The Case for Selection at CCR5-Δ32

Sabeti, Pardis C.; Walsh, Emily; Schaffner, Steve F.; Varilly, Patrick; Fry, Ben; Hutcheson, Holli; Cullen, Mike; Mikkelsen, Tarjei S.; Roy, Jessica; Patterson, Nick; Cooper, Richard; Reich, David; Altshuler, David; O’Brien, Stephen J.; Lander, Eric S.

doi:10.1371/journal.pbio.0030378

Cited by 199 publications

(157 citation statements)

References 28 publications

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“…One possible reason is that the allele and haplotype frequencies of polymorphic loci in innate immunity genes in the study population has been reshaped by natural selection, perhaps because of their long and continued exposure to a high load of pathogens. Specific alleles in many human genes are now known to have been strongly selected in recent human history, especially in relation to exposure to infectious pathogens, such as CCR5 (Novembre et al, 2005;Sabeti et al, 2005) and FY (Hamblin et al, 2002). It has also been speculated that genes related to disease resistance are very likely to show evidence of recent positive selection (Wang et al, 2006), including resistance to infections -such as smallpox, malaria, yellow fever, typhus and cholera -that have become important causes of mortality after the origin and spread of agriculture (McNeill, 1976;Wolfe et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Genetic variation and haplotype structures of innate immunity genes in eastern India

Bairagya

Bhattacharya

et al. 2008

Infection, Genetics and Evolution

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This study reports results of an extensive and comprehensive study of genetic diversity in 12 genes of the innate immune system in a population of eastern India. Genomic variation was assayed in 171 individuals by resequencing ~75 kb of DNA comprising these genes in each individual. Almost half of the 548 DNA variants discovered was novel. DNA sequence comparisons with human and chimpanzee reference sequences revealed evolutionary features indicative of natural selection operating among individuals, who are residents of an area with a high load of microbial and other pathogens. Significant differences in allele and haplotype frequencies of the study population were observed with the HapMap populations. Gene and haplotype diversities were observed to be high. The genetic positioning of the study population among the HapMap populations based on data of the innate immunity genes substantially differed from what has been observed for Indian populations based on data of other genes. The reported range of variation in SNP density in the human genome is one SNP per 1.19 kb (chromosome 22) to one SNP per 2.18 kb (chromosome 19). The SNP density in innate immunity genes observed in this study (>3 SNPs kb −1 ) exceeds the highest density observed for any autosomal chromosome in the human genome. The extensive genomic variation and the distinct haplotype structure of innate immunity genes observed among individuals have possibly resulted from the impact of natural selection.

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Section: Discussionmentioning

confidence: 99%

Genetic variation and haplotype structures of innate immunity genes in eastern India

Bairagya

Bhattacharya

et al. 2008

Infection, Genetics and Evolution

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“…Past studies of complex traits have met with great success in identifying a number of significant genetic variants, although such variants usually account for only a small fraction of the total trait variation and their functional roles typically remain unclear [1][2][3][4][5][6][7][8]. The focus on searching for a few major effect variants is under the null hypothesis in the field of population genetics that the majority of genetic variations are neutral.…”

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Scoring the collective effects of SNPs: association of minor alleles with complex traits in model organisms

Yuan

Zhu

Tan

et al. 2014

Sci. China Life Sci.

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It has long been assumed that most parts of a genome and most genetic variations or SNPs are non-functional with regard to reproductive fitness. However, the collective effects of SNPs have yet to be examined by experimental science. We here developed a novel approach to examine the relationship between traits and the total amount of SNPs in panels of genetic reference populations. We identified the minor alleles (MAs) in each panel and the MA content (MAC) that each inbred strain carried for a set of SNPs with genotypes determined in these panels. MAC was nearly linearly linked to quantitative variations in numerous traits in model organisms, including life span, tumor susceptibility, learning and memory, sensitivity to alcohol and anti-psychotic drugs, and two correlated traits poor reproductive fitness and strong immunity. These results suggest that the collective effects of SNPs are functional and do affect reproductive fitness. collective effects, complex traits, minor alleles, SNPs, recombinant inbred lines, minor allele content (MAC) Citation:

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“…Because LD decays quickly over time, most ASVs are quite recent (14), compared with other approaches that detect selection over longer evolutionary time scales (15, 16). Many human genes are now known to have strongly selected alleles in recent historical times, such as lactase (17,18), CCR5 (19,20), and FY (21). These surveys show that such genes are very common.…”

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Recent acceleration of human adaptive evolution

Hawks

Wang²,

Cochran

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

391

267

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Genomic surveys in humans identify a large amount of recent positive selection. Using the 3.9-million HapMap SNP dataset, we found that selection has accelerated greatly during the last 40,000 years. We tested the null hypothesis that the observed age distribution of recent positively selected linkage blocks is consistent with a constant rate of adaptive substitution during human evolution. We show that a constant rate high enough to explain the number of recently selected variants would predict (i) site heterozygosity at least 10-fold lower than is observed in humans, (ii) a strong relationship of heterozygosity and local recombination rate, which is not observed in humans, (iii) an implausibly high number of adaptive substitutions between humans and chimpanzees, and (iv) nearly 100 times the observed number of highfrequency linkage disequilibrium blocks. Larger populations generate more new selected mutations, and we show the consistency of the observed data with the historical pattern of human population growth. We consider human demographic growth to be linked with past changes in human cultures and ecologies. Both processes have contributed to the extraordinarily rapid recent genetic evolution of our species.HapMap ͉ linkage disequilibrium ͉ Neolithic ͉ positive selection H uman populations have increased vastly in numbers during the past 50,000 years or more (1). In theory, more people means more new adaptive mutations (2). Hence, human population growth should have increased in the rate of adaptive substitutions: an acceleration of new positively selected alleles.Can this idea really describe recent human evolution? There are several possible problems. Only a small fraction of all mutations are advantageous; most are neutral or deleterious. Moreover, as a population becomes more and more adapted to its current environment, new mutations should be less and less likely to increase fitness. Because species with large population sizes reach an adaptive peak, their rate of adaptive evolution over geologic time should not greatly exceed that of rare species (3).But humans are in an exceptional demographic and ecological transient. Rapid population growth has been coupled with vast changes in cultures and ecology during the Late Pleistocene and Holocene, creating new opportunities for adaptation. The past 10,000 years have seen rapid skeletal and dental evolution in human populations and the appearance of many new genetic responses to diets and disease (4).In such a transient, large population, size increases the rate and effectiveness of adaptive responses. For example, natural insect populations often produce effective monogenic resistance to pesticides, whereas small laboratory populations under similar selection develop less effective polygenic adaptations (5). Chemostat experiments on Escherichia coli show a continued response to selection (6), with continuous and repeatable responses in large populations but variable and episodic responses in small populations (7). These results are explained by a model in...

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The Case for Selection at CCR5-Δ32

Cited by 199 publications

References 28 publications

Genetic variation and haplotype structures of innate immunity genes in eastern India

Genetic variation and haplotype structures of innate immunity genes in eastern India

Scoring the collective effects of SNPs: association of minor alleles with complex traits in model organisms

Recent acceleration of human adaptive evolution

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