Category: Human Genetics

Burning down the trees in historical population genetics

By Razib Khan | October 27, 2013 5:07 am

BurnTreephylogenetic tree is an essential tool in understanding the broad scope of natural history, placing particular lineages in specific evolutionary contexts of relatedness. These sorts of trees range from Ernst Haeckel’s classical attempt, depicting relationships which biologists derived from intuition within the framework of a grand evolutionary scheme, all the way down to modern methods implemented in software packages such as Mr. Bayes, which many frankly utilize in a “turnkey” manner. These trees are abstractions, in that they reduce down a wide range of phenomena into schematic representations which impart aspects of particular interest in a stylized form. This is important, because the actual nature of the phenomena being represented may be more complex than is being represented. A simple illustration of what I’m getting is clear when you look at the long history of phylogenetics and phylogeography utilizing mitochondrial DNA lineages (mtDNA). Because mtDNA is copious in comparison to nuclear DNA, it is easy to obtain. And, as there is no recombination and it is inherited in a haploid fashion (mother to daughter) it makes the inference of gene trees much easier. The key problem is that the genealogy of this particular sequence is used to infer aspects about population history, when they may not accurately represent the history of other regions of the genome very well. Different genes may have different histories.

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CATEGORIZED UNDER: Human Genetics
MORE ABOUT: Human Genetics

The inferred distribution of grandparental contribution

By Razib Khan | October 21, 2013 10:38 am

In my write up on variation in inheritance patterns for Slate last week I did not explore the likely quantitative distribution in any detail (frankly, I think that part is confused or muddled at best). My primary focus though was on the empirical reality of variation, which people utilizing personal genomic services will receive, perhaps to their surprise. But in part triggered by that Slate piece and follow-up discussions at Twitter with Michael Eisen, Graham Coop decided to crunch the numbers. More concretely he took the known patterns of recombination in the human genome (from a paper he co-authored, Broad-Scale Recombination Patterns Underlying Proper Disjunction in Humans), and input these values into a simulation which generated distributions of contribution from maternal and paternal grandparents, How much of your genome do you inherit from a particular grandparent?

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CATEGORIZED UNDER: Genetics, Human Genetics
MORE ABOUT: Recombination

Why white men get testicular cancer more than black men

By Razib Khan | October 17, 2013 12:49 pm

Likely an individual with derived allele on KITL locus (Credit: David Shankbone)

An individual polymorphic on the KITL locus? (Credit: David Shankbone)

Pigmentation is one of the few complex traits in the post-genomic era which has been amenable to nearly total characterization. The reason for this is clear in hindsight. As far back as the 1950s (see The Genetics of Human Populations) there were inferences made using human pedigrees which suggested that normal human variation on this trait was controlled by fewer than ten genes of large effect. In other words, it was a polygenic character, but not highly so. This means that the alleles which control the variation are going to have reasonably large response, and be well within the power of statistical genetic techniques to capture their effect.

I should be careful about being flip on this issue. As recently as the mid aughts (see Mutants) the details of this trait were not entirely understood. Today the nature of inheritance in various populations is well understood, and a substantial proportion of the evolutionary history is also known to a reasonable clarity as far as these things go. The 50,000 foot perspective is this: we lost our fur millions of years ago, and developed dark skin, and many of us lost our pigmentation after we left Africa ~50,000 years ago (in fact, it seems likely that hominins in the northern latitudes were always diverse in their pigmentation)

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Taboo genetic truths

By Razib Khan | October 3, 2013 11:59 am

Have no fear

There has been a lot of attention to Erika Check Hayden’s piece Ethics: Taboo genetics, at least judging by people commenting on my Facebook feed. In some ways this is not an incredibly empirically grounded argument, because the biological basis of complex traits is going to be rather difficult to untangle on a gene-by-gene basis. In other words, this isn’t a clear and present “concern.” The heritability of many behavioral traits has long been known. This is not revolutionary, though for cultural reasons may well educated people are totally surprised when confronted with data that many traits, such as intelligence and personality, have robust heritabilities* (the proportion of trait variation explained by variation in genes across the population). The literature reviewed in The Nurture Assumption makes clear that a surprising proportion of contribution any parents make to their offspring is through their genetic composition, and not their modeled example. You wouldn’t know this if you read someone like Brian Palmer of Slate, who seems to be getting paid to reaffirm the biases of the current age among the smart set (pretty much every single one of his pieces that touch upon genetics is larded with phrases which could have been written by a software program designed to sooth the concerns of the cultural Zeitgeist). But the new genomics is confirming the broad outlines of the findings from behavior genetics. There’s nothing really to see there. The bigger issue of any interest is normative; the values we hold dear as a culture.

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Admixture mapping in Northern Europeans?

By Razib Khan | September 19, 2013 7:46 pm

Dienekes has a post up highlighting a preprint out of Pontus Skoglund’s group. It is titled Ancient genomes mirror mode of subsistence rather than geography in prehistoric Europe. It doesn’t seem to be online (fingers crossed that it shows up linked at Haldane’s Sieve soon). In any case I am not surprised by the broad outlines of the thesis. And, it is not as if Skoglund’s group is the only one working in this area, I have suspicions that others are finding something very similar. These results out of Europe are probably reflective of the fact that much of the model in Peter Bellwood’s First Farmers is generally correct, the emergence of an agriculture revolution in a few select world societies produced a cultural and demographic revolution.

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CATEGORIZED UNDER: Agriculture, History, Human Genetics

Peeling back the palimpsest, and finding selection again

By Razib Khan | September 7, 2013 2:04 am

Layers and layers….

There is the fact of evolution. And then there is the long-standing debate of how it proceeds. The former is a settled question with little intellectual juice left. The latter is the focus of evolutionary genetics, and evolutionary biology more broadly. The debate is an old one, and goes as far back as the 19th century, where you had arch-selectionists such as Alfred Russel Wallace (see A Reason For Everything) square off against pretty much the whole of the scholarly world (e.g., Thomas Henry Huxely, “Darwin’s Bulldog,” was less than convinced of the power of natural selection as the driving force of evolutionary change). This old disagreement planted the seeds for much more vociferous disputations in the wake of the fusion of evolutionary biology and genetics in the early 20th century. They range from the Wright-Fisher controversies of the early years of evolutionary genetics, to the neutralist vs. selectionist debate of the 1970s (which left bad feelings in some cases). A cartoon-view of the implication of the debates in regards to the power of selection as opposed to stochastic contingency can be found in the works of Stephen Jay Gould (see The Structure of Evolutionary Theory) and Richard Dawkins (see The Ancestor’s Tale): does evolution result in an infinitely creative assortment due to chance events, or does it drive toward a finite set of idealized forms which populate the possible parameter space?*

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Indo-Aryans, Dravidians, and waves of admixture (migration?)

By Razib Khan | August 8, 2013 12:46 pm

Citation: Genetic Evidence for Recent Population Mixture in India
Moorjani et al.
10.1016/j.ajhg.2013.07.006

The Pith:In India 5,000 years ago there were the hunter-gathers. Then came the Dravidian farmers. Finally came the Indo-Aryan cattle herders.

There is a new paper out of the Reich lab, Genetic Evidence for Recent Population Mixture in India, which follows up on their seminal 2009 work, Reconstructing Indian Population History. I don’t have time right now to do justice to it, but as noted this morning in the press, it is “carefully and cautiously crafted.” Since I am not associated with the study, I do not have to be cautious and careful, so I will be frank in terms of what I think these results imply (note that confidence on many assertions below are modest). Though less crazy in a bald-faced sense than another recent result which came out of the Reich lab, this paper is arguably more explosive because of its historical and social valence in the Indian subcontinent. There has been a trend over the past few years of scholars in the humanities engaging in deconstruction and intellectual archaeology which overturns old historical orthodoxies, understandings, and leaves the historiography of a particular topic of study in a chaotic mess. From where I stand the Reich lab and its confederates are doing the same, but instead of attacking the past with cunning verbal sophistry (I’m looking at you postcolonial“theorists”), they are taking a sledge-hammer of statistical genetics and ripping apart paradigms woven together by innumerable threads. I am not sure that they even understand the depths of the havoc they’re going to unleash, but all the argumentation in the world will not stand up to science in the end, we know that.

Since the paper is not open access, let me give you the abstract first:

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Y, mtDNA, Adam, & Eve

By Razib Khan | August 7, 2013 11:42 am

For various reasons the idea of mitochondrial Eve and Y chromosomal Adam capture the public imagination. This frustrates many people, including me. I’ve gotten into the fatigue stage on this topic, but some sort of counter-attack is necessary against malignant memes. Even geneticists who don’t usually work with populations can get confused by the implications of mtDNA and Y chromosomal phylogenies. Melissa Wilson Sayres, who works on Y chromosomes, has a useful post (promised first of two) at Panda’s Thumb, Y and mtDNA are not Adam and Eve: Part 1. If you have friends/acquaintances who are confused by this issue, it might be a good place to start.

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CATEGORIZED UNDER: Human Genetics, Human Genomics
MORE ABOUT: Adam, Eve, mtDNA, Y chromosome

The Sports Gene, not as reductive as the title

By Razib Khan | August 6, 2013 5:45 pm

Sports Illustrated writer David Epstein has a new book out, The Sports Gene: Inside the Science of Extraordinary Athletic Performance. The title strikes me as coarse and reductive, but I am aware that authors do not always have control over such things. I’ve corresponded with Epstein a bit over the past year, and he’s sent me some passages relating to human evolutionary genetics and paleoanthropology to me to make sure they don’t sound crazy. I haven’t had time to read the book, but judging from the interview I listened to on NPR it’s data rich and theory subtle. Though the title seems to imply that athleticism is a single gene trait where most of the variation in the population is due to genetic variation, Epstein denies this and instead presents the reality that athleticism is a complex trait which many dimensions, subject to numerous genetic and environment variables, and, interactions across those variables. That would make for a less sexy subtitle, but it would have had the attribute of being correct.

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CATEGORIZED UNDER: Anthroplogy, Human Genetics, Sports
MORE ABOUT: David Epstein, Sports

Reconstructing genetic ripples in time and space

By Razib Khan | July 31, 2013 5:04 am

The inimitable Joe Pickrell has dropped his Khoisan-are-part-Italian preprint onto arXiv, Ancient west Eurasian ancestry in southern and eastern Africa. I’m being glib in my characterization of the paper’s core conclusion, but there’s a reason for such a flip response: the inferences that he seems to draw from the genetic data strike me as verging on crazy. But that’s OK, what genetics is telling us is that history was a whole lot crazier than we had imagined.

Let’s back up for a moment here. For several decades now geneticists have assumed that the Bushmen of the Kalahari, the Khoisan-qua-Khoisan, Africa’s last hunter-gatherers who retain their ancestral language along with the Hadza, are the ur-humans. The basal lineage that first diverged from the rest of mankind at the cusp of the Out of Africa event. This is evident in Y chromosomal and mtDNA phylogenies, where the Bushmen and their kin harbor variants which coalesce deeply in time with those of others. And, a few years ago another group revealed the likelihood that Bushmen also are products of an admixture event in the last ~50,000 years with a distinct hominin lineage which diverged ~1 million years before the present from the main line which led up to anatomically modern humanity. Now Pickrell et al. present us with a twist which is perhaps even more astringent than a lime: in their genomes the Bushmen and their Khoisan kin, the Khoe herders, reflect an ancient admixture event with East Africans, who themselves were the outcomes of hybridizations between West Eurasians and indigenous African populations. More relevantly for my concise summation of the conclusion, the West Eurasian component does not necessarily reflect modern Middle Eastern populations, so much as Southern Europeans!

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CATEGORIZED UNDER: Human Genetics, Human Genomics

Alexander’s soldiers left no mark

By Razib Khan | July 30, 2013 12:28 am

It is well known that Alexander the Great invaded the Indus river valley. Coincidentally in the mountains shadowing this region are isolated groups of tribal populations whose physical appearance is at at variance with South Asians. In particular, they are much lighter skinned, and often blonde or blue eyed. Naturally this led to 19th and early 20th century speculation that they were lost white races, perhaps descended from some of the Macedonian soldiers of Alexander. This was partly the basis of the Rudyard Kipling novel The Man Who Would Be King. Naturally over time some of these people themselves have forwarded this idea. In the case of a group such as the Kalash of Pakistan this conjecture is supported by the exotic nature of their religion, which seems to be Indo-European, and similar to Vedic Hinduism, with minimal influence from Islam.

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A Mongolian genome?

By Razib Khan | July 24, 2013 1:43 am

Citation: Xing J, Wuren T, Simonson TS, Watkins WS, Witherspoon DJ, et al. (2013) Genomic Analysis of Natural Selection and Phenotypic Variation in High-Altitude Mongolians. PLoS Genet 9(7): e1003634. doi:10.1371/journal.pgen.1003634

Well, not quite. You have to read the paper, Genomic Analysis of Natural Selection and Phenotypic Variation in High-Altitude Mongolians, to see why I’m skeptical. Frankly it doesn’t seem like they found too much of note in their results, so I’m kind of confused why this paper got into PLOS GENETICS (and to give due credit, this group has published very interesting work in the past which I have smiled upon). So why am I even posting about this paper? Because I was pretty sure they’d release their data, and they have (just page down to the bottom). All researchers who take the trouble to do this should be praised, highlighted, and respected. This improves science. After the AHA fiasco I’m going to redouble the effort to put the spotlight on those who release their data.

Addendum: It must be noted that a “Mongolian” identity is very much an outcome of Genghis Khan’s rise and paramountcy. The Mongols were just one of numerous tribes across what is today Mongolia. With the rise of the Mongol Empire many populations, including Turkic populations who were not part of a dialect continuum in close proximity to the Mongols, were assimilated into that ethnic identity with a few generations. The “Zulu” identity is similar, as it is a function of the rise to prominence of Shaka’s particular clan.

CATEGORIZED UNDER: Human Genetics
MORE ABOUT: Human Genetics

Where the oldest of the old are no more, and are

By Razib Khan | July 20, 2013 7:35 pm

Malaysian “Negritos,” presumably the indigenous people of the Malay peninsula

A few days ago Dienekes pointed to a paper which reports on the presence of anatomically modern humans in China 80-100,000 years before the present. I say “anatomically modern” because there is a presumable distinction between populations which resemble moderns in their gross morphology, which first emerged in southern and eastern Africa 100 to 200 thousand years ago (and were dominant all across the world after 40,000 years before the present), and “behaviorally modern” societies, which exhibit all the hallmarks of protean symbolic cultural expression that are the hallmarks of humanity. The paper reporting on such old specimens is not particularly revolutionary. Rather, it’s part of a growing corpus which contributes to a “counter-narrative” to the dominant model, whereby behaviorally modern humans swept across Eurasia (and Australia) ~50,000 years B.P. after the “Out of Africa” event. Obviously the problem here is that if there were anatomically modern humans in China tens of thousands years before this expansion, were they replaced? Or is the chronology wrong? (e.g. the mutation rate controversy, though please note that the dominant model has many physical anthropologists who support it as well). On Twitter I pointed out to Aylwyn Scally that we do have evidence of substantial population replacement across East and Southeast Asia.

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CATEGORIZED UNDER: Genetics, Human Genetics

Closing the Out of Africa migratory loop

By Razib Khan | July 5, 2013 4:45 pm

Related to Muhammad?
Credit: Ian Beatty

Last year a paper came out in AJHG which reported that Ethiopian populations seem to be a compound of West Eurasians and Sub-Saharan Africans. This is result itself is not too surprising for a host of reasons. First, Ethiopians and other populations of the Horn of Africa are physically equidistant between West Eurasians and Sub-Saharan Africans. 20th century physical anthropologists sometimes placed them in the “Caucasoid” racial classification for this reason. Second, the languages of the Horn of Africa have Afro-Asiatic affinities. The Cushitic languages (e.g. Somali) have deep connections with more familiar tongues such as Arabic, but Semitic Ethiopian languages (e.g. Amharic) are much closer in historical distance. Third, there has been a fair amount of previous genetic analysis of these populations, and their synthetic character was obvious from those (e.g. mtDNA and Y results suggest a diverse array of haplogroups). What the AJHG paper reported was that the Eurasian ancestors of the Ethiopians admixed with the presumably Sub-Saharan indigenes ~3,000 years ago in a single pulse event, and, their closest modern relations in West Asia today are Levantines. To put a mild gloss on it the dating is controversial (using patterns of decayed genetic correlations of markers across the length of the genome). This is not just clinal variation.

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Selection for cholera and Chinese in Bangladesh

By Razib Khan | July 5, 2013 5:45 am

Credit: Sci Transl Med 3 July 2013: Vol. 5, Issue 192, p. 192ra86, Sci. Transl. Med. DOI: 10.1126/scitranslmed.3006338

Right before I was to sleep a reader sent me an email which pointed to a Nick Wade piece in The New York Times, Gene Sleuths Find How Some Naturally Resist Cholera. It’s about new research in ScienceTranslational Medicine, Natural Selection in a Bangladeshi Population from the Cholera-Endemic Ganges River Delta. The authors use the “composite of multiple signals” (CMS) test to ascertain regions of the genome subject to natural selection (look for long haplotypes, high frequency derived alleles, and alleles with high cross population frequency differences). The results aren’t too surprising, I was born in Bangladesh, and I can attest to the fact that it’s a germaphobe’s nightmare. Rather, it is a secondary and very minor aspect of the paper which frankly draws my ire. First let’s quote Wade’s treatment:

As a necessary preliminary to testing for natural selection, the researchers looked at the racial composition of the Bengali population and found that they are an Indian population with a 9 percent admixture of East Asian genes, probably Chinese. The admixture occurred almost exactly 52 generations ago, according to statistical calculation, or around A.D. 500, assuming 29 years per generation. The Gupta empire in India was in decline at this time, but it is unclear whether the intermarriage with East Asians took place through trade or conquest. “We can now go back to the historians and see what happened then,” Dr. Karlsson said.

But sometimes science gets garbled in transmission. What do they say in the paper? Again, the relevant section:

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Genetic diversity and intellectual disability

By Razib Khan | July 5, 2013 2:17 am

Illustration of runs of homozygosity for affected and unaffected siblings
Credit: Intellectual Disability Is Associated with Increased Runs of Homozygosity in Simplex Autism

It is generally understood that inbreeding has some negative biological consequences for complex animals. Recessive diseases are the most straightforward. The rarer a recessive disease is the higher and higher fraction of sufferers of that disease will be products of pairings between relatives (the reason for this is straightforward, as extremely rare alleles which express in a deleterious fashion in homozygotes will be unlikely to come together in unrelated individuals). But when it comes to traits associated with inbred individuals recessive diseases are not what comes to mind for most, the boy from the film Deliverance is usually the more gripping image (contrary to what some of the actors claimed the young boy did not have any condition).

Some are curious about the consequences of inbreeding for a trait such as intelligence. The scientific  literature here is somewhat muddled. But it seems likely that all things equal if two people of average intelligence pair up and are first cousins the I.Q. of their offspring will be expected to be 0-5 points lower than would otherwise be the case. By this, I mean that the studies you can find in the literature suggest when correcting for other variables that the inbreeding depression on the phenotypic level is greater than 0 (there is an effect) but less than 5 (it is not that large, less than 1/3 of a standard deviation of the trait value). Presumably for higher levels of inbreeding the consequences are going to be more dire.

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Yes Virginia, trans-ethnic inferences from GWAS are kosher

By Razib Khan | June 24, 2013 12:00 am

Razib’s daughter’s ancestry composition


An F1, r = 0.5 to Razib

Genome-wide associations are rather simple in their methodological philosophy. You take cases (affected) and controls (unaffected) of the same genetic background (i.e. ethnically homogeneous) and look for alleles which diverge greatly between the two pooled populations. Visually the risk alleles, which exhibit higher odds ratios, are represented via Manhattan plots. But please note the clause: ethnically homogeneous study populations. In practice this means white Europeans, and to a lesser extent East Asians and African Americans (the last because of the biomedical industrial complex in the United States performs many GWAS, and the USA is a diverse nation). Looking within ethnic groups eliminates many false positives one might obtain due to population stratification. Basically, alleles which differ between groups because of their history may produce associations when the groups themselves differ in the propensity of the trait of interest (e.g. hypertension in blacks vs. whites).

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Mother of all microsatellites

By Razib Khan | June 13, 2013 9:21 am

MDS of all samples

Noah Rosenberg’s lab has put out the mother of all microsatellite papers, Population Structure in a Comprehensive Genomic Data Set on Human Microsatellite Variation. It seems to me that this is the culmination of all the work with microsatellite markers which has come out of his lab over the past decade, applying all sorts of fancy analytic techniques they’ve developed (for example, Procrustes transformation). The big thing to note is that the human sample size is nearly 6,000 individuals with over 600 loci. Because microsatellites mutate and diverge very fast (mutation rates 10-4 rather than 10-8as with SNPs) 600 loci is more than sufficient to differentiate populations. Because of this rapid mutation I’m a little dubious about their attempt to explore human-chimp differences using a smaller set ascertained on humans, though that may be simply a proof of principle (if the markers evolve too fast they might not tell you much informative about very deep divergences).

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Intelligence is still heritable

By Razib Khan | June 12, 2013 1:23 am

Sir Francis Galton

Modern evolutionary genetics owes its origins to a series of intellectual debates around the turn of the 20th century. Much of this is outlined in Will Provines’ The Origins of Theoretical Population Genetics, though a biography of Francis Galton will do just as well. In short what happened is that during this period there were conflicts between the heirs of Charles Darwin as to the nature of inheritance (an issue Darwin left muddled from what I can tell). On the one side you had a young coterie around William Bateson, the champion of Gregor Mendel’s ideas about discrete and particulate inheritance via the abstraction of genes. Arrayed against them were the acolytes of Charles Darwin’s cousin Francis Galton, led by the mathematician Karl Pearson, and the biologist Walter Weldon. This school of “biometricians” focused on continuous characteristics and Darwinian gradualism, and are arguably the forerunners of quantitative genetics. There is some irony in their espousal of a “Galtonian” view, because Galton was himself not without sympathy for a discrete model of inheritance!

William Bateson

In the end science and truth won out. Young scholars trained in the biometric tradition repeatedly defected to the Mendelian camp (e.g. Charles Davenport). Eventually, R. A. Fisher, one of the founders of modern statistics and evolutionary biology, merged both traditions in his seminal paper The Correlation between Relatives on the Supposition of Mendelian Inheritance. The intuition for why Mendelism does not undermine classical Darwinian theory is simple (granted, some of the original Mendelians did seem to believe that it was a violation!). Many discrete genes of moderate to small effect upon a trait can produce a continuous distribution via the central limit theorem. In fact classical genetic methods often had difficulty perceiving traits with more than half dozen significant loci as anything but quantitative and continuous (consider pigmentation, which we know through genomic methods to vary across populations mostly due to half a dozen segregating genes or so).

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The genetic legacy of the conquistadors

By Razib Khan | June 9, 2013 9:07 pm

Christopher Columbus

A few year ago there was a minor controversy when some evolutionary genomicists reported that they had reconstructed the genome of the extinct Taino people of Puerto Rico by reassembling fragments preserved in contemporary populations long since admixed. The controversy had to do with the fact that some individuals today claim to be Taino, and therefore, they were not an extinct population. Though that controversy eventually blew over, the methods lived on, and continue to be used. Now some of the same people who brought you that have come out with work which reconstructs the recent demographic history of the Caribbean, both maritime and mainland, using genomics.  Even better, it’s totally open access because it’s up on arXiv, Reconstructing the Population Genetic History of the Caribbean (please see the comments at Haldane’s Sieve as well, kicked off by little old me). Though the authors pooled a variety of data sets (e.g., HapMap, POPRES, HGDP) the focus is on the populations highlighted in the map above.

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