Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs

Background: Genome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world. Methodology: We genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level. Conclusions: Our analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature.