pigmentation

Which population in the 1000 Genomes Project samples has the most Neandertal similarity?

Wed, 2012-02-08 01:14 -- John Hawks

Last December I began writing about an analysis of introgression in the 1000 Genomes Project samples ("Neandertal introgression, 1000 Genomes style"). I left everybody in a bit of suspense, partly because my writing computer was unexpectedly replaced before winter vacation, and partly because of my extensive travel in January.

I'm catching up this week before I go to Ann Arbor, Michigan next week for a talk and visit with many friends. It's a good time to give readers some status updates on the analyses because the release of the high-coverage Denisova genome today will allow us to do some very deep checks on some of the comparisons we've carried out.

Picking up where I left off, in the last post I emphasized that the individual genomes represented in the 1000 Genomes Project samples in Europe and East Asia have a surplus of derived SNP alleles that they share with the Vindija Vi33.16 genome. That surplus compared to genomes in the African population samples represents the evidence for Neandertal ancestry in those populations.

Admixed populations, including African-Americans and Puerto Ricans, shared Neandertal derived SNP alleles in the fraction expected for their African and non-African fractions of ancestry.

As I also pointed out, the population samples in Europe and East Asia are not identical in the number of these shared derived variants. The difference between individuals can be caused by differences in the fraction of their genealogy that traces to Neandertals. The difference may also be caused by other aspects of the individuals' genealogy, if for example some aspect of population history has led to discrepancies in the fraction of ancient variations these people share with a Neandertal genome by incomplete lineage sorting.

Here is the comparison of East Asian samples (Japanese, Han Chinese in Beijing, and Han Chinese originating in South China) and European samples (Tuscans, British, Finn and CEU samples, along with a handful of Spanish):

The Europeans average a bit more Neandertal than Asians. The within-population differences between individuals are large, and constitute noise as far as our comparisons between populations are concerned. At present, we can take as a hypothesis that Europeans have more Neandertal ancestry than Asians. If this is true, we can further guess that Europeans may have mixed with Neandertals as they moved into Europe, constituting a second process of population mixture beyond that shared by European and Asian ancestors.

As we look more closely at the particular gene regions shared between each individual and the Neandertal, we will be able to consider the approximate time that they shared an ancestor for each gene region. That will allow us to distinguish incomplete lineage sorting (ILS) from introgression, although the two will overlap to some extent. We will rely on that test to examine hypotheses about the time and place of population mixture.

The difference between Europeans and Asians when we lump all the samples together is not as interesting as the differences we can see among the samples within each of those regions. For example, here are British people compared to Tuscans:

The Tuscans have the highest level of Neandertal similarity of any of the 1000 Genomes Project samples. They have around a half-percent more Neandertal similarity than Brits or Finns in these samples. The CEU sample is slightly elevated compared to Brits and Finns as well.

It is tempting to interpret these differences as a north-south cline in Neandertal ancestry. I wouldn't jump too quickly on this idea, because Holocene population movements in Europe are now known to have covered up or erased a substantial fraction of the Upper Paleolithic gene pool. If we have a bonus of extra Neandertal ancestry in southern Europe, we need to explain how that cline persisted across subsequent history. Still, the difference is statistically very strong and deserves some explanation.

Likewise, the populations within East Asia have some differences in Neandertal similarity. Here is the comparison of Han Chinese, with the Beijing versus South China origins separated out:

North China has a bit more Neandertal, on average, than South China according to these samples. These are all identified as ethnic Han Chinese, so I expect that the comparison would be much more interesting if some minority populations had been examined. The "cline" here seems opposite in direction compared to the European case. I can add that the Japanese sample is largely intermediate between the CHB and CHS, with an average closer to the Beijing sample.

If there was one thing that surprised me in the comparisons, it was this:

Yoruba have substantially more Neandertal similarity than Luhya. This may seem counter-intuitive, because the geographic location of Luhya in East Africa might seem better placed for Neandertal similarity to appear, whether through ancient population structure and ILS or through recent gene flow or backmigration into Africa of Neandertal descendants.

Instead, it looks like the Yoruba are the recipients of Neandertal genes, whether by means of ancient population structure or introgression and recent trans-Saharan gene flow. I personally think both factors are involved, but again their relative importance will be determined by comparing individual gene regions.

In this vein, it is useful to outline the hypothesis of differential ILS within African samples. We now know from examination of genetic variation within Africa today that some of today's diversity can be traced to ancient population structure in Middle Pleistocene African populations. For example, Neandertals could be more closely related to some African populations than others today because Neandertals actually exchanged genes with some ancient African populations. Or Neandertals might have sprung from one African population among many who lived 250,000 years ago. If some of these ancient populations persisted and contributed genes to different present-day African populations, those populations would share different fractions of genes with a Neandertal genome.

I expect we will learn a substantial amount about African population structure in the MSA by using these Neandertal-similar regions of the genome. It's like having a probe that can trace the movement of people across Africa more than 100,000 years ago. As we combine the archaic genome data with our growing picture of diverse lineages in Africa today, we may discover ancient populations that are not apparent archaeologically. Again, genetics is giving us a totally new picture of the diversity and population dynamics of ancient people.

Next: Which Neandertal-derived variants are shared between regions, and which are unique to one region? I touched on this question last spring by using genotype data. Now, we have sequences capable of telling us much more.

Tags:
Neandertal DNA
introgression
1000 Genomes Project
pigmentation
Synopsis:
Europe has a touch more Neandertal than East Asia; Tuscans have more than any other European sample
Measuring population subdivision

Sun, 2011-11-27 22:58 -- John Hawks
Synopsis:
The statistical measurement of differentiation among populations is Fst
The basic measure of genetic difference between two populations is the statistic, F_ST. In genetics, the term F generally stands for ``inbreeding'', which tends to reduce genetic variation in the population. Genetic variation can be measured by heterozygosity, and so F generally expresses a reduction in the heterozygosity in the population. F_ST is the reduction in heterozygosity in subpopulations compared to the total population of which they are part.

To estimate F_ST, take the following steps:

Find the allele frequencies for each subpopulation.

Find the average allele frequencies for the total population.

Calculate the heterozygosity (2pq) for each subpopulation.

Calculate the average of these subpopulation heterozygosities. This is H_S.

Calculate the heterozygosity based on the total population allele frequencies. This is H_T.

Finally, calculate F_ST=(H_T-H_S)/H_T.

Don't forget that the H_S term is the average across all subpopulations.

Example: The gene SLC24A5 is a key part of the melanin expression pathway, which contributes to skin and hair pigmentation. A SNP that is strongly associated with lighter skin pigment in Europe is rs1426654. The SNP has two alleles, A and G, with G being associated with light skin, at a frequency of 100% in Utah European-Americans. The SNP varies in frequency in populations in the Americas with mixed African and American Indian ancestry. A sample in Mexico had 38% A and 62% G; in Puerto Rico the frequencies were 59% A and 41% G, and a sample of African-Americans from Charleston had 19% A with 81% G. What is the F_ST in this example?
Study terms:
FST
heterozygosity
subpopulation
Tags:
Anthropology 105
explainer
laboratory
race
pigmentation
Why do people differ in skin color?

Wed, 2011-11-16 08:43 -- John Hawks
Synopsis:
Pigmentation in humans reflects UV radiation and its effects on biology and health in recent human evolution.
The color of human skin is determined by the amount of two pigments, eumelanin and pheomelanin. These pigments are the basic ones underlying all kinds of coloration in animals — even blue colors like those in the irises of blue eyes result from light reflecting above a layer of dark brown-black eumelanin. The darkest human skin and hair tones contain an abundance of eumelanin, while brown and reddish hair and freckles of the skin contain a large proportion of pheomelanin.

Genes can influence skin and hair pigmentation in many ways. The overall color of the skin results from both the number of pigment-making cells (called melanocytes) and their level of activity. Most skin is capable of tanning, which means that exposure to UV radiation induces greater melanin production. Today, more than 20 genes are known to influence skin pigmentation in humans. Genetic changes can alter the development and migration of melanocytes, the regulation and expression of genes that generate melanin, or the chemical steps in the synthesis of the pigments themselves. As a result of such genetic changes, two people who live in the same environment may have very different shades or patterns of skin coloration.

Some of the genes that influence skin pigmentation also cause variation in hair color or eye color. For example, variation in the gene OCA2 explains most of the variation in eye color in Europeans. People with blue eyes are mostly homozygotes for an allele of this gene; these people also tend to have slightly lighter skin due to this allele. Likewise, the variation in the gene MC1R explains some of the variation in skin color in Europe, but also explains a large proportion of variation in hair color. Red and blond hair each result from some of the distinctive alleles of MC1R.

Dark skin evolved in ancient humans

Relatively light-skinned populations include the native inhabitants of Europe, West Asia, East Asia, the Arctic, and the Americas. The lightest skin tones are found in Europe, while the darkest are in tropical Africa, southern India, Indonesia and Melanesia, and Australia. The level of skin pigmentation shows a close correspondence with latitude — people living near the equator tend to have dark skin, while light-skinned people live nearer the poles.

Selection on skin color depends on the level of UV radiation.

Cline of skin color in global human populations

Skin pigmentation correlates with latitude because it serves as a defense against UV radiation. Like all solar radiation, UV is more intense at lower latitudes, where the sun is more often directly overhead. High-energy UV light damages and destroys the molecules that skin is made of. In sufficient amounts, this UV radiation can cause severe burns, that are painful and leave the skin unable to maintain its normal protective and cooling functions. UV radiation also can cause long-term damage to the DNA of skin cells, resulting in dangerous skin cancers.

Dark-skinned people have a lower incidence of skin cancers in most countries compared to people with less pigmentation. The highest skin cancer rates in the world are suffered by people of European origin who currently live in equatorial places; Australia is presently the highest. Still, skin cancer may be a relatively weak cause of natural selection, because deaths from skin cancer tend to occur later than the mid-30s, relatively late in most peoples' reproductive lifespan.

Dark skin reduces the incidence of skin cancer and sunburn.

Possibly more important was the incidence of heat stroke in severely sunburned people. Today, relatively few people in Western societies succumb to heat exhaustion and heat stroke today, but this was potentially a great danger in the past and remains so in some places today. This danger of sunburn especially influences children, whose smaller masses allow less room for error in water loss and overheating.

Some evidence suggests that dark skin pigmentation first appeared in humans within the last 500,000 years. African apes are polymorphic in skin coloration. Chimpanzees in particular are variable — some chimpanzees have quite light skin, and others have very dark skin; skin color tends to darken with age in these primates. But humans who live in equatorial Africa today show very little variation in skin color. Dark skin has been strongly selected in that population. One gene that contributes to skin pigmentation phenotypes, MC1R, shows evidence for positive selection in Africans sometime between 200,000 and 1 million years ago [1]. This date is interesting — humans first appeared nearly 2 million years ago, and our divergence from chimpanzees was far earlier, at over 6 million years ago. So the evolution of dark skin pigmentation was continuing at a relatively recent date. One suggestion is that people lost their body fur sometime during the last million years. With fur, there was no survival benefit to dark skin, but exposed skin creates the susceptibilities that select for darker pigmentation.

Light skin pigmentation evolved recently

Light skin pigmentation is a more difficult problem than dark pigmentation. The advantages of dark skin are clear, and genetic evidence shows that dark skin has been around for a long time. But light skin evolved relatively recently.

The variation among light-skinned populations helps to illuminate the problem. Europeans and Asians today are broadly similar in their range of pigmentation. Northern Europeans average a bit lighter in skin color than north Asians, but the ranges of variation in pigmentation greatly overlap. Still, there are regional differences. For example, both hair and eye coloration are more polymorphic in Europeans than in living Asians. These phenotypes suggest that different alleles may affect pigmentation in these populations.

Recently, geneticists have identified more than a dozen different genes influencing skin coloration in Europeans and Asians. The variation in pigmentation associated with these genes is mostly explained by new alleles under recent positive selection. For example, northern Europeans carry a new allele from a gene called SLC24A5 at a frequency near 100 percent. This allele has spread as far west as Spain, and as far east as Pakistan; it is also common in North Africa. Yet, the new mutation originated very recently, approximately 6000 years ago. Likewise, a gene called DCT has a new allele common in China, which appears to have originated less than 10,000 years ago. Both Europeans and Asians have 10 or more alleles influencing their light skin pigmentation, but these alleles are only rarely shared between these populations. Variation in eye color in Europeans is mostly explained by a recnet mutation in the gene OCA2. This same gene has another allele under recent selection in China, which does not strongly influence eye color. European hair color variation is mostly explained by variation in MC1R; this gene has many new alleles in Europe, but does not greatly influence hair color in East Asia. In every case, the new mutations occurred recently and have not yet had time to spread and proliferate from one end of Eurasia to the other.

The recent evolution of light skin can only be explained by a strong pattern of selection favoring it. Scientists have focused on ways that dark skin may create disadvantages for people in places with lower natural UV radiation. One way that UV radiation is necessary is in the metabolism of vitamin D. Humans synthesize vitamin D in the skin, where exposure to UV radiation allows the transformation of precursor molecules into the necessary vitamin. Vitamin D is necessary for normal bone development, and people who suffer from a deficiency of vitamin D get a disorder known as rickets, characterized by deformation of the bones. Such abnormalities in bone growth can be potent causes of selection, either by decreasing mating attractiveness or by impeding normal activities. Such problems can extend to reproduction itself, as a pelvis deformed by rickets can make it impossible for a woman to give birth normally.

There is some evidence that dark skin is less capable of maintaining vitamin D metabolism. Most notably, people with darker skin living at higher latitudes in historic times, such as in London, apparently have suffered a higher incidence of rickets. However, today people acquire vitamin D primarily through dietary supplements, including dairy foods enriched with the vitamin, so that dietary differences between peoples of different skin tones in Western nations may partially account for differences in rickets incidence. Nevertheless, vitamin D metabolism remains the most prominent hypothesis to account for the distribution of light skin in the northern parts of the world.

Even so, some differences in skin color are probably explained by other factors. For example, northern Europeans are markedly lighter in skin color than people who live at the same latitude in East Asia. Many Europeans also have less melanin in their hair, which ranges in tone from blond to brown and red, while most high-latitude Asians have black hair.

It is possible that some of these differences may be the result of sexual selection, as different populations create different long-term patterns in sexual attractiveness and mating. Scientists have also applied sexual selection to explain differences in hair form among populations, from short and kinky to long and straight, and differences in hair color among equatorial populations. In all such cases, there is no ready environmental explanation for the differences. Even so, human cultures are very flexible and change rapidly, especially when compared to biological evolution, so that a stable sexual preference for such a characteristic as skin color or hair color, expressed over many hundreds of generations, would appear to conflict with the rapid cultural changes that affect mating preferences.

References
Rogers AR, Iltis D, and Wooding S. 2004. Genetic Variation at the \\emph{MC1R} Locus and the Time Since Loss of Body Hair. Current Anthropology [Internet] 45:105–108. Available from: http://dx.doi.org/10.1086/381006
Study questions:
Pigmentation varies among other species of primates, with different coat colors and color patterns. Do you think the same explanations work for these primates as for humans?

Some humans in the distant past lived at high latitudes, like the Neandertals. What would you expect about their pigmentation?
Study terms:
MC1R
OCA2
SLC24A5
UV radiation
melanin
melanocyte
vitamin D
pheomelanin
eumelanin
Tags:
pigmentation
Anthropology 105
explainer
adaptation
Eye pigmentation and allele frequencies

Tue, 2011-09-06 00:46 -- John Hawks
Synopsis:
A single nucleotide polymorphism is associated with blue eyes in Europeans, leading to explanation of genetic associations.

Eye pigmentation in humans varies along a spectrum of colors from dark brown, through lighter brown, hazel, and green, to light blue. These differences are caused by variation in the content of the dark pigment, eumelanin, in the layers of the iris. Several genes are involved in the variation in color, but most of the lighter colors require a change in the expression of a gene called OCA2.

Photo credit: blue and brown by Look Into My Eyes, on Flickr. Mixed eye color can sometimes occur, due to somatic mutations that affect the pigment expression in the iris.

The lighter eye colors are most common in Europe, and in northern Europe in particular. Much of the variation in eye pigmentation in this population is associated with one area of the genome, on chromosome 15 in the region of the genes HERC2 and OCA2. The strongest association is with a single site, 28365618 nucleotides from the beginning of chromosome 15 in the current draft of the human genome. At this site, some human sequences carry an A, and others have a G.

This kind of variation is called a single nucleotide polymorphism (SNP). The word polymorphism meaning "many forms", but in fact this SNP has only two different forms, or alleles in human populations.

There are millions of SNPs in the human genome. When they sequence many people, geneticists often find SNPs they have never noticed before, and enter them into a catalog called dbSNP. Each SNP gets a catalog number, beginning with the letters "rs". This one, associated with eye color in Europeans, is known as rs12913832 (dbSNP link).

We know that rs12913832 is associated with variation in eye color because it has been genotyped in thousands of people. Blue-eyed people are very likely to carry two G's here. Why this SNP is associated with eye color is not yet clear. OCA2 is essential to forming normal pigmentation, but rs12913832 does not change the amino acid sequence of this gene. In fact, it lies within another gene, HERC2. The SNP may change the regulation of OCA2, or it may be linked on the same chromosome sequence to another mutation that does. Or the activity of HERC2 may itself affect pigmentation. Right now, scientists simply don't know.

Finding a genetic association, like a correlation, is not the same as finding a cause. An association doesn't necessarily tell us that the genetic change caused a change in the body; it merely indicates that one form of the gene is common in people with a particular trait.

An association may give some hint about the history of a trait. In the case of eye color, blue eyes are most common in northern Europe, and occur more rarely across southern Europe, north Africa, and West Asia. The G allele of rs12913832 has roughly the same distribution:

Allele frequencies of rs12913832 in human populations surveyed as part of the Human Genome Diversity Project. Map courtesy of HGDP Selection Browser.

The G allele is most common in northern Europe, and is rare or absent in most of Africa and East Asia. However, the indigenous people of South America actually have fairly high frequencies (up to 30-40%) for this allele. Those populations do not have blue eyes at any appreciable frequency. What can explain this discrepancy?

Again, a genetic association is not the same as a genetic cause. This SNP allele may be linked to blue eyes in Europe because of its history: Another mutation that causes blue eyes may have happened on a copy of chromosome 15 that carried this SNP allele. Meanwhile, a different copy of chromosome 15 carrying this SNP allele but unrelated to eye pigmentation was in the population that entered the New World some 15,000 years ago, and became common in the ancestors of South American populations.

Understanding the history of human movements helps us to uncover the genetic causes of traits. In this case, the SNP allele reflects two different histories in western Eurasia and in the New World.
Study questions:
Use the genome browser to look around rs12913832. Use the tools to zoom out until you can see the gene OCA2. How far away is OCA2 from this SNP?

The population of the United States was not surveyed in the project that gave rise to the map above. What do you predict about the allele frequencies of rs12913832 in the present U.S. population?

What is the frequency of the trait blue eyes in your classroom?
Study terms:
association
single nucleotide polymorphism (SNP)
mutation
chromosome
allele
allele frequency
Tags:
Anthropology 105
teaching
explainer
pigmentation
Violet eyes

Sun, 2011-03-27 18:03 -- John Hawks

Oh, I suppose I should go ahead and link to that Elizabeth Taylor mutation article:

Double rows of eyelashes are usually the result of a mutation at FOXC2, a gene that influences all kinds of tissue development in embryos. FOXC2 mutations are thought to be responsible for, among other things, lymphedema-distichiasis syndrome, a hereditary disease that can cause disorders of the lymphatic system in addition to double eyelashes.

It's interesting, in its way. But I really want to pick a bone with this:

I was slightly crushed, then, to discover that, by most official accounts, Taylor's eyes were actually a deep blue that appeared purple when enhanced by lighting and makeup. (Truly violet eyes occur only in albinos.)

Blue eyes are blue because of the quality of light available for diffraction. There's no blue pigment in them, just as there is no blue pigment in the sea to make it blue. (Amusement park water is a different story...). This is why we can talk sensibly about eyes that always seem to be changing in color.

I see no reason to deny the woman her violet eyes. Heck, in my yard the violets (the sweet yard-growing kind, not the African kind) aren't even violet! Dark blue eyes with a touch of eumelanin in a shallower configuration might not match the crayon for color, but could easily be violet to anyone at Richard Burton distance.

Tags:
celebrities
pigmentation
Denisovans did not have red hair

Sun, 2011-01-09 16:55 -- John Hawks
At least, the Denisova sequence does not have any of the variants in humans that are associated with red hair. Nor does it share the unique Neandertal variant argued to affect hair color in that group.

It's hard to make very confident predictions about pigmentation phenotypes from our current knowledge of gene associations. But it's fair to say that there's no evidence of anything other than dark hair for this individual. What may be equally interesting is that at least one Neandertal individual (Vi33.26) also appears to lack the unique variant in other Neandertals -- meaning that this group was probably polymorphic in hair pigmentation.

The unique Neandertal mutation observed by Lalueza-Fox and coworkers [1] is an A to G substitution at position 919 relative to the beginning of the coding sequence -- this mutation changes position 307 of the amino acid sequence from arginine to glycine (abbreviated Arg307Gly). This mutation was not otherwise observed in living people, but Lalueza-Fox and colleagues suggested on the basis of computational modeling that the change would reduce Mc1r activity, having a similar effect to known mutations that correlate with red hair. I wrote extensively about the study at the time ("The flame-haired Neandertals"). Lalueza-Fox and colleagues could not confirm that the sampled individuals (El Sidrón 1252 and the Monti Lessini specimen) were homozygotes for this mutation, but their multiple confirmation showed that the mutation must have been present. Hence they included the concept of "varying pigmentation" in the title of their paper.

The MC1R sequence has very limited coverage in the Neandertal draft genome data. Only one read from one individual (Vi33.26) covers this position of the genome; this read has the normal human allele (A) at this site. The Denisova sequence has reasonably good coverage across this site, with four reads covering it and one ending on it. All of these have the normal (A) allele. So Lalueza-Fox and colleagues were likely right -- this is a polymorphism in Neandertals. And it wasn't shared with Denisovans.

The coverage caveat

The exercise raises a problem, which really has no good solution: How many reads must we see to be confident that an ancient genome has an allele? All the available ancient genomes are very low-coverage, and have a high fraction of sequence errors. The Denisova sequence reads are vastly better than the reads from the Neandertals -- maybe even as good as the sequence reads from the human data provided alongside them. When we look at the living human genomes acquired with the same technology, we find reads riddled with errors. Beyond that, alignment of these short reads with the human reference genome is itself a statistical test that sometimes the computers fail. When a single read of 30 nucleotides is different from the human reference genome in three or four places, we can probably disregard it, even if the reported sequencing quality is high. When the first of last nucleotide is different, we can probably disregard that too, at least unless it is replicated in other reads. But when all we have is a single read, and when it differs from the human reference in a reasonable location -- or if it shares an allele with some known humans or chimpanzees -- what are we to make of it? Restricting ourselves to known polymorphisms -- either within humans or between humans and other species -- helps us to ignore the majority of spurious differences in these ancient sequences, but it does not eliminate the occasional error, and it may miss many interesting sites.

I tend to ignore sites where only a single read shows a difference between the ancient and consensus sequence. Where two reads overlap (as long as they don't look like multiple clones of the same read), I note the differences, and say that they might be interesting, but we really need more coverage. Where sequence differences occur in multiple reads, we can have a bit more confidence. If a site is a known polymorphism in humans or primates, I'm willing to believe the allelic state in a single read, but I feel better when there are several reads.

We won't be able to do anything with the genotypes of these ancient genomes until we have substantially higher coverage, and that makes interpreting the data very difficult. Remember, we're diploids, and we'll need even more reads to start considering genotypes and heterozygosity within these ancient genomes. At present, the statistical variance of this strange hybrid consensus genome is not what we expect from an actual single copy of the genome. That is our burden for relying on high-throughput sequencing these days, we just have to deal with it.

Known human polymorphisms

Now, if we really want to know about the function of Mc1r in the Denisova individual, we need to consider all the known human polymorphisms and their effects on the phenotype. Our knowledge of pigmentation variation attributable to MC1R in humans is not complete. Some combinations of alleles are shared by only very few people, and promoter polymorphisms which might affect Mc1r expression are tightly linked to coding polymorphisms, making it hard to assess their effects [2]. But we can certainly run down the known coding polymorphisms and see which alleles are in the Denisova and Neandertal sequence reads.

Harding and colleagues [3] provided an early assessment of sequence variation in the MC1R coding region among living humans. Chimpanzees differ from all sampled humans at 15 nucleotides. The Denisova individual is represented by at least one sequence read for every one of these substitutions, matching the human consensus sequence for all of them. The Neandertal sequence data do not have nearly as good coverage over this interval; they also match the human sequence where they are represented.

Where human SNPs are concerned, Harding and colleagues placed the root of the human genealogy between two haplotypes that differ by a mutation at site rs2228478, near the end of MC1R coding sequence. This is a synonymous mutation with no effect on the amino acid sequence, and it is a common variant in most human populations. The Denisova and Vindija 33.26 sequences both share the ancestral G allele for this SNP, meaning that they do not share the oldest derived variant present in most populations.

The ancestral G is more common (around 50%) in Africa than in Eurasia (10-25%). Its present geographic distribution of this variant doesn't tell us much about its early evolution, in part because the variant today is linked to nonsynonymous substitutions that may have been selected in Eurasian populations.

Neither Denisova nor any of the Vindija sequences possess any other derived SNPs found in human populations. That includes the variants known to be associated with pigmentation. Moreover Denisova does not present any sequence differences from the hg18 reference sequence that are represented by more than a single read. The sequence has reasonable coverage (3-4x) across much of this interval, so the lack of differences is somewhat informative. The Neandertal coverage is very low but also has no differences from hg18 that are represented by more than one read.

So, no novel polymorphisms in these individuals that we can confirm, and no derived SNP variants shared with any other humans. For most of the human SNPs, that's no surprise -- most of them occurred on chromosomes that carried the derived variant at rs2228478, while the Denisova and Neandertal sequences have the ancestral variant. The three derived SNP variants linked to the ancestral variant at rs2228478 give some resolution inside this branch of the MC1R genealogy, but Harding and colleagues found these derived alleles to be very low frequency within the samples they studied. The comparison therefore isn't surprising, but it is illuminating.

I started scanning the noncoding region upstream of MC1R, which was sequenced in a sample of humans by Makova and colleagues [4], but I didn't get too far into it. It's sort of rough comparing older sequence data to a genome assembly, because people often numbered across gaps in their sequences without noting them. At that time, the exact sizes of gaps were often unknown, particularly if they included length polymorphisms. So, using old data means realigning, which isn't what I'm up to right now.

I'll get back to this region, though, because it has rather an old coalescent with a fairly deep root outside Africa.

References

Lalueza-Fox C, Römpler H, Caramelli D, Stäubert C, Catalano G, Hughes D, Rohland N, Pilli E, Longo L, Condemi S, et al. 2007. A Melanocortin 1 Receptor Allele Suggests Varying Pigmentation Among Neanderthals. Science [Internet] 318:1453–1455. Available from: http://dx.doi.org/10.1126/science.1147417

Makova K, and Norton H. 2005. Worldwide polymorphism at the locus and normal pigmentation variation in humans. Peptides [Internet] 26:1901–1908. Available from: http://dx.doi.org/10.1016/j.peptides.2004.12.032

Harding RM, Healy E, Ray AJ, Ellis NS, Flanagan N, Todd C, Dixon C, Sajantila A, Jackson IJ, Birch-Machin MA, et al. 2000. Evidence for Variable Selective Pressures at {MC1R}. American Journal of Human Genetics 66:1351–1361.

Makova KD, Ramsay M, Jenkins T, and wen-Hsiung Li. 2001. Human DNA Sequence Variation in a 6.6-kb Region Containing the Melanocortin 1 Receptor Promoter. Genetics [Internet] 158:1253–1268. Available from: http://www.genetics.org/cgi/content/abstract/158/3/1253
Tags:
Denisova
Neandertals
Vindija
Neandertal DNA
pigmentation
Synopsis:
Our research is looking for evidence of Neandertal similarities within the Denisova genome, including a unique MC1R polymorphism.
Quote: Boyd on New World pigmentation clines

Tue, 2010-09-28 16:44 -- John Hawks
I'm using some statistics out of William Boyd's 1956 printing of Genetics and the Races of Man[1]. It gives a good accounting of blood group data known more than fifty years ago, which I'm using to illustrate my intro lectures. Meanwhile, there are some interesting passages, from the standpoint of today's knowledge of the human genome and its variation.

On skin pigmentation -- this is the earliest statement I've run across of the argument that the New World pigmentation cline is shallower than the Old World cline because of the relative recency of occupation (pp. 178-180):

The aborigines of the New World, though not by any means identical, agree in having on the whole considerable skin pigmentation. If pigmentation is adaptive, and conforms to climate, why are not the Eskimo and the inhabitants of Tierra del Fuego as light as Europeans? This looks like a considerable difficulty, but the solution is probably comparatively simple. The aborigines of the New World have not been here for more than about 25,000 years, or about 1000 generations. They are by origin Asiatic, and in Asia skin pigmentation is fairly heavy. Unless the selection of light skin as opposed to dark were fairly intense, the time elapsed has simply not been enough to allow for much adaptation to occur (12). As a matter of fact, the populations which might have been expected to become lighter, namely the Fuegans and the Eskimo, have probably had a shorter time in which to achieve this end than other American aborigines, for it is reasonable to suppose that the Fuegians did not reach their present home until long after their northern neighbors were well installed. And all students of the Eskimo agree in recognizing them as probably the most recent (aside of course from the whites) arrivals in America. It could well be that there has just not been enough time for selection to bleach the skins of the American aborigines.

Reference 12 is Haddon's Races of Man, which I have requested from the library.

I'm following up, because skin pigmentation is one of the traits most clearly subject to recent rapid selection. The new mutations that lighten skin tone in Europe and Asia are only partially shared between those populations. Many alleles are very common in one population, but nearly absent in the other. So far, the estimates of dates for these new variants are all within the last 20,000 years, but many remain undated. So we can't specify the level of pigmentation of people 15,000-20,000 years ago, yet, but it would have been substantially darker than those populations today.

Which leaves us with the same question, but from the opposite perspective. We now know that pigmentation evolved rapidly in Eurasia, the strong gradient of pigmentation having increased greatly within the last 20,000 years. We also know that the occupation of temperate South America began quite early, with people having been there longer than 10,000 years. So why did the New World end up with a more gradual cline -- darker pigmentation in the temperate and Arctic regions, lighter in the tropics than in the Old World? Was selection less intense? Can we attribute the difference to demography? Or chance?

Boyd next alluded to a demographic explanation -- low population density:

In any case, the pre-Columbian population was so sparse compared with that of Asia and India that on a statistical basis alone we should be justified in asserting that skin pigmentation conforms to climate.

Them's some tricky statistics.

We would of course today recognize that the sheer number of people is not especially relevant; much more powerful is the independent occurrence of a similar response in two long-separated populations. But Boyd was concerned with a different issue: Some had been claiming pigmentation as a neutral trait, making it more useful as a race marker:

This has been denied chiefly by those who were concerned to prove skin color a non-adaptive character, so that it might safely be used in the classification of races (12). Since the more up-to-date students of anthropology have given up the idea of relying on non-adaptive characters, or even believing that any such exist (13), there is no longer much dispute about the probable adaptive value of skin color (emphasis added).

Well, makes me glad to be an "up-to-date" student! There in fact has been an ongoing debate about "non-adaptive characters" as concerns the relationship of Pleistocene people. Many geneticists were surprised to discover the persistence of Neandertal genes, but in fact the skeletons of Upper Paleolithic Europeans clearly bear Neandertal traits. The debate for the last 30 years hasn't been chiefly about the presence of these traits, but instead about whether they were adaptive. Some argued that adaptive traits were not suitable evidence for a relationship, because they could emerge by parallelism in distinct populations.

Others observed that adaptive traits were more likely to be shared among populations linked by gene flow.

Now, of course, we have remaining unanswered questions about these shared traits. The shared traits are clearest between Upper Paleolithic Europeans and European Neandertals. We don't have genetic information yet telling us about the extent of Neandertal gene sharing with these early Europeans. Was it more than elsewhere? The traits would argue for it.

What about the Neandertal genes in populations far from Europe? One might expect Neandertal-like morphology to show up at some low level. Of course morphological features are polygenic, so that phenotypic resemblance falls much faster than genic identity. And Holocene populations have continued to evolve. Maybe early Asian skeletal remains like the Upper Cave skulls (ca. 11,000-20,000 years old) actually reflect that Neandertal heritage to a greater extent than recent samples.

Then there is the likelihood of other contributions, more local ones, to later populations.

Returning to the topic of pigmentation, many of us used to assume that the light skin of Europeans in part reflects Neandertal ancestry. That is, just as Boyd suggested, it would have taken a lot longer than 25,000 years to get the current strong cline of skin pigmentation in the Old World. If you could have longer, getting lighter pigmentation from earlier inhabitants of Europe, for example, you could explain a stronger cline with the same strength of selection.

I no longer think this is necessary. It's still possible that we got some pigmentation variants from Neandertals, but we haven't found any yet. And we've been looking. It does seem that Neandertals had some of their own pigmentation variants. Maybe we'll find many more of those, maybe not.

References

Boyd WC. 1956. Genetics and the Races of Man. Boston.
Tags:
quotes
introgression
Zhoukoudian
America
pigmentation
recent selection
Neandertal DNA
China
American Indians
Mailbag: Neandertal colors

Thu, 2010-05-13 08:41 -- John Hawks

Regarding that cool new app from Apple/Smithsonian... I know it's really all just for fun, but seeing that there is only one Neandertal face for everyone to use, I began to wonder about adaptations they may have gone through in their 400,000 year reign. Seems to me that from France to China to the Levant that skin shades and certain facial features would arise (probably not the right word there) and that to keep the app really interesting that they should have a couple different Neandertal faces to choose from. Otherwise everyone will start to look too much alike.

Please know I know you have nothing to do with the app... just was curious about your thoughts on Neandertal adaptations and if what I'm griping (lightheartedly) about is reasonable?

I agree completely. It is characteristic for artist reconstructors to use skin tones and hair shades that reflect present-day people -- so the Near Eastern Neandertals are tanner and black-haired; the European ones light-haired and pale.

But that assumes a lot about the nature of the present variation. Now that we know that the genes with the largest effects on pigmentation are in fact very recently selected, there's really no reason to think that we fit our environments very well now (or in recent pre-industrial history). We might be stopped in the middle of going to even more extreme differences; or we might have gone much farther because of the availability of more adaptive variation to work with.

The variation in a long-adapted population like Neandertals might well be more than ours. Or less -- because they were a much smaller population with fewer chances at adaptive changes. It's really hard to predict .

Tags:
Neandertals
pigmentation
Pigment controller OCA2

Fri, 2010-03-05 15:23 -- John Hawks

Razib: "OCA2 makes East Asians white and Europeans blue."He discusses a study out of Esteban Parra's lab in PLoS Genetics (open access), which characterizes a non-synonymous polymorphism in China that lies on a recently selected haplotype. The genotypes correlate additively with skin melanin -- a very different effect from the European new mutant allele.

Edwards M, Bigham A, Tan J, Li S, Gozdzik A, et al. (2010) Association of the OCA2 Polymorphism His615Arg with Melanin Content in East Asian Populations: Further Evidence of Convergent Evolution of Skin Pigmentation. PLoS Genet 6(3): e1000867. doi:10.1371/journal.pgen.1000867

Tags:
China
pigmentation
recent selection
Lizard whitening

Sat, 2010-01-09 07:30 -- John Hawks

Ed Yong reports on a study of pigmentation evolution in the lizards of White Sands, New Mexico: "Three desert lizards evolve white skins through different mutations to the same gene".

The gene is MC1R, also responsible for pigment variation in humans and, apparently, Neandertals. That makes for an interesting story of parallelism of pigment loss. Cave fish have recurrently lost pigmentation due to a different gene, homologous to our OCA2, best known as the "blue-eye" gene. It makes me wonder why lizards broke MC1R repeatedly -- were they using their OCA2 for something else?

Tags:
non-primate
pigmentation