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

PLOS ONE, Nov 2009

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.

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

et al. (2009) Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs. PLoS ONE 4(11): e7888. doi:10.1371/journal.pone.0007888 Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs David Lo pez Herra ez 0 Marc Bauchet 0 Kun Tang 0 Christoph Theunert 0 Irina Pugach 0 Jing Li 0 Madhusudan R. Nandineni 0 Arnd Gross 0 Markus Scholz 0 Mark Stoneking 0 John Hawks, University of Wisconsin, United States of America 0 1 Max Planck Institute for Evolutionary Anthropology , Leipzig, Germany , 2 Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China , 3 National Drug Screening Laboratory, China Pharmaceutical University , Nanjing City , China , 4 Laboratory of DNA Fingerprinting, Centre for DNA Fingerprinting and Diagnostics , Nampally, Hyderabad , India , 5 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig , Leipzig , Germany 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. - Funding: This work was supported by the Max Planck Society, a Max Planck India Visiting Scientist Fellowship [to M.N.], and by the German Federal Ministry for Education and Research [01KN0702 to M.Sc. and A.G.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. The introduction of rapid, efficient, and relatively inexpensive platforms for simultaneous genotyping of hundreds of thousands of single-nucleotide polymorphisms (SNPs) has revolutionized diseaseassociation studies, as genome-wide scans have identified many SNPs associated with complex diseases [1,2]. One outcome of these efforts, the HapMap project [3,4], has lead to new insights into the demographic history [5] of the three major HapMap populations (Yoruba, European, and Chinese/Japanese), as well as the identification of potential signals of recent positive selection [610]. More recently, genome-wide scans have been applied to worldwide [1114], regional [1517] and local [18,19] populations, resulting in new insights into the genetic structure and relationships of human populations. An important resource that has substantially advanced studies of worldwide genetic variation is the CEPH Human Genetic Diversity Panel (HGDP-CEPH), a collection of some 1064 cell lines from 52 worldwide populations [20], from which DNA is made available. In order to provide useful background information for ongoing studies of genome-wide variation in particular population samples in our laboratory, we decided to genotype a subset of 255 individuals from the HGDP-CEPH, consisting of 5 individuals from each of the 51 populations, for approximately 500,000 SNPs with the Affymetrix GeneChip Human Mapping 500 K Array Set. During the course of this work, genotypes became available for 938 individuals from the HGDP-CEPH, analysed for approximately 650,000 SNPs with Illumina HumanHap 650 K Beadchips [13]. The overlap between t (...truncated)


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David López Herráez, Marc Bauchet, Kun Tang, Christoph Theunert, Irina Pugach, Jing Li, Madhusudan R. Nandineni, Arnd Gross, Markus Scholz, Mark Stoneking. Genetic Variation and Recent Positive Selection in Worldwide Human Populations: Evidence from Nearly 1 Million SNPs, PLOS ONE, 2009, 11, DOI: 10.1371/journal.pone.0007888