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Complex Traits

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Claes, Peter, et al. “Modeling 3D Facial Shape from DNA.” PLoS genetics 10.3 (2014): e1004224.

A few weeks ago a paper came out in PLoS GENETICS, Modeling 3D Facial Shape from DNA, which attempts to push the ball forward when it comes to mapping complex traits like facial morphology from genetic data. The long term goal here is clear: to forensically infer one’s phenotype purely from genetic information. For simple quasi-Mendelian traits like blue vs. brown eye color difference this is already possible with a high degree of certainty (or at least far higher than eyewitness reports) because much of the trait variation is controlled by one or a few genes. But for complex traits like height where variance is distributed across thousands of loci this is not feasible because the understanding of the genetic architecture is far more primitive and incomplete. The most explanatory height loci are on the order of ~1 percent of the variance of the trait in a population. In contrast blue vs. brown eye color variance within Europeans has a ~75 percent explanatory proportion at the HERC2-OCA2 locus.

The technical details of how they modeled facial morphology is rather interesting, but I’m not going to focus on that (they zeroed in on a mixed-race population to maximize phenotypic and genotypic variance). Rather, note that the authors can now relate phenotype and genotype very precisely on a population wide basis. In the past you would have to look at someone and assess their racial background or sex status. But today genetics can give you a very precise estimate of their racial ancestry, or an accurate prediction of their biological sex. The correlations are good, but observe that there are deviations from a strict association. These are perhaps just as interesting over the long term.

When it come to the domain of sociology and culture there are many models of how your physical appearance impacts how others perceive you, and how you develop as a person. You can see in the chart that there are many people who have more African ancestry, but less African features, than other sets of people (Rashida Jones and Joakim Noah likely fall into this class of pairs; Rashida Jones’ father is 66% African in ancestry, while Noah’s is 50%, so she is likely to have more African ancestry, despite having more European facial features by most accounts). By looking at these deviations from expectation you can actually test the power of genetics vs. sociology. In the case of the Duffy antigen trait clearly genetics will be determinative. On the other hand there are all sorts of medical (e.g., hypertension) and behavioral (e.g., intelligence test scores) differences between the socially understood black and white American populations where looking at individuals who vary in genotype and phenotype might illuminate the weight of the variables.

And I’m not talking rocket science here. Within 10 years surely much research will have been done in this area simply by looking at numerous genetic data sets, and combining them with phenotypic information. If scientists don’t do it, I suspect marketing and credit rating firms will, because they already have huge piles of data on most Americans (i.e., phenotypes, or instrumental variables to infer phenotypes). And this does not apply to just race. Though the difference between male and female faces is striking, there is some overlap there as well. Questions could be asked about the outcomes of men and women conditional on their facial morphology. The existence of AIS individuals would be another dimension to explore.

• Category: Race/Ethnicity, Science • Tags: Complex Traits 
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Aka Pygmies

The Pith: There has been a long running argument whether Pygmies in Africa are short due to “nurture” or “nature.” It turns out that non-Pygmies with more Pygmy ancestry are shorter and Pygmies with more non-Pygmy ancestry are taller. That points to nature.

In terms of how one conceptualizes the relationship of variation in genes to variation in a trait one can frame it as a spectrum with two extremes. One the one hand you have monogenic traits where the variation is controlled by differences on just one locus. Many recessively expressed diseases fit this patter (e.g., cystic fibrosis). Because you have one gene with only a few variants of note it is easy to capture in one’s mind’s eye the pattern of Mendelian inheritance for these traits in a gestalt fashion. Monogenic traits are highly amenable to a priori logic because their atomic units are so simple and tractable. At the other extreme you have quantitative polygenic traits, where the variation of the trait is controlled by variation on many, many, genes. This may seem a simple formulation, but to try and understand how thousands of genes may act in concert to modulate variation on a trait is often a more difficult task to grokk (yes, you can appeal to the central limit theorem, but that means little to most intuitively). This is probably why heritability is such a knotty issue in terms of public understanding of science, as it concerns the component of variation in quantitative continuous traits which is dispersed across the genome. The traits where there is no “gene for X.” Additionally, quantitative traits are likely to have a substantial environmental component of variation, confounding a simple genotype to phenotype mapping. Arguably the classic quantitative trait is height. It is clear and distinct (there aren’t arguments about the validity of measurement as occurs in psychometrics), and, it is substantially heritable. In Western societies with a surfeit of nutrition height is ~80-90% heritable. What this means is that ~80-90% of the variance of the trait value within the population is due to variance of the genes within the population. Concretely, there will be a very strong correspondence between the heights of offspring and the average height of the two parents (controlled for sex, so you’re thinking standard deviation units, not absolute units). And yet height is at the heart of the question of the “missing heriability” in genetics. By this, I mean the fact that so few genes have been associated with variation in height, despite the reality that who your parents are is the predominant determination of height in developed societies.

The issue gets even more thorny when you talk about variation across societies. This is a simple and yet complex issue. On the one hand we know that over time people across the world have gotten taller as nutrition has gotten better. What is less well known is that human populations have been shrinking until the past few centuries since the the Last Glacial Maximum ~20,000 years ago. Why? One can posit many reasons, both genetic and environmental, but it does point us to the reality that the story of height is not monotonic. That is, it doesn’t go in one direction, and has no simple one size fits all answer.

But that’s just the dimension of time. How about space? The question of whether different populations have final different genetic potentials for height is a disputed one. And yet it seems plausible that at the extremes there are genuine differences in the gene frequencies across populations which will speak to their different distributions in trait values. This is particularly interesting in the case of very populations characterized by low median adult heights, often termed “pygmies.” Of particular note are the Pygmies of Central Africa, who exist in a state of cultural symbiosis with their Bantu and Nilotic neighbors, adopting their languages, but remaining distinct.

These populations have very low median heights, but they are clearly not dwarfs (they are proportionate). Thankfully at least the population genetics of the Pygmies of Africa are now relatively well understood. It seems that the Western and Eastern Pygmy populations are very distinct clusters, with a common ancestry perhaps on the order of tens of thousands of years in the past. And not surprisingly the genetic distance between the Pygmy groups and their non-Pygmy neighbors is very large. The Western Pygmies tend to show more evidence of admixture with their Bantu neighbors than the Eastern ones (I suspect this is due to the longer residence of Bantus in this region). But for me the hardest issue to grapple with is the reality that the Pygmies of Central Africa seem to be genetically closer to the Khoisan people of Southern Africa than their Bantu or Nilotic neighbors! I believe this is evidence of an ancient hunter-gatherer continuum within Africa which has been marginalized and overlain by the recent expansion of Bantu farmers and Nilotic pastoralists.

In any case, what does all this have to do with the genetics of height? A new paper in the American Journal of Physical Anthropology synthesizes the inferences generated from population genetics with the basic logical assumptions of quantitative genetics to adduce that the difference between Pygmies and non-Pygmies in height is actually likely to be due to heritable differences. Indirect evidence for the genetic determination of short stature in African Pygmies:

Central African Pygmy populations are known to be the shortest human populations worldwide. Many evolutionary hypotheses have been proposed to explain this short stature: adaptation to food limitations, climate, forest density, or high mortality rates. However, such hypotheses are difficult to test given the lack of long-term surveys and demographic data. Whether the short stature observed nowadays in African Pygmy populations as compared to their Non-Pygmy neighbors is determined by genetic factors remains widely unknown. Here, we study a uniquely large new anthropometrical dataset comprising more than 1,000 individuals from 10 Central African Pygmy and neighboring Non-Pygmy populations, categorized as such based on cultural criteria rather than height. We show that climate, or forest density may not play a major role in the difference in adult stature between existing Pygmies and Non-Pygmies, without ruling out the hypothesis that such factors played an important evolutionary role in the past. Furthermore, we analyzed the relationship between stature and neutral genetic variation in a subset of 213 individuals and found that the Pygmy individuals’ stature was significantly positively correlated with levels of genetic similarity with the Non-Pygmy gene-pool for both men and women. Overall, we show that a Pygmy individual exhibiting a high level of genetic admixture with the neighboring Non-Pygmies is likely to be taller. These results show for the first time that the major morphological difference in stature found between Central African Pygmy and Non-Pygmy populations is likely determined by genetic factors.

First, is there a plausible physiological reason for the difference in adult height between Pygmies and non-Pygmies? The authors review the relevant evidence:

Endocrinologists have described the physiological determination of the African Pygmies’ short stature: serum levels of Insulin-Like Growth Factor 1 (IGF1) and of Growth Hormone Binding Protein (GHBP) are abnormally low, whereas the levels of Growth Hormone (GH) and IGF2 do not differ from Non-Pygmy controls…In this context, Merimee…proposed that the short stature of African Pygmies could be attributed to the absence of a growth spurt during puberty and that the genetic factor(s) implicated in the Pygmy stature were to be found in the GH-IGF1 axis…A recent gene-expression study further showed a slight (1.8-fold) under-expression of GH and a more dramatic (8-fold) under-expression of the GH receptor in adult African Pygmies, which was not found in Non-Pygmy Bantu speakers…However, the only genetic study focusing specifically on Pygmies’ stature, failed to find allele frequency differences in the promoter region of the gene encoding IGF1 between two African Pygmy populations and Non-Pygmy controls…In this context, whether the Pygmy populations’ short stature is solely due to environmental pressures experienced by individuals during growth (i.e., phenotypic plasticity), or to a complex genetic mechanism, remains to be demonstrated.

I believe that IGF can be found in meat and milk, so there are plausible dietary reasons that one could imagine this difference. As far as looking at differences between the genes which are known to impact height within populations across populations, there simply aren’t that many genes known which could account for the large between population differences. Not to mention that many of the current studies have used European populations, and so would likely have an ascertainment bias which might miss a lot of variance which is common within African populations.

The basic method in this paper is not too difficult to understand:

1) Use STRUCTURE, a program which assigns different ancestral quanta to individuals.

2) And compare the variation in a particular Pygmy-modal quantum across the population with variation in height.

If there are many genetic variants of small effect within the Pygmy genome which are resulting in their relatively low adult median height then dollops of Pygmy genome through admixture will reduce the height of non-Pygmies and dollops of non-Pygmy admixture in Pygmies will increase their height. The presumption is that if there are strong environmental impacts on height due to social differences then the disjunction between genetic identity and anthropological identity will be informative. For example, if Pygmies are put under particular stress or deprived specific nutritional intake because of their communal identity as marginalized Pygmies then different admixture levels with non-Pygmies should not matter much (and vice versa).

There’s a lot of statistics toward the aim of achieving significance in this paper (p-value > 0.05). And I really don’t understand the point of disaggregating males and females, for example. Just convert them to standard deviation units deviated from sex median! But in any case the major correlation is well illustrated by the two panels below. Pygmies are in red and non-Pygmies are in blue:

The y-axis is straightforward, height. You can see the Pygmies in their sample are shorter, on average. The x-axis is an ancestral component inferred from STRUCTURE which is generally found in non-Pygmies. You can see that as expected non-Pygmies have more of this than the Pygmies, but the descriptive statistic of a correlation between the non-Pygmy ancestry and height in Pygmies is evident even in this plot. Conversely, the Pygmy ancestry is correlated with lower adult height in non-Pygmies.

As a single result this particular finding isn’t too earth-shaking. If there was one population which was short due to genetic factors, I suspect that one would have to bet on the Pygmies of Central Africa. And as noted in the paper Pygmoid morphology is found among other hunter-gatherer tropical populations. This may not be a human ancestral type, but it is a type which has emerged repeatedly in our history, whether due to genetic or environmental factors. The big picture is that this same general procedure can be used to explore the differences in genetic dispositions across groups for many quantitative traits. With the coming era of cheap genotyping and sequencing I’m sure it will be done. A intrepid researcher has plenty of admixed populations in the New World to select from. There are in Brazil people who are socially identified and self-identify as white who have less European ancestry than those who are socially identified and self-identify as non-white. To compare the the social and genetic valences of African and European ancestral contributions for medical and psychological quantitative traits these sorts of populations will be of great future interest.

Link credit: Dienekes

Citation: Becker NS, Verdu P, Froment A, Le Bomin S, Pagezy H, Bahuchet S, & Heyer E (2011). Indirect evidence for the genetic determination of short stature in African Pygmies. American journal of physical anthropology PMID: 21541921

(Republished from Discover/GNXP by permission of author or representative)
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Razib Khan
About Razib Khan

"I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. If you want to know more, see the links at"