Signatures Of Recent Positive Selection Research Articles

Haplotype allelic classes for detecting ongoing positive selection

BackgroundNatural selection eliminates detrimental and favors advantageous phenotypes. This process leaves characteristic signatures in underlying genomic segments that can be recognized through deviations in allelic or haplotypic frequency spectra. To provide an identifiable signature of recent positive selection that can be detected by comparison with the background distribution, we introduced a new way of looking at genomic polymorphisms: haplotype allelic classes.ResultsThe model combines segregating sites and haplotypic information in order to reveal useful data characteristics. We developed a summary statistic, Svd, to compare the distribution of the haplotypes carrying the selected allele with the distribution of the remaining ones. Coalescence simulations are used to study the distributions under standard population models assuming neutrality, demographic scenarios and selection models. To test, in practice, haplotype allelic class performance and the derived statistic in capturing deviation from neutrality due to positive selection, we analyzed haplotypic variation in detail in the locus of lactase persistence in the three HapMap Phase II populations.ConclusionsWe showed that the Svd statistic is less sensitive than other tests to confounding factors such as demography or recombination. Our approach succeeds in identifying candidate loci, such as the lactase-persistence locus, as targets of strong positive selection and provides a new tool complementary to other tests to study natural selection in genomic data.

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

BackgroundGenome-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.MethodologyWe 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.ConclusionsOur 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.

Evolutionary Trajectories of Primate Genes Involved in HIV Pathogenesis

The current availability of five complete genomes of different primate species allows the analysis of genetic divergence over the last 40 million years of evolution. We hypothesized that the interspecies differences observed in susceptibility to HIV-1 would be influenced by the long-range selective pressures on host genes associated with HIV-1 pathogenesis. We established a list of human genes (n = 140) proposed to be involved in HIV-1 biology and pathogenesis and a control set of 100 random genes. We retrieved the orthologous genes from the genome of humans and of four nonhuman primates (Pan troglodytes, Pongo pygmaeus abeli, Macaca mulatta, and Callithrix jacchus) and analyzed the nucleotide substitution patterns of this data set using codon-based maximum likelihood procedures. In addition, we evaluated whether the candidate genes have been targets of recent positive selection in humans by analyzing HapMap Phase 2 single-nucleotide polymorphisms genotyped in a region centered on each candidate gene. A total of 1,064 sequences were used for the analyses. Similar median K(A)/K(S) values were estimated for the set of genes involved in HIV-1 pathogenesis and for control genes, 0.19 and 0.15, respectively. However, genes of the innate immunity had median values of 0.37 (P value = 0.0001, compared with control genes), and genes of intrinsic cellular defense had K(A)/K(S) values around or greater than 1.0 (P value = 0.0002). Detailed assessment allowed the identification of residues under positive selection in 13 proteins: AKT1, APOBEC3G, APOBEC3H, CD4, DEFB1, GML, IL4, IL8RA, L-SIGN/CLEC4M, PTPRC/CD45, Tetherin/BST2, TLR7, and TRIM5alpha. A number of those residues are relevant for HIV-1 biology. The set of 140 genes involved in HIV-1 pathogenesis did not show a significant enrichment in signals of recent positive selection in humans (intraspecies selection). However, we identified within or near these genes 24 polymorphisms showing strong signatures of recent positive selection. Interestingly, the DEFB1 gene presented signatures of both interspecies positive selection in primates and intraspecies recent positive selection in humans. The systematic assessment of long-acting selective pressures on primate genomes is a useful tool to extend our understanding of genetic variation influencing contemporary susceptibility to HIV-1.

Interrogating 11 Fast-Evolving Genes for Signatures of Recent Positive Selection in Worldwide Human Populations

Different signatures of natural selection persist over varying time scales in our genome, revealing possible episodes of adaptative evolution during human history. Here, we identify genes showing signatures of ancestral positive selection in the human lineage and investigate whether some of those genes have been evolving adaptatively in extant human populations. Specifically, we compared more than 11,000 human genes with their orthologs in chimpanzee, mouse, rat, and dog and applied a branch-site likelihood method to test for positive selection on the human lineage. Among the significant cases, a robust set of 11 genes was then further explored for signatures of recent positive selection using single nucleotide polymorphism (SNP) data. We genotyped 223 SNPs in 39 worldwide populations from the HGDP-CEPH diversity panel and supplemented this information with available genotypes for up to 4,814 SNPs distributed along 2 Mb centered on each gene. After exploring the allele frequency spectrum, population differentiation and the maintenance of long unbroken haplotypes, we found signals of recent adaptative phenomena in only one of the 11 candidate gene regions. However, the signal of recent selection in this region may come from a different, neighboring gene (CD5) rather than from the candidate gene itself (VPS37C). For this set of positively selected genes in the human lineage, we find no indication that these genes maintained their rapid evolutionary pace among human populations. Based on these data, it therefore appears that adaptation for human-specific and for population-specific traits may have involved different genes.

The G Allele of SNP E1/A118G at the µ-Opioid Receptor Gene Locus Shows Genomic Evidence of Recent Positive Selection

Opioid drug response and pain perception differs greatly amongst different individuals. The micro-opioid receptor (MOR) is the main receptor target for important opioid analgesics. As SNPs may contribute to interindividual differences in drug response, in silico signatures of recent positive selection (RPS) were utilized to seek out potentially functional SNPs in the MOR gene in order to facilitate the prioritization of SNPs for evaluation in genetic association studies. Out of over 1000 SNPs at the MOR locus, 184 high-frequency SNPs were interrogated for signatures of RPS. A total of five SNPs (four noncoding and one nonsynonymous coding) demonstrated in silico evidence of RPS. Significantly, the nonsynonymous E1/A118G SNP, which was previously reported to be functionally important, showed in silico evidence of RPS. This reaffirms the feasibility of utilizing in silico signatures of RPS to identify potentially functionally significant SNPs for association studies. Interestingly, the positively selected G allele of this RPS SNP was also predicted to create a novel exon splice enhancer as well as p53 binding sites.

Signals of recent positive selection in a worldwide sample of human populations

Genome-wide scans for recent positive selection in humans have yielded insight into the mechanisms underlying the extensive phenotypic diversity in our species, but have focused on a limited number of populations. Here, we present an analysis of recent selection in a global sample of 53 populations, using genotype data from the Human Genome Diversity-CEPH Panel. We refine the geographic distributions of known selective sweeps, and find extensive overlap between these distributions for populations in the same continental region but limited overlap between populations outside these groupings. We present several examples of previously unrecognized candidate targets of selection, including signals at a number of genes in the NRG-ERBB4 developmental pathway in non-African populations. Analysis of recently identified genes involved in complex diseases suggests that there has been selection on loci involved in susceptibility to type II diabetes. Finally, we search for local adaptation between geographically close populations, and highlight several examples.

The dystrobrevin-binding protein 1 gene: features and networks

The dystrobrevin-binding protein 1 (DTNBP1) gene has been one of the most studied and promising schizophrenia susceptibility genes since it was first reported to be associated with schizophrenia in the Irish Study of High Density Schizophrenia Families (ISHDSF). Although many studies have been performed both at the functional level and in association with psychiatric disorders, there has been no systematic review of the features of the DTNBP1 gene, protein or the relationship between function and phenotype. Using a bioinformatics approach, we identified the DTNBP1 gene in 13 vertebrate species. The comparison of these genes revealed a conserved gene structure, protein-coding sequence and dysbindin domain, but a diverse noncoding sequence. The molecular evolutionary analysis suggests the DTNBP1 gene probably originated in chordates and matured in vertebrates. No signature of recent positive selection was seen in any primate lineage. The DTNBP1 gene likely has many more alternative transcripts than the current three major isoforms annotated in the NCBI database. Our examination of risk haplotypes revealed that, although the frequency of a single nucleotide polymorphism (SNP) or haplotype might be significantly different in cases from controls, difference between major geographic populations was even larger. Finally, we constructed the first DTNBP1 interactome and explored its network features. Besides the biogenesis of lysosome-related organelles complex 1 and dystrophin-associated protein complex, several molecules in the DTNBP1 network likely provide insight into the role of DTNBP1 in biological systems: retinoic acid, beta-estradiol, calmodulin and tumour necrosis factor. Studies of these subnetworks and pathways may provide opportunities to deepen our understanding of the mechanisms of action of DTNBP1 variants.

The Timing of Selection at the Human FOXP2 Gene

Krause J, Lalueza-Fox C, Orlando L, et al. recently examined patterns of genetic variation at FOXP2 in 2 Neanderthals. This gene is of particular interest because it is involved in speech and language and was previously shown to harbor the signature of recent positive selection. The authors found the same 2 amino acid substitutions in Neanderthals as in modern humans. Assuming that these sites were the targets of selection and no interbreeding between the 2 groups, they concluded that selection at FOXP2 occurred before the populations split, over 300 thousand years ago. Here, we show that the data are unlikely under this scenario but may instead be consistent with low rates of gene flow between modern humans and Neanderthals. We also collect additional data and introduce a modeling framework to estimate levels of modern human contamination of the Neanderthal samples. We find that, depending on the assumptions, additional control experiments may be needed to rule out contamination at FOXP2.

A new framework for the selection of tag SNPs by multimarker haplotypes

This paper proposes a new framework for the selection of tag SNPs based on haplotypes instead of on a single SNP. The tag SNPs found by this framework form a set of haplotypes completely predictive of the alleles of all untyped SNPs. We refer to this problem as MTMH, which is defined as follows: given a set of SNPs, find a minimum subset of SNPs (called tag SNPs) which defines a set of haplotypes completely predictive of the alleles of all untyped SNPs. The MTMH problem is solved by dividing into three subproblems, two of which are shown to be NP-hard. Several exact and approximation algorithms are proposed to solve these subproblems. We describe a framework which integrates these algorithms and develop a program called HapTagger for finding tag SNPs. HapTagger is compared with existing methods as well as the official tagging tool (called Haploview) of the International HapMap project using a variety of real data sets. Our theoretical analysis and experimental results indicate that HapTagger consistently identifies a smaller set of tag SNPs and runs much faster than existing methods. HapTagger avoids the need of incorporating a linkage disequilibrium statistic and thus significantly improves the computational efficiency. We also present an algorithm (specific to HapTagger) for reconstructing alleles of untyped SNPs. It is worth mentioning that these predictive haplotypes selected by HapTagger can be used as signatures of recent positive selection or co-evolution. HapTagger is available at http://www.csie.ntu.edu.tw/~kmchao/tools/HapTagger/.

Molecular population genetics of PCSK9: a signature of recent positive selection

Proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a newly discovered serine protease that plays a key role in regulating plasma low density lipoprotein (LDL) cholesterol levels. Both rare mutations and common variants in the coding regions of PCSK9 affect LDL cholesterol levels and coronary heart disease risk, as well as response to lipid-lowering therapy. The authors characterized the patterns of variation at the PCSK9 locus in African-Americans and European-Americans using resequenced data from the SeattleSNPs database (pga.gs.washington.edu). The authors performed a test of population differentiation and the long-range haplotype test to detect signatures of recent position selection on PCSK9. A significantly high FST (a measure of population differentiation) between African-Americans and European-Americans was noted for single nucleotide polymorphism (SNP) rs505151 (FST=0.309). The long-range haplotype test was suggestive of non-neutral evolution of two SNPs, rs505151 and rs562556 that are associated with elevated LDL cholesterol levels ('gain-of-function' mutations). The modes of selection were different between African-Americans and European-Americans. The authors observed signals of recent positive selection on the ancestral allele of nonsynonymous SNP rs505151 (E670G, P=0.0227 and P=0.0001 in theoretical and empirical distribution, respectively) and the derived allele of nonsynonymous SNP rs562556 (I474V, P=0.0227 and 0.0001) in African-Americans, whereas in European-Americans the ancestral allele of SNP rs562556 (P=0.1320 and 0.0370) appeared to be under positive selection. The authors' findings suggest that evolutionary dynamics may underlie the 'gain-of-function' mutations in PCSK9 that are associated with higher LDL cholesterol levels.

A New Approach for Using Genome Scans to Detect Recent Positive Selection in the Human Genome

Genome-wide scanning for signals of recent positive selection is essential for a comprehensive and systematic understanding of human adaptation. Here, we present a genomic survey of recent local selective sweeps, especially aimed at those nearly or recently completed. A novel approach was developed for such signals, based on contrasting the extended haplotype homozygosity (EHH) profiles between populations. We applied this method to the genome single nucleotide polymorphism (SNP) data of both the International HapMap Project and Perlegen Sciences, and detected widespread signals of recent local selection across the genome, consisting of both complete and partial sweeps. A challenging problem of genomic scans of recent positive selection is to clearly distinguish selection from neutral effects, given the high sensitivity of the test statistics to departures from neutral demographic assumptions and the lack of a single, accurate neutral model of human history. We therefore developed a new procedure that is robust across a wide range of demographic and ascertainment models, one that indicates that certain portions of the genome clearly depart from neutrality. Simulations of positive selection showed that our tests have high power towards strong selection sweeps that have undergone fixation. Gene ontology analysis of the candidate regions revealed several new functional groups that might help explain some important interpopulation differences in phenotypic traits.

Signatures of recent positive selection at the ATP-binding cassette drug transporter superfamily gene loci

Members of the ATP-binding cassette (ABC) superfamily of transporters have been implicated as major players in drug response. Single nucleotide polymorphisms (SNPs) in the ABC transporter genes may account for variation in drug response between individuals. Given the abundance of SNPs within the human genome, identification of functionally important SNPs is difficult. Here, we utilized signatures of recent positive selection (RPS) to identify SNPs in ABC genes that have potential functional significance by using the long-range-haplotype test to search for signatures of RPS at 18 ABC genes involved in drug transport. From the genotype data of these 18 ABC genes in four populations extracted from the HapMap database, at least one SNP in each of these genes displayed genomic signatures of RPS in at least one population. However, only 13 SNPs in 10 ABC genes from three populations retained statistical significance after Type I error reduction. The functional significance of six of these RPS SNPs, including those that failed multiple testing correction (MTC), has been reported previously. We experimentally confirmed a functional effect for two SNPs, including one that failed to show evidence of RPS after MTC. These observations suggest that Type I error reduction may inadvertently increase Type II error. Although the remaining positively selected SNPs have yet to be functionally validated, our study illustrates the feasibility of using this strategy to identify SNPs within 'adaptive' genes that may confer functional effect, prior to testing their roles in individual/population drug response variation or in complex disease susceptibility.

A Practical Genome Scan for Population-Specific Strong Selective Sweeps That Have Reached Fixation

Phenotypic divergences between modern human populations have developed as a result of genetic adaptation to local environments over the past 100,000 years. To identify genes involved in population-specific phenotypes, it is necessary to detect signatures of recent positive selection in the human genome. Although detection of elongated linkage disequilibrium (LD) has been a powerful tool in the field of evolutionary genetics, current LD-based approaches are not applicable to already fixed loci. Here, we report a method of scanning for population-specific strong selective sweeps that have reached fixation. In this method, genome-wide SNP data is used to analyze differences in the haplotype frequency, nucleotide diversity, and LD between populations, using the ratio of haplotype homozygosity between populations. To estimate the detection power of the statistics used in this study, we performed computer simulations and found that these tests are relatively robust against the density of typed SNPs and demographic parameters if the advantageous allele has reached fixation. Therefore, we could determine the threshold for maintaining high detection power, regardless of SNP density and demographic history. When this method was applied to the HapMap data, it was able to identify the candidates of population-specific strong selective sweeps more efficiently than the outlier approach that depends on the empirical distribution. This study, confirming strong positive selection on genes previously reported to be associated with specific phenotypes, also identifies other candidates that are likely to contribute to phenotypic differences between human populations.

A whole genome long-range haplotype (WGLRH) test for detecting imprints of positive selection in human populations

The identification of signatures of positive selection can provide important insights into recent evolutionary history in human populations. Current methods mostly rely on allele frequency determination or focus on one or a small number of candidate chromosomal regions per study. With the availability of large-scale genotype data, efficient approaches for an unbiased whole genome scan are becoming necessary. We have developed a new method, the whole genome long-range haplotype test (WGLRH), which uses genome-wide distributions to test for recent positive selection. Adapted from the long-range haplotype (LRH) test, the WGLRH test uses patterns of linkage disequilibrium (LD) to identify regions with extremely low historic recombination. Common haplotypes with significantly longer than expected ranges of LD given their frequencies are identified as putative signatures of recent positive selection. In addition, we have also determined the ancestral alleles of SNPs by genotyping chimpanzee and gorilla DNA, and have identified SNPs where the non-ancestral alleles have risen to extremely high frequencies in human populations, termed 'flipped SNPs'. Combining the haplotype test and the flipped SNPs determination, the WGLRH test serves as an unbiased genome-wide screen for regions under putative selection, and is potentially applicable to the study of other human populations. Using WGLRH and high-density oligonucleotide arrays interrogating 116 204 SNPs, we rapidly identified putative regions of positive selection in three populations (Asian, Caucasian, African-American), and extended these observations to a fourth population, Yoruba, with data obtained from the International HapMap consortium. We mapped significant regions to annotated genes. While some regions overlap with genes previously suggested to be under positive selection, many of the genes have not been previously implicated in natural selection and offer intriguing possibilities for further study. the programs for the WGLRH algorithm are freely available and can be downloaded at http://www.affymetrix.com/support/supplement/WGLRH_program.zip.

Haplotype Homozygosity and Derived Alleles in the Human Genome

Haplotype-based techniques are being used to estimate the relative age of alleles--particularly in screening loci for signals of recent positive selection--but does this approach capture even coarse age differences? Using simulations and empirical data from the International HapMap Project, we show that a simple pairwise metric of haplotype homozygosity gives significantly higher mean values for human single-nucleotide-polymorphism alleles that appear to be derived than for those that appear to be ancestral, as determined by comparison with the chimpanzee genome. Our results support the use of haplotype-based techniques, such as extended haplotypic homozygosity, to assess the age of alleles.

A Map of Recent Positive Selection in the Human Genome

The identification of signals of very recent positive selection provides information about the adaptation of modern humans to local conditions. We report here on a genome-wide scan for signals of very recent positive selection in favor of variants that have not yet reached fixation. We describe a new analytical method for scanning single nucleotide polymorphism (SNP) data for signals of recent selection, and apply this to data from the International HapMap Project. In all three continental groups we find widespread signals of recent positive selection. Most signals are region-specific, though a significant excess are shared across groups. Contrary to some earlier low resolution studies that suggested a paucity of recent selection in sub-Saharan Africans, we find that by some measures our strongest signals of selection are from the Yoruba population. Finally, since these signals indicate the existence of genetic variants that have substantially different fitnesses, they must indicate loci that are the source of significant phenotypic variation. Though the relevant phenotypes are generally not known, such loci should be of particular interest in mapping studies of complex traits. For this purpose we have developed a set of SNPs that can be used to tag the strongest ∼250 signals of recent selection in each population.

A functional polymorphism within the MRP1 gene locus identified through its genomic signature of positive selection

Searching for genomic evidence of positive selection has been hailed as an attractive strategy for identifying functional polymorphisms. Here, we demonstrate the feasibility of identifying functional polymorphism at the MRP1 gene locus using this strategy. The 190 kDa MRP1 protein is an efflux pump that regulates the accumulation of xenobiotics and drugs in cells. Functional sequence variations within this gene might account, in part, for inter-individual and population differences in drug response. To identify single nucleotide polymorphisms (SNPs) within the MRP1 gene with potentially important functional significance, we scanned for genomic signatures of recent positive selection at this locus in approximately 480 individuals sampled from the Chinese, Malay, Indian, European-American and African-American populations. The genetic profile of SNPs at this locus revealed high haplotype diversity and weak linkage disequilibrium (LD). Despite this weak LD, major allele G of SNP 5'FR/G-260C contained within a high frequency haplotype exhibited extended haplotype homozygosity across 135 kb in European-Americans. Using two independent genomic tests, long-range haplotype (LRH) test and the F(ST) statistic, we found statistical evidence of positive selection for this allele in the European-American population. When this SNP was recapitulated in an in vitro MRP1 promoter-reporter assay, significantly lower activity was observed from the G-containing promoter when compared with the C-containing promoter in all four cell lines that we tested (P<0.01). These observations confirm the power of this strategy in identifying functionally different alleles of genes and suggest that the different alleles at this SNP locus in the MRP1 gene may account, in part, for inter-individual variations and population differences in drug response.