Beyond the Genome: genomics research ten years after the human genome sequence

A report on the meeting 'Beyond the Genome', Boston, USA, 11-13 October 2010

A Tale of Two Haplotypes: The \u3cem\u3eEDA2R/AR\u3c/em\u3e Intergenic Region is the most Divergent Genomic Segment between Africans and East Asians in the Human Genome

Single nucleotide polymorphisms (SNPs) with large allele frequency differences between human populations are relatively rare. The longest run of SNPs with an allele frequency difference of one between the Yoruba of Nigeria and the Han Chinese is found on the long arm of the X chromosome in the intergenic region separating the EDA2R and AR genes. It has been proposed that the unusual allele frequency distributions of these SNPs are the result of a selective sweep affecting African populations that occurred after the Out-of-Africa migration. To investigate the evolutionary history of the EDA2R/AR intergenic region, we characterized the haplotype structure of 52 of its highly-differentiated SNPs. Using a publicly-available dataset of 3,000 X chromosomes from 65 human populations, we found that nearly all human X chromosomes carry one of two modal haplotypes for these 52 SNPs. The predominance of two highly divergent haplotypes at this locus was confirmed using a subset of individuals sequenced to high coverage. The first of these haplotypes, the α haplotype, is at high frequencies in most of the African populations surveyed and likely arose prior to the separation of African populations into distinct genetic entities. The second, the β haplotype, is frequent or fixed in all non-African populations and likely arose in East Africa prior to the Out-of-Africa migration. We also observed a small group of rare haplotypes with no clear relationship to the α and β haplotypes. These haplotypes occur at relatively high frequencies in African hunter-gatherer populations, like the San and Mbuti Pygmies. Our analysis indicates that these haplotypes are part of a pool of diverse, ancestral haplotypes that have now been almost entirely replaced by the α and β haplotypes. We suggest that the rise of the α and β haplotypes was the result of the demographic forces that human populations experienced during the formation of modern African populations and the Out-of-Africa migration. However, we also present evidence that this region is the target of selection in the form of positive selection on the α and β haplotypes and of purifying selection against α/β recombinants

Characterization of X-Linked SNP genotypic variation in globally distributed human populations

An analysis of X-linked genetic variation in human populations provides insights into population structure and demographic patterns

Melanesian and Asian origins of Polynesians: mtDNA and Y chromosome gradients across the Pacific

The human settlement of the Pacific Islands represents one of the most recent major migration events of mankind. Polynesians originated in Asia according to linguistic evidence or in Melanesia according to archaeological evidence. To shed light on the genetic origins of Polynesians, we investigated over 400 Polynesians from 8 island groups, in comparison with over 900 individuals from potential parental populations of Melanesia, Southeast and East Asia, and Australia, by means of Y chromosome (NRY) and mitochondrial DNA (mtDNA) markers. Overall, we classified 94.1% of Polynesian Y chromosomes and 99.8% of Polynesian mtDNAs as of either Melanesian (NRY-DNA: 65.8%, mtDNA: 6%) or Asian (NRY-DNA: 28.3%, mtDNA: 93.8%) origin, suggesting a dual genetic origin of Polynesians in agreement with the "Slow Boat" hypothesis. Our data suggest a pronounced admixture bias in Polynesians toward more Melanesian men than women, perhaps as a result of matrilocal residence in the ancestral Polynesian society. Although dating methods are consistent with somewhat similar entries of NRY/mtDNA haplogroups into Polynesia, haplotype sharing suggests an earlier appearance of Melanesian haplogroups than those from Asia. Surprisingly, we identified gradients in the frequency distribution of some NRY/mtDNA haplogroups across Polynesia and a gradual west-to-east decrease of overall NRY/mtDNA diversity, not only providing evidence for a west-to-east direction of Polynesian settlements but also suggesting that Pacific voyaging was regular rather than haphazard. We also demonstrate that Fiji played a pivotal role in the history of Polynesia: humans probably first migrated to Fiji, and subsequent settlement of Polynesia probably came from Fiji

Genome-Wide Association Study SNPs in the Human Genome Diversity Project Populations: Does Selection Affect Unlinked SNPs with Shared Trait Associations?

Genome-wide association studies (GWAS) have identified more than 2,000 trait-SNP associations, and the number continues to increase. GWAS have focused on traits with potential consequences for human fitness, including many immunological, metabolic, cardiovascular, and behavioral phenotypes. Given the polygenic nature of complex traits, selection may exert its influence on them by altering allele frequencies at many associated loci, a possibility which has yet to be explored empirically. Here we use 38 different measures of allele frequency variation and 8 iHS scores to characterize over 1,300 GWAS SNPs in 53 globally distributed human populations. We apply these same techniques to evaluate SNPs grouped by trait association. We find that groups of SNPs associated with pigmentation, blood pressure, infectious disease, and autoimmune disease traits exhibit unusual allele frequency patterns and elevated iHS scores in certain geographical locations. We also find that GWAS SNPs have generally elevated scores for measures of allele frequency variation and for iHS in Eurasia and East Asia. Overall, we believe that our results provide evidence for selection on several complex traits that has caused changes in allele frequencies and/or elevated iHS scores at a number of associated loci. Since GWAS SNPs collectively exhibit elevated allele frequency measures and iHS scores, selection on complex traits may be quite widespread. Our findings are most consistent with this selection being either positive or negative, although the relative contributions of the two are difficult to discern. Our results also suggest that trait-SNP associations identified in Eurasian samples may not be present in Africa, Oceania, and the Americas, possibly due to differences in linkage disequilibrium patterns. This observation suggests that non-Eurasian and non-East Asian sample populations should be included in future GWAS

The Role of Selection in Shaping Diversity of Natural M. tuberculosis Populations

Mycobacterium tuberculosis ( M.tb ), the cause of tuberculosis (TB), is estimated to infect a new host every second. While analyses of genetic data from natural populations of M.tb have emphasized the role of genetic drift in shaping patterns of diversity, the influence of natural selection on this successful pathogen is less well understood. We investigated the effects of natural selection on patterns of diversity in 63 globally extant genomes of M.tb and related pathogenic mycobacteria. We found evidence of strong purifying selection, with an estimated genome-wide selection coefficient equal to −9.5×10 −4 (95% CI −1.1×10 −3 to −6.8×10 −4 ); this is several orders of magnitude higher than recent estimates for eukaryotic and prokaryotic organisms. We also identified different patterns of variation across categories of gene function. Genes involved in transport and metabolism of inorganic ions exhibited very low levels of non-synonymous polymorphism, equivalent to categories under strong purifying selection (essential and translation-associated genes). The highest levels of non-synonymous variation were seen in a group of transporter genes, likely due to either diversifying selection or local selective sweeps. In addition to selection, we identified other important influences on M.tb genetic diversity, such as a 25-fold expansion of global M.tb populations coincident with explosive growth in human populations (estimated timing 1684 C.E., 95% CI 1620–1713 C.E.). These results emphasize the parallel demographic histories of this obligate pathogen and its human host, and suggest that the dominant effect of selection on M.tb is removal of novel variants, with exceptions in an interesting group of genes involved in transportation and defense. We speculate that the hostile environment within a host imposes strict demands on M.tb physiology, and thus a substantial fitness cost for most new mutations. In this respect, obligate bacterial pathogens may differ from other host-associated microbes such as symbionts. Mycobacterium tuberculosis ( M.tb ), the etiologic agent of tuberculosis (TB), is a highly prevalent pathogen of humans, estimated to infect one-third of the world's population. Previous investigations of M.tb evolution have emphasized the influence of chance events on populations of these bacteria. To understand why this organism is so well adapted to its niche, we sought to characterize the influence of natural selection on M.tb . DNA sequence data from M.tb populations appeared to be strongly influenced by genome-wide selection against deleterious mutations. This type of selection was particularly evident in three functional categories: genes essential for infection (identified in an animal model of TB), genes involved in protein translation, and genes involved in trafficking and metabolism of inorganic ions. By contrast, a fourth category (‘defense’ genes) exhibited high levels of diversity, consistent with selection for advantageous mutations. In addition to effects of selection on M.tb genomic data, we identified the influence of a pronounced recent expansion in M.tb populations, coincident with explosive growth of human populations around the world. Our results suggest that growth of M.tb populations parallels that of its human host population, and that complex influences lead to emergence and maintenance of adaptive traits in M.tb

A Tale of Two Haplotypes: The EDA2R/AR Intergenic Region Is the Most Divergent Genomic Segment between Africans and East Asians in the Human Genome

Single nucleotide polymorphisms (SNPs) with large allele frequency differences between human populations are relatively rare. The longest run of SNPs with an allele frequency difference of one between the Yoruba of Nigeria and the Han Chinese is found on the long arm of the X chromosome in the intergenic region separating the EDA2R and AR genes. It has been proposed that the unusual allele frequency distributions of these SNPs are the result of a selective sweep affecting African populations that occurred after the out-of-Africa migration. To investigate the evolutionary history of the EDA2R/AR intergenic region, we characterized the haplotype structure of 52 of its highly differentiated SNPs. Using a publicly available data set of 3,000 X chromosomes from 65 human populations, we found that nearly all human X chromosomes carry one of two modal haplotypes for these 52 SNPs. The predominance of two highly divergent haplotypes at this locus was confirmed by use of a subset of individuals sequenced to high coverage. The first of these haplotypes, the α-haplotype, is at high frequencies in most of the African populations surveyed and likely arose before the separation of African populations into distinct genetic entities. The second, the β-haplotype, is frequent or fixed in all non-African populations and likely arose in East Africa before the out-of-Africa migration. We also observed a small group of rare haplotypes with no clear relationship to the α- and β-haplotypes. These haplotypes occur at relatively high frequencies in African hunter-gatherer populations, such as the San and Mbuti Pygmies. Our analysis indicates that these haplotypes are part of a pool of diverse, ancestral haplotypes that have now been almost entirely replaced by the α- and β-haplotypes. We suggest that the rise of the α- and β-haplotypes was the result of the demographic forces that human populations experienced during the formation of modern African populations and the out-of-Africa migration. However, we also present evidence that this region is the target of selection in the form of positive selection on the α- and β-haplotypes and of purifying selection against α/β recombinants