Friday, February 08, 2008

SNPs that may have made human populations different and the genes they're in

The authors of this new paper (abstract below) look at Fst values for 2.8 milion HapMap SNPs and consider the location and potential physiological impact of the nonsynonymous SNPs that show high Fst values (indicating positive selection). They use a program called Polyphen, that I haven't heard of before, that "predicts the functional effect of impact of an amino acid substitution on the structure and function of a human protein". They publish a list of 582 genes that contain at least one nonsynonymous high Fst SNP in the suppl. material, and list a few of them in the paper.
This paper has generated some news stories that seem to focus on the relevance of population differentiation to disease. There's some funny, catchy titles:
Human Survival Genes Pinpointed
Humans are evolving to resist disease

They throw out the idea of phenotypic hitchhiking. It probably does happen, but their example is not very well supported. They should have put a reference for this statement about EDAR and tooth shape and how it "probably does not affect fitness":
For example, EDAR regulates hair follicle density and the development of sweat glands and teeth in humans and mice[24, 25]. In humans, selective pressures on EDAR favoring changes in body temperature regulation and hair follicle density in response to colder climates may have influenced tooth shape, although this trait probably does not affect population fitness. This anecdotal example shows how 'phenotypic hitchhiking' in genes under positive selection may have substantially increased the observed number of physiological and morphological traits differentiating modern human populations.
They find that genes that show "signs of positive selection are observed in genes involved in disease". Related to diabetes, they briefly discuss a mutation in ENPP1:
Another important selective pressure that has confronted modern humans is adaptation to variable nutritional resources. Several genes involved in the regulation of insulin and in metabolic syndrome seem to have undergone positive selection (Table 1). For example, ENPP1 harbors a mutation with a derived state known to protect against obesity and type II diabetes27 that is present in 90% of non-Africans but virtually absent in Africans (rs1044498; FST = 0.77, Supplementary Note). ENPP1 and several other examples of derived protective alleles28 indicate that, in contrast to the situation with mendelian diseases, alleles that increase complex disease risk are not necessarily new mutations, but rather ancestral alleles that have become disadvantageous after changes of environment and lifestyle.
Natural selection has driven population differentiation in modern humans
Luis B Barreiro, Guillaume Laval, Hélène Quach, Etienne Patin & Lluís Quintana-Murci
Nature Genetics Published online: 3 February 2008
Abstract: The considerable range of observed phenotypic variation in human populations may reflect, in part, distinctive processes of natural selection and adaptation to variable environmental conditions. Although recent genome-wide studies have identified candidate regions under selection1, 2, 3, 4, 5, it is not yet clear how natural selection has shaped population differentiation. Here, we have analyzed the degree of population differentiation at 2.8 million Phase II HapMap single-nucleotide polymorphisms6. We find that negative selection has globally reduced population differentiation at amino acid–altering mutations, particularly in disease-related genes. Conversely, positive selection has ensured the regional adaptation of human populations by increasing population differentiation in gene regions, primarily at nonsynonymous and 5'-UTR variants. Our analyses identify a fraction of loci that have contributed, and probably still contribute, to the morphological and disease-related phenotypic diversity of current human populations.

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