the less than 0.1% of white Americans with this sort of pattern. If he was a Latin American white, or a identified white person of Arab ancestry, I’d be willing to accept the results as plausible on the face of it. But the reality is that European Americans with relatively well documented histories usually do not have a high probability of having African ancestry. And if they do, 14% is a great deal. I have seen this among my friends (or more honestly, 5-10%, which is not far off), but that was due to a cryptic (though somewhat known within the family) non-paternity event.

The media isn’t consistent about which firm tested Craig Cobb, so I’m not going to make accusations specifically, but he says he’s getting other tests done, and he’ll release the results. I’ll be curious to see the raw results. To me this is reminiscent of the constant Facebook shares I get from the Daily Currant from friends who confuse satire for reality because of their biases (not to say those biases are unfounded or not). Just because the story is awesome does not mean we should set skepticism to the side, and not evaluate the probability of alternative outcomes, given what we know prior.

Related: Has anyone followed up the old story that James Watson was part black? The timing was a little suspicious to me.

The post Is that white supremacist part black? appeared first on Gene Expression.

Is that white supremacist part black?

Filed under: Craig Cobb,race — Razib Khan @ 9:45 am

Goebbels, Nordic superman! Credit: Bundesarchiv, Bild

Goebbels, Nordic superman! 
Credit:, Bundesarchiv, Bild

Many of you probably know about Dave Chappelle’s black white supremacist sketch (NSFW video!), though fewer are aware of Leo Felton, a white supremacist (ex, after he was outed) with a black father (a less tragic outcome than Dan Burros, the Jewish American Nazi). I know, these sound like they’re out of South Park episodes, though the last two are actually not fictional. But now the media is exploding with news that a DNA test has suggested that a notorious white supremacist is 14 percent black. The same one who was recently profiled in The New York Times promoting a separatist racial vision in a small North Dakota town. I’ll be honest and admit that I don’t think that these results will hold up. (though personally I would think it was rich and very funny if they did, just like everyone else).

Credit: ScottH

Credit: ScottH

The reason is the chart to the left. It’s from 23andMe‘s data set. Out of their ~100,000 white American individuals tested, ~5% have any evidence of African ancestry. Of those, you see the distribution of results. If Craig Cobb, the white supremacist, is ~14% Sub-Saharan African, he’s in the less than 0.1% of white Americans with this sort of pattern. If he was a Latin American white, or a identified white person of Arab ancestry, I’d be willing to accept the results as plausible on the face of it. But the reality is that European Americans with relatively well documented histories usually do not have a high probability of having African ancestry. And if they do, 14% is a great deal. I have seen this among my friends (or more honestly, 5-10%, which is not far off), but that was due to a cryptic (though somewhat known within the family) non-paternity event.

The media isn’t consistent about which firm tested Craig Cobb, so I’m not going to make accusations specifically, but he says he’s getting other tests done, and he’ll release the results. I’ll be curious to see the raw results. To me this is reminiscent of the constant Facebook shares I get from the Daily Currant from friends who confuse satire for reality because of their biases (not to say those biases are unfounded or not). Just because the story is awesome does not mean we should set skepticism to the side, and not evaluate the probability of alternative outcomes, given what we know prior.

Related: Has anyone followed up the old story that James Watson was part black? The timing was a little suspicious to me.

The post Is that white supremacist part black? appeared first on Gene Expression.

Isn’t he special!

Filed under: Ecological genetics,Guppies — Razib Khan @ 3:50 am

Credit: Marrabbio2

Credit: Marrabbio2

There’s a nice letter in Nature right now with an understated title, Mating advantage for rare males in wild guppy populations. But if you dig deeper you see some moderately grand claims being made. The key issue is that the authors seem to be implying that negative frequency dependent selection (NFDS) is a major factor in maintaining genetic diversity in populations. A reductio ad absurdum of the problem might be to ask why a superior and ideally fit morph does not dominate the whole planet? A more elaborated question lay at the heart of Charles Darwin’s The Origin of Species. Fundamentally: why diversity? There have been many answers posited (e.g., see W. D. Hamilton’s ideas in regards to sex, Narrow Roads of Gene Land). We needn’t try to tackle the whole problem here, no matter what needs to be written in grant applications. Guppies are sufficient and interesting in and of themselves.


Hughes, Kimberly A., et al. "Mating advantage for rare males in wild guppy populations." Nature 503.7474 (2013): 108-110.

Hughes, Kimberly A., et al. “Mating advantage for rare males in wild guppy populations.” Nature 503.7474 (2013): 108-110. Legend: a, Number of mates and offspring assigned to common (white, n = 124) or rare (dark grey, n = 42) males. Centre values are marginal means from the full generalized linear mixed model; bars indicate s.e.m. adjusted for model covariance parameters. **P < 0.005 and *P = 0.01, respectively; see Extended Data Table 1. b, c, Association between square-root orange area and reproductive success in Quare River 7 (solid line, n = 34), Quare River 1 (dashed line, n = 72) and Mausica River (dotted line, n = 60), predicted from the full model. b, Predicted mates. c, Predicted offspring; see Extended Data Table 2. Minimum and maximum values along abcissa indicate range of values recorded.

This particular paper is not a lark. Believe or not there is a large body of behavioral ecological research on guppies. I highly recommend Lee Alan Dugatkin’s The Imitation Factor: Evolution Beyond The Gene, and dare you to not be convinced that guppies (and other animals) can’t give very general insights. So what’s NFDS? Basically it’s the opposite of the Matthew effect; the poor (rare) get rich (frequent), and the rich (frequent) get poor (rare). In a co-evolutionary scenario with pathogens the logic is simple. Imagine an allele, a, which confers resistance to a pathogen in a fixed state, P. Eventually the allele frequency will begin to rise. At this point the pathogen will begin to adapt. New variants among the pathogens will be favored, and the resistence overcome. At this stage a will no longer be quite so favored. The ancestral allele, A, may be favored again. And so on. A complex dance will naturally occur as alleles swing about the equilibria in a series of oscillations contingent upon other factors.

What the authors above showed is that rare color phenotype seems to be favored by females among guppies. They established these results by manipulating natural populations, and perturbing phenotype proportions. The problem is that in natural populations the phenotypic frequencies will be near equilibrium, and so the advantage accrued to the rare males will be diminished…because very few are truly rare. The advantage to the males in these experiments (two-fold) was very convincing to me. They might not be natural conditions, but they illustrate the underlying power of the dynamic of rare male advantage. And there are many researchers who don’t believe that this phenomenon of phenotypic diversification is limited to just guppies. It may apply to humans.

But obviously there are many unanswered questions. Some types of rarity are selected against because they are repulsive. We know this intuitively. So the parameter space of morphological diversity is constrained. A sort of unity in the diversity. And the authors here have no overpowering rationale for why rarity might be favored. They say:

Despite strong evidence for the rare-male effect in guppies, the evolutionary processes that account for its prevalence are not known. Mate preference for males with unusual colouration might have evolved as a mechanism for inbreeding avoidance, as a consequence of generalized neophilia, or because females avoid remating with previous mates and also reject males with colouration similar to that of previous mates. It has been previously proposed that a survival advantage to rare morphs, as demonstrated in ref. 8, could also drive the evolution of mate preference for rare phenotypes, even though rarity itself is not heritable.

And yet I have confidence the answers will come some day. Once the general framework is in place the machinery of science and publication will begin to start moving….

Citation: Hughes, Kimberly A., et al. “Mating advantage for rare males in wild guppy populations.” Nature 503.7474 (2013): 108-110.

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bioRxiv is here

Filed under: bioRxiv,science — Razib Khan @ 1:45 am

bioRxivFor years many in the biological sciences community have been jealous of the exist of arXiv. This preprint server allows researchers to distribute their work widely to all comers. On occasion when when there have been debates about mimicking arXiv for biology there has been skepticism about the nature of the outcomes (my own rejoinder is that fields where a preprint culture is the norm, such as economics and physics, don’t seem to be doing badly). Now we’ll see if the end is nigh in biological science due to preprints; bioRxiv is live (sponsored by CSHL). The first paper, The Population Genetic Signature of Polygenic Local Adaptation. There’s not much up yet, but there will be.

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Vaccination, and social information networks

Filed under: Medicine,public health,Vaccination — Razib Khan @ 1:34 am

Preventable

If you have not read Julia Ioffe’s story about getting whooping cough at the age of 31 (also see follow up), you might want to. Here’s some further context, Vaccine Refusals Fueled California’s Whooping Cough Epidemic. This topic has been covered and dissected in great detail by many writers and scientists, so I won’t repeat what you already know in regards to herd immunity. There’s no point in preaching to the choir.


Rather, I want to offer a personal perspective. Over the past few years I’ve become much more aware of cultural streams in public health, and the public’s reaction to that health advice, because I have become a father. More specifically, when my wife was pregnant with my daughter, and after she was born, we encountered major pressure from peer networks to not vaccinate. In the social circles in which we were embedded, “progressive,” “crunchy,” and “alternative,” vaccinating one’s child was the heterodox decision. It was rather obvious to us that one of the major reasons that many people do not vaccinate their children is that many of their friends, and vocal people whom they trust, do not vaccinate their children. We were able to resist and rebuff any peer pressure rather easily because we have a much stronger scientific background than most Americans, but it isn’t hard to imagine being ignorant and trusting those in whom you normally put your trust.

In some ways I am not totally unsympathetic to the skepticism that some in the public have toward the medical establishment. Modern scientific medicine is a genuine miracle, but most of its gains arguably occurred in the first half of the 20th century through public health campaigns, vaccination and antiobiotics. Though the decline in heart disease is a major result which we should celebrate, it is arguably less significant than the sharp reduction in deaths of the young due to numerous infections (heart disease tends to effect the old). Additionally, diseases such as cancer are subject to the problem of what Jim Manzi terms “high causal density”. Cancers, like many diseases of late life, can have many triggers and factors impacting their likelihood, so solving the problem at the root may not be so simple. In reaction to this complexity and uncertainty I do believe that on occasion the medical profession and the public health establishment have unduly emphasized their certainty.

Like the reality that the variegated public health concerns we have today, such as type 2 diabetes and cancer, are probably better problems than endemic smallpox, tuberculosis, or scarlet fever, the downsides of having a medical establishment which on occasion oversteps the bounds of its reasonable confidence are overridden by the upsides. We have empirical evidence of this, because there are nations without medical establishments, and they are not flourishing. But that does not change the reality that a population shielded from the brutal knife of infectious disease and plague is somewhat befuddled by the mysteries of the slow and subtle ailments which are the afflictions of modernity.

One response is the liberal individualist one. Though we may bemoan Steve Jobs’ experimentation with alternative therapies for his cancer, it was his individual choice. It gets more complicated what you have children, who are under the control of their parents. Again, I’m not going to go over the controversies over groups like Christian Scientists, whose children have died due to withholding medical treatment. The cultural consensus seems to be that parents have a right to impose all sorts of crazy beliefs and practices upon their children, but not those which may result in death. Then you move to the issue that when it comes to vaccination one can’t seal off individual choice from consequences to the public. It seems entirely likely that for the next decade we may be seeing a conflagration of preventable diseases among certain segments of the American demographic, and those who they live among, because of cultural fashion. The collective choices of parents opting out from vaccination is subject to negative feedback dynamics. Early dissenters can “free-ride” on herd immunity, and indulge their quackery, but beyond a particular threshold disease and death will come back to the fore. But human beliefs are often rather well insulated against falsification for a great deal of time. The AIDS denialst community is a testament to this phenomenon; it persists despite mysteriously (to them) high mortality rates among its most vocal proponents.

So is there a solution? Conscience is a value which Americans pride, even unto death. I do not see the powers that be intervening in these cases. Rather, this groundswell of denialism must be countered by public opprobrium, and yes, shaming. Peer pressure kills, but it can also save lives. As a matter of safety people with small children should investigate rates of vaccination in their community (young infants are not vaccinated, and so are particularly vulnerable to infections which are dampened by herd immunity). They should move when a dangerous critical mass is present. If people ask, those who leave should explain their rationale. Actions can speak louder than words. Where Authorité falls on deaf ears, the judgment of the populace might be heeded.

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November 10, 2013

Open Thread, 11/10/2013

Filed under: Administration,Open Thread — Razib Khan @ 11:35 am

Change is the only constant.

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November 8, 2013

Selection happens; but where, when, and why?

Filed under: Anthroplogy,Genetics,Genomics,Pigmentation — Razib Khan @ 1:49 am
Distribution of SLC452 variation at SNP rs1426654. Credit, HGDP Browser

Distribution of SLC452 variation at SNP rs1426654. Credit, HGDP Browser

Nina Davuluri, Miss America 2014, Credit: Andy Jones

Nina Davuluri, Miss America 2014, Credit: Andy Jones

One of the secondary issues which cropped up with Nina Davuluri winning Miss America is that it seems implausible that someone with her complexion would be able to win any Indian beauty contest. A quick skim of Google images “Miss India” will make clear the reality that I’m alluding to. The Indian beauty ideal, especially for females, is skewed to the lighter end of the complexion distribution of native South Asians. Nina Davuluri herself is not particularly dark skinned if you compared her to the average South Asian; in fact she is likely at the median. But it would be surprising to see a woman who looks like her held up as conventionally beautiful in the mainstream Indian media. When I’ve pointed this peculiar aspect out to Indians* some of them of will submit that there are dark skinned female celebrities, but when I look up the actresses in question they are invariably not very dark skinned, though perhaps by comparison to what is the norm in that industry they may be. But whatever the cultural reality is, the fraught relationship of color variation to aesthetic variation prompts us to ask, why are South Asians so diverse in their complexions in the first place? A new paper in PLoS Genetics, The Light Skin Allele of SLC24A5 in South Asians and Europeans Shares Identity by Descent, explores this genetic question in depth.

Much of the low hanging fruit in this area was picked years ago. A few large effect genetic variants which are known to be polymorphic across many populations in Western Eurasia segregate within South Asian populations. What this means in plainer language is that a few genes which cause major changes in phenotype are floating around in alternative flavors even within families among people of Indian subcontinental origin. Ergo, you can see huge differences between full siblings in complexion (African Americans, as an admixed population, are analogous). While loss of pigmentation in eastern and western Eurasia seems to be a case of convergent evolution (different mutations in overlapping sets of genes), the H. sapiens sapiens ancestral condition of darker skin is well conserved from Melanesia to Africa.


So what’s the angle on this paper you may ask? Two things. The first is that it has excellent coverage of South Asian populations. This matters because to understand variation in complexion you should probably look at populations which vary a great deal. Much of the previous work has focused on populations at the extremes of the human distribution, Africans and Europeans. There are obvious limitations using this approach. If you are looking at variant traits, then focusing on populations where the full range of variation is expressed can be useful. Second, this paper digs deeply into the subtle evolutionary and phylogenomic questions which are posed by the diversification of human pigmentation. It is often said that race is often skin deep, as if to dismiss the importance of human biological variation. But skin is a rather big deal. It’s our biggest organ, and the pigmentation loci do seem to be rather peculiar.

You probably know that on the order of ~20% of genetic variation is partitioned between continent populations (races). But this is not the case at all genes. And pigmentation ones tend to be particular notable exceptions to the rule. In late 2005 a paper was published which arguably ushered in the era of modern pigmentation genomics, SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. The authors found that one nonsynonomous mutation was responsible for on the order of 25 to 33% of the variation in skin color difference between Africans and Europeans. And, the allele frequency was nearly disjoint across the two populations, and between Europeans and East Asians. When comparing Europeans to Africans and East Asians almost all the variation was partitioned across the populations, with very little within them. The derived SNP, which differs from the ancestral state, is found at ~100% frequency in Europeans, and ~0% in Africans and East Asians. It is often stated (you can Google it!) that this variant is the second most ancestrally informative allele in the human genome in relation to Europeans vs. Africans.

SLC24A5 was just the beginning. SLC45A2, TYR, OCA2, and KITLG are just some of the numerous alphabet soup of loci which has come to be understood to affect normal human variation in pigmentation. Despite the relatively large roll call of pigmentation genes one can safely say that between any two reasonably distinct geographic populations ~90 percent of the between population variation in the trait is going to be due to ~10 genes. Often there is a power law distribution as well. The first few genes of large effect are over 50% of the variance, while subsequent loci are progressively less important.

So how does this work to push the overall results forward?

- With their population coverage the authors confirm that SLC24A5 seems to be polymorphic in all Indo-European and Dravidian speaking populations in the subcontinent. The frequency of the derived variant ranges from ~90% in the Northwest, and ~80% in Brahmin populations all over the subcontinent, to ~10-20% in some tribal groups.

- Though there is a north-south gradient, it is modest, with a correlation of ~0.25. There is a much stronger correlation with longtitude, but I’m rather sure that this is an artifact of their low sampling of Indo-European populations in the eastern Gangetic plain. As hinted in the piece the correlation with longitude has to do with the fact that Tibetan and Burman populations in these fringe regions tend to lack the West Eurasian allele.

- Using haplotype based tests of natural selection the authors infer that the frequency of this allele has been driven up positively in north, but not south, India. It could be that the authors lack power to detect selection in the south because of lower frequency of the derived allele. And, I did wonder if selection in the north was simply an echo of what occurred in West Eurasia. But if you look at the frequency of the A allele in the north most of the populations seem to have a higher frequency of the derived variant than they do of inferred “Ancestral North Indian”.

What’s perhaps more interesting is the bigger picture of human evolutionary dynamics and phylogenetics that these results illuminate. Resequencing the region around SLC24A5 these researchers confirmed it does look like the derived variant is identical by descent in all populations across Western Eurasia and into South Asia. What this means is that this mutation arose in someone at some point around the Last Glacial Maximum, after West Eurasians separated from East Eurasians. The authors gives some numbers using some standard phylogenetic techniques, but admit that it is ancient DNA that will give true clarity on the deeper questions. When I see something written like that my hunch, and hope, is that more papers are coming soon.

When I first read The Light Skin Allele of SLC24A5 in South Asians and Europeans Shares Identity by Descent, I thought that it was essential to read Ancient DNA Links Native Americans With Europe and Efficient moment-based inference of admixture parameters and sources of gene flow. The reason goes back to the plot which I generated at the top of this post: notice that Native Americans do not carry the West Eurasian variant of SLC24A5. What the find of the ~24,000 Siberian boy, and his ancient DNA, suggest is that there was a population with affinities closer to West Eurasians than East Eurasians that contributed to the ancestry of Native Americans. The lack of the European variant of SLC24A5 in Native Americans suggests to me that the sweep had not begun, or, that the European variant was disfavored. What the other paper reports is that on the order of 20-40% of the ancestry of Europeans may be derived from an ancient North Eurasian population, unrelated to West Eurasians (or at least not closely related). It is likely that this population has something to do with the Siberian boy. Since Europeans are fixed for the derived variant of SLC24A5, that implies to me that sweep must have occurred after 24,000 years ago.

journal.pgen.1003912.g002At this point I have to admit that I believe need to be careful calling this a “European variant.” Just because it is nearly fixed in Europe, does not imply that the variant arose in Europe. If you look at the frequency of the derived variant you see it is rather high in the northern Middle East. Looking at some of the populations in the Middle Eastern panel the ancestral variant might be all explained by admixture in historical time from Africa. If the sweep began during the last Ice Age, then most of Europe would have been uninhabited. The modern distribution is informative, but it surely does not tell the whole story.

Where we are is that SLC24A5 , and pigmentation as a whole, is coming to be genomically characterized fully. We don’t know the whole story of why light skin was selected so strongly. And we don’t quite know where the selection began, and when it began. But through gradually filling in pieces of the puzzle we may come to grips with this adaptively significant trait in the nearly future.

Citation: Basu Mallick C, Iliescu FM, Möls M, Hill S, Tamang R, et al. (2013) The Light Skin Allele of SLC24A5 in South Asians and Europeans Shares Identity by Descent. PLoS Genet 9(11): e1003912. doi:10.1371/journal.pgen.1003912

* From my personal experience American born Indians often do not share the same prejudices and biases, partly because subtle shades of brown which are relevant in the Indian context seem ludicrous in the United States.

The post Selection happens; but where, when, and why? appeared first on Gene Expression.

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