Size (sample) matters more than coverage


We live in an age where it’s almost anachronistic to talk about “-omics.” When a technology becomes seamless in our day to day life it becomes unworthy of notice. That being said we’re still in the phase of genomics where a lot of the details of “best practices” are being hashed out (the proliferation of “pipelines” for relatively pedestrian tasks makes that clear). Recently I stumbled upon two papers which I thought would be useful to give a little more coverage to, Population genomics based on low coverage sequencing: how low should we go? and Assessing the Effect of Sequencing Depth and Sample Size in Population Genetics Inferences. At issue here is coverage versus sample size. By coverage I mean the expected number of reads that will hit a nucleotide. If you have 100× you’ll expect to get 100 hits on a base, and if you have 1× you’re only getting one hit. Because of variation lots of positions are going to be above or below your expected coverage. Why this matters on the most prosaic level is that there is going to error in the results you get back from sequencing, and if you have many hits on the same position you can distinguish true from false polymorphism. For many projects people today seem to prefer on the order of 30×.

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Please update links/bookmarks to my new location

Just a request to readers who have blogs: please update your links to this new website ( I’ve noticed that there are very few referrals to other websites coming in right now, though plenty of people are coming in via my Twitter account. Also, if you subscribe via RSS please point to That’s the easiest way to get all my content. Thanks.

Russia as the Occident’s Orient

Discussion about foreign policy reminds me a lot of the sports pages: lots of opinion, little resolution or depth. That’s one reason I’m more respectful of normative frameworks for decision making in international relations than I used to be. Almost no one seems to know anything, so what’s the point in being pragmatic and informed? It’s amusing to poke fun at neoconservatives who don’t know what Kurds are, but American liberal internationalists are just as pathetic when they’re befuddled at how the Arab Spring turned out so illiberally, or why gay rights is not a major priority in post-Maidan Ukraine. Many foreign policy positions seem to arise out of projections of oneself in others.

The American ignorance of the true texture of reality in foreign policy is front and center whenever I read attempts at analysis in The New York Times.  A few years ago David Kirkpatrick, their Middle East correspondent, wrote a piece titled Hopes for a Qaddafi Exit, and Worries of What Comes Next. It wasn’t first person reportage, something Kirkpatrick can do with reasonable skill, as far as I can tell. Rather, it attempted to draw upon a superficial understanding of Middle Eastern history and ethnography, to tragicomic effect. For example, he stated “Even one religious leader associated with Sufism — a traditionally pacifist sect something like the Islamic equivalent of the Quakers.” This is totally inaccurate as a description of Sufism. The Naqshbandi order, to name one prominent Sufi sect, has been involved in political, social, and military affairs, across the Islamic world for hundreds of years. More relevantly in that specific case Libyan anti-colonial nationalism was in large part drawn from militarization of a Sufi order!

9780521450119.OL.0.mNow that Ukraine and the revived rivalry between Russia and the United States have come to the fore we’re treated to a similar level of analysis from the usual suspects, the American media and their associated pseudo-intelligentsia. To truly understand the dynamics of the issue at hand we need to actually look at it from the perspective of the players, and not just our own. To do this as an outsider history by necessity is important, because what the players may take as implicit givens, unstated and perhaps not accessible reflectively, we must comprehend rationally. The history lived by others is often part of the substrata of their culture. There are many things about race relations in the United States which are understood and taken for granted, but seem confusing and mystifying to outsiders. As part of my own personal attempt to understand what’s going on I’m reading some Russian history, something I’ve neglected over the years. At the center of the current debate is Ukraine, but to understand Ukraine one must understand the history of Poland-Lithuania and Russia. To Americans Lithuania is a small country on the shores of the Baltic, but during the late medieval period it was the core of a multi-ethnic and multi-religious polity, which eventually fused in personal union with the monarchy of Poland. Though Poland and Russia are the early modern antipodes of the cultural axis which divides the West Slav from the East Slav, I have found it useful to explore the history of the Lithuanians, because it can shed light from a different perspective outside of the one dominant dimension. Lithuania Ascending: A Pagan Empire within East-Central Europe details in passing just how much by the late medieval period Russia as we understand it had diverged in its self-conception, and the perception of others, from being a normal part of European Christendom (e.g., Orthodox Christians were little better than pagans to many Western Catholic Christians). Ultimately Lithuania’s choice was toward the West, but this was not foreordained.

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Open Thread, 3/27/2014


There’s been lots of talk about “Ancient North Eurasians” (ANE) and “Basal Eurasians” (BEu) on this weblog recently. Both are examples of what David Reich calls “Ghost Populations,” they contributed to the ancestry of moderns, but they no longer exist as distinct exemplars from which we can draw judgments (“Ancestral South Indians,” ASI, are another case of this). But one does wonder what they might have looked like. God knows that human populations can change in physical appearance rapidly, but submitted for your approval, the late Sardinian actress Pier Angeli, and Sioux chief Red Cloud. I chose these individuals because it seems likely that these two populations have the highest fractions today of BEu and ANE respectively. And through a random conversation with a friend I realized that Native American peoples had distinctive noses in comparison to other East Asians, often, if not always, high and aquiline. Perhaps this is the mark of the ANE?

Biology and the preprint revolution

Over the past decade now there has been a shift away from “gated” model of scientific publication. One of the models has been to imitate what fields such as physics, computer science, and economics, have been doing for a while now, and focus on preprints. See Joe Pickrell’s posts Genomes Unzipped for the general argument, and Haldane’s Sieve as a model of how it might play out. Hopi Hoekstra pointed me to a trend on bioRxiv on who is putting up preprints:

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Plows of the gods

How Europeans became Europeans is a big question, in large part because Europeans (i.e., “whites”) are still what an ideology in disrepute would term the herrenvolk of the world. But this reality, the truth of which sows discord in any discourse, does not need to negate the fact that the question itself is of interest, and today is eminently answerable. Europe has a long history of archaeology and its climate is mild-to-frigid in a manner which might aid in preservation of subfossils. For decades archaeologists have debated whether the ancestors of modern Europeans were farmers or hunters. It seems quite likely that the real answer is both, and, it’s complicated.

But the Gordian knot of history’s inscrutable veil is now be shredded by Thor’s hammer of Truth. More literally Pontus Skoglund has another paper out in in Science (how many times will I type that?), Genomic Diversity and Admixture Differs for Stone-Age Scandinavian Foragers and Farmers. If you don’t have academic access, the supplements are quite rich.

ancientDNAThe panel to the left shows the where and when of the samples. The key is that some of these are farmers and some of these are hunter-gatherers (as inferred by their cultural association). They’ve been examined before with more primitive techniques, but this latest paper ups the ante, even granting genomic coverage as relatively modest by current standards. The authors reiterated that there was a massive genetic difference between the first farmers who arrived in Sweden ~5,000 years ago, and a native hunter-gatherer tradition. The Fst was on the order of 0.05. To get a sense of scale the maximum Fst for modern Europeans is between Finns (a highly drifted group) and southern Italians (a highly admixed group with significant Near Eastern ancestry), at ~0.01. The Fst between modern Europeans and modern East Asians is on the order of ~0.10. In other words, two contemporaneous ancient populations in Sweden which were in near proximity for many generations had a genetic distance on the order of half the distance of Eurasia today. In fact this Fst is familiar to me. A few years ago at ASHG an Indian group had a poster which talked about the fact that coexistent South Asian groups (castes, jatis, etc.) within a region might have an Fst as incredibly high as…0.05! Obviously I’m not saying that ancient Sweden was characterized by caste, but I am asserting that genetic distinctiveness in Europe on the cusp of full agriculture within a local region probably mirrored modern India, where occupation and community identity are as informative as geography.

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The quest for a better world

David & "Tyler Durden"
David & “Tyler Durden”

Men’s Journal has an expansive story up chronicling the rise of intensive training as a necessary condition for being a leading man in Hollywood today, Building a Bigger Action Hero. But there is a qualification on the “bigger” aspect, as the beau ideal today is not the steroid inflated archetype of Stallone or Schwarzenegger, but the sleek and hungry physique cultivated by Brad Pitt in his iconic role as Tyler Durden in Fight Club. The regimen seems to involve both training to bulk up sufficiently, but perhaps even more critically burn away all the fat so that one’s definition becomes all the more salient.

In modern Hollywood this trend began with the 2007 film 300, which showcased relative unknowns whose bodies were reshaped by trainers into something that could impart the verisimilitude of being warriors born, bred, and trained from their youth as a cohesive unit. With the rise of the “comic book” movie one has seen the decline of marquee leading men, and emergence of a formula which can substitute bodies, with a minimum of charisma required from the actors. The edge then is not on acting chops, but the perfect idealized form, which serves to anchor the action sequences.

The tone of the piece seems clearly disapproving of the trend, and is in line with the thought that the flabbier bodies of leading men from decades past were somehow more respectable and honest. But that too was just a cultural trend. I can’t for example agree with this section:

Six-packs and bulky chests can look freakishly anachronistic in a prestige period picture: It’s not just that Tudor princes and Victorian lotharios didn’t have waxed chests and 12-packs – it’s that almost nobody had bodies like these until the last decades of supplements and fitness science.

If such bodies are freaks of modern science it is peculiar that Michelangelo’s David seems to resemble Brad Pitt in Fight Club. More to the point I remember being struck in 1990 in rural Bangladesh by the cut physique of a young farmer who was attending to his rice paddy. He was small and compact, but his low body fat and constant toil sculpted a form which was not anachronistic at all.

Science allows modern humans to be incredibly wealthy in terms of what we can consume in services and materials. We can make a better version of ourselves, and be the best we can be. Beauty of body and acuity of mind are within our grasp if we could shake off our sloth. Contemporary norms are such as we are told to love who we are, but that neglects the reality that who we could be is within our grasp. The extremities which drive actors to reduce their body fat to 3 percent are not necessary, and may be injurious, but we shouldn’t take from that the lesson that sculpted bodies with definition are somehow a freak artifact of modern Frankenstein science.

Neandertals on the edge of existence

Citation: Patterns of coding variation in the complete exomes of three Neandertals PNAS 2014; doi:10.1073/pnas.1405138111
Citation: Patterns of coding variation in the complete exomes of three Neandertals
PNAS 2014; doi:10.1073/pnas.1405138111

A new paper in PNAS, Patterns of coding variation in the complete exomes of three Neandertals, reiterates what seems to be an emerging fact about ancient northern Eurasian hominins: they were rather inbred. The chart above illustrates it by focusing on regions of the genome that code for proteins. The ratio of benign to deleterious for Neandertals is obviously not optimal. As noted in the paper the authors suggest that this implies small population sizes which could not purge the deleterious variants through negative selection. The operative dynamic here is that when populations are small, drift becomes very strong relative to selection, and can therefore increase frequencies of mutations which would otherwise be swept out of the genome.

And it is clear from a variety of standard population genetic metrics that these Neandertals, separated geographically by the expanse of all of Eurasia, and distinct over ~20,000 years, would be considered quite inbred if they were examined today. This is curious because it is often stated that humans, our own neo-African lineage, are a relatively homogeneous population which expanded rapidly in size recently. We haven’t had that much time to diverge, and non-Africans tend to have genomes suggestive of bottlenecks in the deep past. And yet looking at these Neandertals, as well the Denisovan individual, modern humans seem a positively genetically variegated lot in comparison. But the authors of the above paper also found something else interesting, the Neandertals were themselves very distinct from each other, more distinct in terms of between population variation than modern human lineages. The main caveat is that the individuals were separated in time by thousands of years, in additional to geography, and the authors don’t seem to have corrected for this aspect of drift (though then they’d have to have an explicit demographic model, which they may not have enough information to construct). Additionally I do wonder if pre-Holocene humans also exhibited the same pattern of high genetic distance over small regions, and that only the demographic expansions and admixtures of the past 10,000 years have produced the reduced Fst values that we take for granted as expectations.

Finally, I have to emphasize that looking at hominins on the edge of the human range on the north may not be representative of archaic lineages more broadly. It seems possible that meta-population dynamics characterized by extinctions and expansions, and very low effective population size, were much more normal on the northern fringe of marginal habitation than further south in the core of the hominin range. Imagine taking Amerindians as representative of human variation, as an analogy. Because of the preservation bias in ancient DNA we’ll always over-sample these northern locales, but we should be wary of over-generalizing.

Addendum: I didn’t say much about the functional differences, because I’m not sure that we can say much with the data sets that they had. It is suggestive that they found differences in genes related to skeletal morphology in Neandertals, but that is not surprising. The fact that modern humans may be enriched for differences and evolution in regards to pigmentation seems likely to be a bias of the fact that this area has been well studied in modern humans. Obviously there haven’t been genome-wide associations for this trait in Neandertals, since we don’t have cases and controls (to my knowledge).

Philosophy of the babes


Lately my daughter has been expressing unintentionally philosophical questions. For example, when we were discussing as a family events from the “deep past,” i.e., before her existence, she asked “Where was I?” And we don’t even need to get into questions about the nature of death, which does come up when companion animals expire.

This dovetails with another thought which has been percolating in my mind recently: is there any point to philosophy of the existential kind once you have children? Men such as Plato and St. Paul did not have a family life in a conventional sense, though Aristotle did marry, and also had a son. Does this perhaps reflect itself in the nature of the philosophies expounded by Plato and his most famous pupil? Since becoming a father I have difficulty even understanding why the nature of Being and existence bothered me at all as a younger man. Children seem to give an answer to many of the “deep” questions we might have, on an emotional if not rational, level.* This is all ironic because it seems to me that children are the ones who most naively probe the root of the gaps in our comprehension of ontology.

* It is then of note that celibacy is common in many “higher religions” for professional clerical elites.

The personal is the racist

Conservatives sometimes like to recycle this picture from the 2012 Obama headquarters as the victory results were coming in. What one can see is the surfeit of pallor, not that there’s anything wrong with that as such. Except that many Left-liberals make the Right’s lack of diversity ipso facto evidence of racial animus. But many liberal/progressive individuals also live in a rather white world. Not that this hasn’t been noted on occasion. But you still have the background assumption which motivated this notorious Chris Hayes quote:

It is undeniably the case that racist Americans are almost entirely in one political coalition and not the other.

I think the underlying model is simple. Since white conservatives are racist, broadly construed, the whiteness of their milieu adds to the confidence of the hypothesis of their racism. In contrast, since white liberals are not racist, the whiteness of their milieu is irrelevant. More precisely, the lack of diversity in some progressive segments of society is not highlighted to the same extent that it would be in conservative segments of society.

The reality is that both liberals and conservatives among whites engage in self-segregation (as do people of all races, religions, etc., more or less!). This despite a Left-Right convergence on issues such as “diversity” and anti-racism. To make this more quantitative I decided to look at the RACHOME variable in the General Social Survey. Asked between 1974 and 2006 it is as follows: “During the last few years, has anyone in your family brought a friend who was a (negro/black/African-American) home for dinner?” This is a very broad question. Here are the results plotted from ’74 to ’06:

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