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Distribution of rs17822931 from HGDP

Distribution of rs17822931 from HGDP

Yoshiura, Koh-ichiro, et al. "A SNP in the ABCC11 gene is the determinant of human earwax type." Nature genetics 38.3 (2006): 324-330.

Yoshiura, Koh-ichiro, et al. “A SNP in the ABCC11 gene is the determinant of human earwax type.” Nature genetics 38.3 (2006): 324-330.

I’ve talked about rs17822931 in ABCC11 several times. The reasons are manifold. First, on many traits of interest it exhibits variation across populations in a simple Mendelian (recessive expression) manner. Second, there are suggestive variations in distribution. Third, the traits are kind of interesting without being biomedical. In other words, it’s a cool illustration of pleiotropy and human genetic variation that isn’t going to depress you. If you check out the SNPedia page you note that it is associated with variation in earwax type (wet vs. dry), body odor, and colostrum secretion. This is not the full list, and I’m moderately confident that biologists haven’t hit on all the major phenotypes that this affects variation in.

Until recently I’ve really only been interested in the population genetics of the trait. But talking with a few friends who were molecular biologists I realized I should follow up and dig deeper, and what I found was very interesting. Specifically, as it relates to body odor, which, like it or not is a phenotype of significance in the modern world. The trait happens to segregate within my family. My son is a TT genotype, because his parents are heterozygotes. That means he will exhibit less body odor as an adult. How much less?

In The Journal of Dermetological Science I found Functional characterisation of a SNP in the ABCC11 allele—Effects on axillary skin metabolism, odour generation and associated behaviours. Obviously this is not a journal I read often, but some of the tables are fascinating. The subjects were a few hundred Filipins. This is a population where the allele of interest segregates in intermediate frequencies. So there are many individuals with dry earwax as well as wet earwax, and all the associated traits.

Here are some tables I extracted*:

Mean malodour scores
5 hours 24 hours
TT 2.59 2.6
CT 3.26 3.4
CC 3.21 3.5
Genotype
TT CT CC
Uses deodorant 0.5 0.86 0.97
Does not use 0.5 0.14 0.03

I have no idea how subjective malodour scales work, but the moral is pretty straightforward. Those with the TT genotype saturate at a much lower point. This manifests in daily behavior. There is a fair amount of Japanese data that people who go to the doctor for body odor issues are much more likely to have wet earwax. This data from the Philippines illustrates that individuals with the derived genotype, TT, must be conscious enough of their lack of body odor to forgo deodorant purchases, even though I assume it is normative in the American influenced culture of the Philippines.

1-s2.0-S0923181113003058-gr1But most interesting to me are the chemical differences of the sweat of the different genotypes. They note that there were differences in Nα-3-methyl-3-hydroxy-hexanoylglutamine (HMHA-Gln), Nα-3-methyl-2-hexenoyl-glutamine (3M2H-Gln), and 3-methyl-3-sulfanyl-hexanol-cysteine-glycine between the genotypes. I don’t know much about these chemicals, except that they are “malodour conjugate precursors”. Not surprisingly there’s some difference in the microbial flora of the individuals as a function of genotype.

There have been attempts to understand the selection processes which may have shaped the distribution of the regional variation of this trait, but I’m not entirely convinced of what I’ve seen. Especially when the authors presume that earwax phenotype is in some ways causal (or at least it can give insight to causality, if that makes sense), when it may just be a developmental side effect. A consideration is that some models assume a recessive expression of the trait, which is true for body odor and earwax. But we don’t know if selection occurred that it was on these traits. Because of pleiotropy traits due to variation at a given gene may exhibit different levels of dominance, from full dominance, to additivity, to recessive expression. The target of selection may exhibit a different dominance coefficient than many of the side effect phenotypes (to give you a concrete example, the locus responsible for blue vs. non-blue eye color in Europeans exhibits some recessivity, but it is also responsible for variation in skin color where it is additive).

A 2009 paper using the HGDP data set found evidence of selection on ABCC11 using XP-EHH but not iHS. In other words, extended haplotype differences across populations, but not within them, which often imply sweeps near fixation between populations, rather than ongoing ones within them. To get a better sense of the distribution of the allele I decided to query the SNP in the 1000 Genomes Browser. I invite you to look at the data yourself. The sample sizes start to get pretty large in some of these populations. It is interesting that in West African populations the ancestral variant is nearly fixed, or totally so. The cases where it is not so can pretty easily be hypothesized as due to recent (last 10,000 years) Eurasian admixture. In Europe the frequency of the derived variant is low, on the order of ~10%, but in the Finnish sample it peaks at ~25%. This aligns with patterns in the HGDP data set. African populations tend to be fixed for the ancestral variant, C, while European populations have a low frequency of the derived variant, T, with a cline toward the northeast from the southwest (i.e., peaks in the Russians, lowest fraction in Sardinians). But, Middle Eastern samples in the HGDP data set have European proportions of T as well, though the Mozabites in North Africa do not. The South Asian samples in the HGDP have higher levels of the derived variant than Europeans, intermediate between that group and East Asians. But the 1000 Genomes data results in a thickening of the plot (and, with large sample sizes!). The Bangladeshis are at even a higher fraction than the Pakistani populations. The genotype counts are like so: 12 CC, 54 CT, TT. When I saw this I assumed it was the East Asian admixture, on the order of 10-20%, which might account for the enrichment of T in relation to Pakistan groups. But that is not correct. Here are the counts for Indian Telegus: 20 CC, 49 CT, and 33 TT. And Sri Lankan Tamils: 23 CC, 49 CT and 30 TT. Many hypotheses about the derived variant involve adaptations to cold climates in Northeast Asia. This may still be the case in Northeast Asia, but what you see here is a NW to SE cline of ancestral to derived variant of ABCC11 in South Asia. The Punjabis and Gujaratis have higher fractions of the ancestral variant, as you’d except from the HGDP data.** (the fraction in the Bangladeshi sample might be elevated by East Asian admixture)

The results form East Asian samples in the 1000 Genomes is also illuminating. With sample sizes of around 200 each the Dai minority (related to the Tai people culturally as their antecedents) has a frequency of 56% for T, the Han from Beijing have 97%, the Han from South China are at 86%, the Japanese 88%, and the Vietnamese from the southern region of the country 64%. First, my intuition is that this seems a strange pattern for a allele which was selected on a recessive trait. Rather, it looks more likely for selection on a dominant trait, where the equilibrium frequency remains below 100% because of recessive expression of the unfavored state. Second, the fraction for the Dai seems rather high for the ancestral state. This particular population is sampled from the Mekong region of southern China, as far south as you can go in the nation. This sort of cline correlated with latitude goes a long way to explaining why the thesis often emerged that this variation is somehow related to climate (there is something of a north-south cline in Japan as well).

Where does this leave us? I honestly don’t think we can make a general conclusion about the nature of selection around this variation. To me it looks as it was functionally constrained in Africa. African populations have the derived variant, but those that do can be explained via recent Eurasian admixture pretty easily (e.g., the LWK sample are Kenyan Bantus who have mixed with Nilotic peoples, who do have Eurasian ancestry. The same for the samples from Gambia or Senegal in relation to Eurasian mixed Fula). But once you leave Africa it look as if the constraint was removed, and lots of populations have low frequencies of the derived nonsynonymous mutation. The 2006 paper which focused in on the SNP of interest had Oceanian samples, and the derived variant fraction is too high to simply be a matter of Austronesian admixture. Could it be some form of balancing selection outside of Africa? Who knows. It might be neutral in some areas, under positive selection in others, balanced in a few locations, and under constraint in Africa.

But despite the evolutionary enigma of this locus, the phenotypic correlations keep building up. It’s a classical genetics illustration because of its Mendelian character. In terms of morphology I should emphasize that the body odor related information probably relates to the apocrine glands, which are localized in the armpits and genitals, and also are precursors to mammary secretion glands. Someone who understands these sorts of pathways and how they influence development could probably say much more. I’m sure at some point we’ll be able to answer the big evolutionary questions about this locus, and how it relates to human biological variation, but that will probably necessitate a better catalog of its phenotypic consequences.

Addendum: If you have a 23andMe account, here is the link that will show you your genotype (and anyone else on your account): https://www.23andme.com/you/explorer/snp/?snp_name=Rs17822931 (be logged in ahead of time).

* I flipped the strand, so converted T to A and G to C.

** To be fair, there was some evidence from Tamils in earlier studies, but two South Indian populations in the 1000 Genomes with high sample sizes nails it.

 
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Yoshiura, Koh-ichiro, et al. "A SNP in the ABCC11 gene is the determinant of human earwax type." Nature genetics 38.3 (2006): 324-330.

Yoshiura, Koh-ichiro, et al. “A SNP in the ABCC11 gene is the determinant of human earwax type.” Nature genetics 38.3 (2006): 324-330.

When I was in college a Korean American friend confided to me that his roommate had an issue. He had seen a q-tip in the waste-bin, and what was at the end of it was shocking to him. What my friend was describing was wet earwax (Google it yourself if you want to see it). As this was the first time he was living with a non-Korean he had assumed that everyone’s earwax was dry, like his own. The maps above and to the left show you the frequencies of the allele which has an extremely strong correlation with this trait. In Korea the frequency of dry earwax is close to 100%. Since the expression pattern for dry earwax is recessive, you need two copies of the derived allele, so in any population where the ancestral variant exists in appreciate frequencies you’ll have the wet variant of the trait.

This is why in 2006 a Japanese group published research in this area, A SNP in the ABCC11 gene is the determinant of human earwax type. A substantial minority of Japanese happen to have wet earwax. And it turns out that wet earwax has some other associations of interest.

bodyodor

Nakano, Motoi, et al. “A strong association of axillary osmidrosis with the wet earwax type determined by genotyping of the ABCC11 gene.” BMC genetics 10.1 (2009): 42.

Axillary osmidrosis is scientific for body odor. These results show a very strong association between someone with the ancestral allele which results in wet earwax, and strong body odor. Obviously this is a “news you can use” sort of result, so no surprise at seeing this paper: Dependence of Deodorant Usage on ABCC11 Genotype: Scope for Personalized Genetics in Personal Hygiene:

Earwax type and axillary odor are genetically determined by rs17822931, a single-nucleotide polymorphism (SNP) located in the ABCC11 gene. The literature has been concerned with the Mendelian trait of earwax, although axillary odor is also Mendelian. Ethnic diversity in rs17822931 exists, with higher frequency of allele A in east Asians. Influence on deodorant usage has not been investigated. In this work, we present a detailed analysis of the rs17822931 effect on deodorant usage in a large (N~17,000 individuals) population cohort (the Avon Longitudinal Study of Parents and Children (ALSPAC)). We found strong evidence (P=3.7 × 10−20) indicating differential deodorant usage according to the rs17822931 genotype. AA homozygotes were almost 5-fold overrepresented in categories of never using deodorant or using it infrequently. However, 77.8% of white European genotypically nonodorous individuals still used deodorant, and 4.7% genotypically odorous individuals did not. We provide evidence of a behavioral effect associated with rs17822931. This effect has a biological basis that can result in a change in the family’s environment if an aerosol deodorant is used. It also indicates potential cost saving to the nonodorous and scope for personalized genetics usage in personal hygiene choices, with consequent reduction of inappropriate chemical exposures for some.

I don’t want to get into the biology of this is too much detail. Suffice it to say that the SNP in ABCC11 has a lot of effects. It looks like there might have been a selection event to drive up its frequency at some point. I’m intrigued at the fact that among European populations it is among Sardinians that the derive allele is least common. If it was selection I’m pretty sure don’t know the target phenotype. Less body odor is probably simply a nice side effect. Ultimately though this is personal. If you read NPR’s stupid Code Switch blog you will have seen that Study Says Your Race Determines Your Earwax Scent. Actually, obviously no. This gene has a high between population difference as far as genes go, but the wet and dry phenotypes segregate in many families, and are found in appreciable frequencies in many populations. Both alleles are found in my own immediate family. My wife and myself carry both alleles. We’re heterozygotes. My daughter is a homozygote for the ancestral variant. My soon-to-be-born son is homozygote for the derived variant. Perhaps we’ll be saving on deodorant purchases?

 
• Category: Race/Ethnicity, Science • Tags: ABCC11, Body Odor, Earwax, Human Genetics 
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EarWhen I was in college I would sometimes have late night conversations with the guys in my dorm, and the discussion would random-walk in very strange directions. During one of these quasi-salons a friend whose parents were from Korea expressed some surprise and disgust at the idea of wet earwax. It turns out he had not been aware of the fact that the majority of the people in the world have wet, sticky, earwax. I’d stumbled onto that datum in the course of my reading, and had to explain to most of the discussants that East Asians generally have dry earwax, while convincing my Korean American friend that wet earwax was not something that was totally abnormal. Earwax isn’t something we explore in polite conversation, so it makes sense that most people would be ignorant of the fact that there was inter-population variation on this phenotype.

But it doesn’t end there. Over the past five years the genetics of earwax has come back into the spotlight, because of its variation and what it can tell us about the history and evolution of humans since the Out of Africa event. Not only that, it seems the variation in earwax has some other phenotypic correlates. The SNPs in and around ABCC11 are a set where East Asians in particular show signs of being different from other world populations. The variants which are nearly fixed in East Asia around this locus are nearly disjoint in frequency with those in Africa. Here are the frequencies of the alleles of rs17822931 on ABCC11 from ALFRED:
abcc11A


ResearchBlogging.org The expression of the dry earwax phenotype is contingent on an AA genotype, it has recessive expression. So in a population where the allele frequency of A ~0.50, the dry earwax phenotype would have a ~0.25 frequency. In a population where the A allele has a ~0.20 frequency, the dry earwax phenotype would be at ~0.04 frequency. Among people of European descent the dry earwax phenotype is present at proportions of less than ~5%. Because of recessive expression a larger minority of Japanese and Chinese should manifest wet earwax, though interestingly the ALFRED database indicates that Koreans are fixed for the A allele. In Africa conversely the G allele seems to be fixed.

So the question is: why? A new paper in Molecular Biology and Evolution argues that the allele frequency differences are a function of positive directional selection since humans left Africa ~100,000 years ago. The impact of natural selection on an ABCC11 SNP determining earwax type:

A nonsynonymous single nucleotide polymorphism (SNP), rs17822931-G/A (538G>A; Gly180Arg), in the ABCC11 gene determines human earwax type (i.e., wet or dry) and is one of most differentiated nonsynonymous SNPs between East Asian and African populations. A recent genome-wide scan for positive selection revealed that a genomic region spanning ABCC11, LONP2, and SIAH1 genes has been subjected to a selective sweep in East Asians. Considering the potential functional significance as well as the population differentiation of SNPs located in that region, rs17822931 is the most plausible candidate polymorphism to have undergone geographically restricted positive selection. In this study, we estimated the selection intensity or selection coefficient of rs17822931-A in East Asians by analyzing two microsatellite loci flanking rs17822931 in the African (HapMap-YRI) and East Asian (HapMap-JPT and HapMap-CHB) populations. Assuming a recessive selection model, a coalescent-based simulation approach suggested that the selection coefficient of rs17822931-A had been approximately 0.01 in the East Asian population, and a simulation experiment using a pseudo-sampling variable revealed that the mutation of rs17822931-A occurred 2006 generations (95% credible interval, 1023 to 3901 generations) ago. In addition, we show that absolute latitude is significantly associated with the allele frequency of rs17822931-A in Asian, Native American, and European populations, implying that the selective advantage of rs17822931-A is related to an adaptation to a cold climate. Our results provide a striking example of how local adaptation has played a significant role in the diversification of human traits.

The region around ABCC11 has come under scrutiny with the emergence of tests of natural selection predicated on inspecting patterns of linkage disequilibrium (LD). LD is basically measuring the association of genetic variants within the genome shifted away from expectation. A selective sweep tends to generate a lot of LD around the target of natural selection because as the allele in question rises in frequency its neighbors also hitchhike along. The hitchhiking process means that within a population you may see regions of the genome which exhibit long sequences of correlated single-nucelotide polymorphisms (SNPs), haplotypes. An initial selective event will presumably generate a very long homogenized block, which over time will break apart through recombination and mutation, as variation is injected back into the genome. The extent and decay of LD then can help us gauge the time and strength of selection events.

But LD can emerge via other processes besides natural selection. Imagine for example that a population of Africans and Europeans mix in a given generation. Europeans and Africans have different genetic makeups, on average, so the initial generations will have more LD than expectation because recombination will only slowly break apart the physical connection between genomic regions from European and African ancestors. The decay of LD then can give one a sense of the time since admixture as well as selection. Not only that, stochastic demographic events and processes are also important and may drive the emergence of LD. Consider a bottleneck where the frequency of a particular haplotype is driven up by random genetic drift alone. The details of these alternative scenarios are explored in the 2009 paper The role of geography in human adaptation.

All this is preamble to the fact that there’s a lot of LD around ABCC11. Here’s a visualization from the HapMap populations:

abcc11B

abc11From left to right you have Chinese & Japanese, Utah whites, and the Yoruba from Nigeria. An absolute value of D’ ~0 means that there’s linkage equilibrium; the default or null state where there are no atypical excessive correlations of alleles across the genome. The axes here are pairwise combinations of SNPs around ABCC11, with a focus around rs17822931, a nonsynonymous SNP which seems to be the likely functional source of the variance in earwax and other phenotypes. In terms of LD rank order the results are not surprising, across the genome East Asians tend to exhibit more LD than Europeans, and Europeans exhibit more LD than the Yoruba. Part of this is probably a function of population history, a serial bottleneck model Out of Africa would posit that drift and other stochastic forces would have a stronger impact on the genomes of East Asians than Europeans. But this seems like it can’t be the whole picture here; note the variance in allele frequency in the New World as well as in Oceania. Some of the Amerindian populations seem to have a higher frequency of the ancestral G allele on rs17822931. The figure above is easier to understand, the Y-axis is showing you the extent of heterozygosity at a given location. GA is heterozygous, GG is homozygous. Africans again tend to exhibit more heterozygosity than non-Africans, but note the sharply diminished heterozygosity for the East Asian sample around rs17822931 in ABCC11. Remember that heterozygosity tends not to go above 0.50 in a random mating population in a diallelic model (though in selective breeding it may go above 0.50 for F1 generations).

The major findings of this paper beyond what was known before seem to be a) an explicit model of how East Asians could have arrived at a high frequency of the AA genotype at rs17822931, and, b) the correlation between climate and the frequency of A. I’ll get to the second point in a bit, but what about the first? Using the nature of variation in two microsatellites flanking the SNP of interest in East Asians, and assuming a recessive selection model, the authors posit that the A allele began to rise in frequency ~50,000 years ago, and, that the selection coefficient was ~1% per generation. This a significant value for the selection parameter, and the timing is possible in light of the separation of non-Africans into a western and eastern group around that period.

But honestly I’m pretty skeptical of this. The confidence intervals don’t inspire confidence, and from what little I know selection for recessive traits should exhibit less linkage disequilibrium. At low frequencies there is very little affect of natural selection on the allele because it is mostly “masked” in heterozygotes, and therefore there will be a long period before its proportion begins to rise more rapidly. During this time recombination will have time to chop up the haplotypes around the SNP, reducing the length of the statistically associated haplotype block. Also, the authors themselves don’t seem to believe that the phenotype of earwax itself was the target of selection, so its recessive expression pattern should be less important from where I stand.

abcc11dThe idea that the genes around ABCC11 might have something to do with adaptation to cold is suggestive, but almost every East Asian trait of distinction has been hypothesized to have something to do with cold at some point by physical anthropologists. You’d figure that the Cantonese lived in igloos going by all the myriad adaptations to frigid conditions which they exhibit. The reality is that much of China, Korea and Japan are subtropical today. In any case the last figure shows the correlation across several lineages. Earlier they found that by comparing variation around this region in humans with other primates that Africans seem to be subject to purifying selection. This means that there’s constraint so that neutral forces don’t change the frequencies of functionally significant regions. It is well known that on average Africans are more diverse than non-Africans, probably because the latter are a sampling of the former, but, on a small minority of genes the reverse is true. This is likely due to the relaxation of functional constraint as humans left the ancestral African environment. And this is clearly true for rs17822931; most non-African populations exhibit some heterozygosity. East Asians here are an exception, not the rule, at having derived allele frequencies nearly fixed. The regression lines in this last figure are all statistically significant. It is interest that there are particularly strong correlations between latitude and and frequency of the derived A allele among Europeans and Native Americans. In contrast the relationship within Asian populations is weaker. Only 17% of the allele frequency variance can be explained by latitude variance among the Asian ALFRED sample.

But we shouldn’t allow the hypothesis to rise and fall just on this evidence. After all there have likely been substantial movements of populations within the last 10,000. Perhaps especially in East Asia, where the expansion of the Han south may have triggered the movement of both the Thai and Vietnamese people out of South China and into mainland Southeast Asia. The best evidence of adaptation would be among admixed populations; presumably those at higher latitudes would have higher frequencies of the AA genotype than those at lower latitudes. Instead of categorizing the populations into three coarse classes probably a more sophisticated treatment using ancestral quanta derived from STRUCTURE or ADMIXTURE as independent variables would be informative. Remember, adaptation should show evidence of decoupling ancestry from phenotype.

Finally, I have to point to this section of the discussion:

What is the cause of the selective advantage of rs17822931-A? Although the physiological function of earwax is poorly understood (Matsunaga 1962), dry earwax itself is unlikely to have provided a substantial advantage. The rs17822931-GG and GA genotypes (wet earwax) are also strongly associated with axillary osmidrosis, suggesting that the ABCC11 protein has an excretory function in the axillary apocrine gland (Nakano et al. 2009)…,

I really didn’t know what this meant. So I looked it up. Here’s what I found, A strong association of axillary osmidrosis with the wet earwax type determined by genotyping of the ABCC11 gene:

Apocrine and/or eccrine glands in the human body cause odor, especially from the axillary and pubic apocrine glands. As in other mammals, the odor may have a pheromone-like effect on the opposite sex. Although the odor does not affect health, axillary osmidrosis (AO) is a condition in which an individual feels uncomfortable with their axillary odor, regardless of its strength, and may visit a hospital. Surgery to remove the axillary gland may be performed on demand. AO is likely an oligogenic trait with rs17822931 accounting for most of the phenotypic variation and other unidentified functional variants accounting for the remainder. However, no definite diagnostic criteria or objective measuring methods have been developed to characterize the odor, and whether an individual suffers from AO depends mainly on their assessment and/or on examiner’s judgment. Human body odor may result from the breakdown of precursors into a pungent odorant by skin bacteria….

Perhaps the paper should have been titled “why barbarians smell bad”? In any case, an idea for a book title on Korean genetics: “the least smelly race.”*

Citation: Ohashi J, Naka I, & Tsuchiya N (2010). The impact of natural selection on an ABCC11 SNP determining earwax type. Molecular biology and evolution PMID: 20937735

* I’m referencing The Cleanest Race.

(Republished from Discover/GNXP by permission of author or representative)
 
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Razib Khan
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"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 http://www.razib.com"