Signatures Of Natural Selection Research Articles

Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum

The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.

Transcriptome sequencing of a highly salt tolerant mangrove species Sonneratia alba using Illumina platform

Mangroves are critical and threatened marine resources, yet few transcriptomic and genomic data are available in public databases. The transcriptome of a highly salt tolerant mangrove species, Sonneratia alba, was sequenced using the Illumina Genome Analyzer in this study. Over 15 million 75-bp paired-end reads were assembled into 30,628 unique sequences with an average length of 581 bp. Of them, 2358 SSRs were detected, with di-nucleotide repeats (59.2%) and tri-nucleotide repeats (37.7%) being the most common. Analysis of codon usage bias based on 20,945 coding sequences indicated that genes of S. alba were less biased than those of some microorganisms and Drosophila and that codon usage variation in S. alba was due primarily to compositional mutation bias, while translational selection has a relatively weak effect. Genome-wide gene ontology (GO) assignments showed that S. alba shared a similar GO slim classification with Arabidopsis thaliana. High percentages of sequences assigned to GO slim category ‘mitochondrion’ and four KEGG pathways, such as carbohydrates and secondary metabolites metabolism, may contribute to salt adaptation of S. alba. In addition, 1266 unique sequences matched to 273 known salt responsive genes (gene families) in other species were screened as candidates for salt tolerance of S. alba, and some of these genes showed fairly high coverage depth. At last, we identified four genes with signals of strong diversifying selection ( K a/ K s > 1) by comparing the transcriptome sequences of S. alba with 249 known ESTs from its congener S. caseolaris. This study demonstrated a successful application of the Illumina platform to de novo assembly of the transcriptome of a non-model organism. Abundant SSR markers, salt responsive genes and four genes with signature of natural selection obtained from S. alba provide abundant sequence sources for future genetic diversity, salt adaptation and speciation studies.

Genome-Wide Survey of Natural Selection on Functional, Structural, and Network Properties of Polymorphic Sites in Saccharomyces paradoxus

To characterize the genetic basis of phenotypic evolution, numerous studies have identified individual genes that have likely evolved under natural selection. However, phenotypic changes may represent the cumulative effect of similar evolutionary forces acting on functionally related groups of genes. Phylogenetic analyses of divergent yeast species have identified functional groups of genes that have evolved at significantly different rates, suggestive of differential selection on the functional properties. However, due to environmental heterogeneity over long evolutionary timescales, selection operating within a single lineage may be dramatically different, and it is not detectable via interspecific comparisons alone. Moreover, interspecific studies typically quantify selection on protein-coding regions using the D(n)/D(s) ratio, which cannot be extended easily to study selection on noncoding regions or synonymous sites. The population genetic-based analysis of selection operating within a single lineage ameliorates these limitations. We investigated selection on several properties associated with genes, promoters, or polymorphic sites, by analyzing the derived allele frequency spectrum of single nucleotide polymorphisms (SNPs) in 28 strains of Saccharomyces paradoxus. We found evidence for significant differential selection between many functionally relevant categories of SNPs, underscoring the utility of function-centric approaches for discovering signatures of natural selection. When comparable, our findings are largely consistent with previous studies based on interspecific comparisons, with one notable exception: our study finds that mutations from an ancient amino acid to a relatively new amino acid are selectively disfavored, whereas interspecific comparisons have found selection against ancient amino acids. Several of our findings have not been addressed through prior interspecific studies: we find that synonymous mutations from preferred to unpreferred codons are selected against and that synonymous SNPs in the linker regions of proteins are relatively less constrained than those within protein domains. We present the first global survey of selection acting on various functional properties in S. paradoxus. We found that selection pressures previously detected over long evolutionary timescales have also shaped the evolution of S. paradoxus. Importantly, we also make novel discoveries untenable via conventional interspecific analyses.

Scanning the genome for gene SNPs related to climate adaptation and estimating selection at the molecular level in boreal black spruce

Outlier detection methods were used to scan the genome of the boreal conifer black spruce (Picea mariana [Mill.] B.S.P.) for gene single-nucleotide polymorphisms (SNPs) potentially involved in adaptations to temperature and precipitation variations. The scan involved 583 SNPs from 313 genes potentially playing adaptive roles. Differentiation estimates among population groups defined following variation in temperature and precipitation were moderately high for adaptive quantitative characters such as the timing of budset or tree height (Q(ST) = 0.189-0.314). Average differentiation estimates for gene SNPs were null, with F(ST) values of 0.005 and 0.006, respectively, among temperature and precipitation population groups. Using two detection approaches, a total of 26 SNPs from 25 genes distributed among 11 of the 12 linkage groups of black spruce were detected as outliers with F(ST) as high as 0.078. Nearly half of the outlier SNPs were located in exons and half of those were nonsynonymous. The functional annotations of genes carrying outlier SNPs and regression analyses between the frequencies of these SNPs and climatic variables supported their implication in adaptive processes. Several genes carrying outlier SNPs belonged to gene families previously found to harbour outlier SNPs in a reproductively isolated but largely sympatric congeneric species, suggesting differential subfunctionalization of gene duplicates. Selection coefficient estimates (S) were moderate but well above the magnitude of drift (>>1/N(e)), indicating that the signature of natural selection could be detected at the nucleotide level despite the recent establishment of these populations during the Holocene.

Non-equilibrium allele frequency spectra via spectral methods

A major challenge in the analysis of population genomics data consists of isolating signatures of natural selection from background noise caused by random drift and gene flow. Analyses of massive amounts of data from many related populations require high-performance algorithms to determine the likelihood of different demographic scenarios that could have shaped the observed neutral single nucleotide polymorphism (SNP) allele frequency spectrum. In many areas of applied mathematics, Fourier Transforms and Spectral Methods are firmly established tools to analyze spectra of signals and model their dynamics as solutions of certain Partial Differential Equations (PDEs). When spectral methods are applicable, they have excellent error properties and are the fastest possible in high dimension; see Press et al. (2007). In this paper we present an explicit numerical solution, using spectral methods, to the forward Kolmogorov equations for a Wright–Fisher process with migration of K populations, influx of mutations, and multiple population splitting events.

Putative causes and consequences of MHC variation within and between locally adapted stickleback demes

Genes of the major histocompatibility complex (MHC) have been a source of considerable research interest, owing in large part to the growing body of evidence that they may be subject to both natural and sexual selection. However, much remains to be learned about the dynamics of MHC genes in subdivided populations, particularly those characterized by divergent ecological pressures. In this study, we attempt to disentangle the relative roles of both parasite-mediated selection and MHC-mediated mate choice in an open estuarine system inhabited by two parapatric, adaptively divergent threespine stickleback (Gasterosteus aculeatus) demes. We sequenced the putative peptide-binding region (PBR) of an estimated four Class IIβ loci from 127 individuals, identifying 329 sequence variants (276 translated amino acid sequences). Demes differed significantly both in the frequency of MHC alleles and in the communities of helminth parasites infecting resident sticklebacks. Strong signatures of natural selection were inferred from analyses of codon substitutions, particularly in the derived (freshwater) rather than the ancestral (marine) deme. Relationships between parasite load and MHC diversity were indicative of balancing selection, but only within the freshwater deme. Signals of MHC-mediated mate choice were weak and differed significantly between demes. Moreover, MHC-mediated mate choice was significantly influenced by environmental salinity and appeared of secondary importance to tendencies towards assortative mating. We discuss the implications of these findings in respect to ecological adaptation and the potential demographic consequences of possible outcomes of MHC-mediated mate choice.

A map of human genome variation from population-scale sequencing.

The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.

SNP genotyping defines complex gene-flow boundaries among African malaria vector mosquitoes.

Mosquitoes in the Anopheles gambiae complex show rapid ecological and behavioral diversification, traits that promote malaria transmission and complicate vector control efforts. A high-density, genome-wide mosquito SNP-genotyping array allowed mapping of genomic differentiation between populations and species that exhibit varying levels of reproductive isolation. Regions near centromeres or within polymorphic inversions exhibited the greatest genetic divergence, but divergence was also observed elsewhere in the genomes. Signals of natural selection within populations were overrepresented among genomic regions that are differentiated between populations, implying that differentiation is often driven by population-specific selective events. Complex genomic differentiation among speciating vector mosquito populations implies that tools for genome-wide monitoring of population structure will prove useful for the advancement of malaria eradication.

Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data.

High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.

Comparative Proteomics Uncovers the Signature of Natural Selection Acting on the Ejaculate Proteomes of Two Cricket Species Isolated by Postmating, Prezygotic Phenotypes

Two of the most well-supported patterns to have emerged over the past two decades of research in evolutionary biology are the occurrence of divergent natural selection acting on many male and female reproductive tract proteins and the importance of postmating, prezygotic phenotypes in reproductively isolating closely related species. Although these patterns appear to be common across a wide variety of taxa, the link between them remains poorly documented. Here, we utilize comparative proteomic techniques to determine whether or not there is evidence for natural selection acting on the ejaculate proteomes of two cricket species (Allonemobius fasciatus and A. socius) which are reproductively isolated primarily by postmating, prezygotic phenotypes. In addressing this question, we compare the degree of within-species polymorphism and between-species divergence between the ejaculate and thorax proteomes of these two species. We found that the ejaculate proteomes are both less polymorphic and more divergent than the thorax proteomes. Additionally, we assessed patterns of nucleotide variation for two species-specific ejaculate proteins and found evidence for both reduced levels of variation within species and positive selection driving divergence between species. In contrast, non-species-specific proteins exhibited higher levels of within-species nucleotide variation and no signatures of positive selection. Nucleotide and putative functional data for the two species-specific proteins, along with data for a third protein (ejaculate serine protease), suggest that all three of these genes are candidate speciation genes in need of further study. Overall, these patterns of proteome and nucleotide divergence provide support for the hypothesis that there is a causative link between selection-driven divergence of male ejaculate proteins and the evolution of postmating, prezygotic barriers to gene flow within Allonemobius.

Genomic signals of diversification along ecological gradients in a tropical lizard

Studies of rainforest diversification that simultaneously consider the effects of genetic drift and natural selection are rare. We use Amplified Fragment Length Polymorphism genome scans of the African rainforest lizard Trachylepis affinis from Cameroon to examine the spatial patterns and environmental associations of both neutrally evolving loci and those thought to be under selection. Bayesian selection scans revealed that approximately 7% of the genome may be under divergent selection. Using non-linear environmental modelling techniques, we fit patterns of genetic differentiation recovered from the pooled neutral data and from individual loci showing a signature of natural selection. Neutral differentiation occurred along a cline from coastal lowland rainforest inland toward the gallery forests-savanna mosaic (ecotone), and was associated with both geographic distance and changing precipitation patterns. Loci under selection were differentiated predominantly along the forest-ecotone gradient-in concordance with morphological divergence in traits related to fitness. A second set of these loci was differentiated between lowland and montane habitats. A third set of loci was indicative of divergent selection between rainforest refugia. Niche models and demographic signals in mitochondrial sequence data support a population expansion out of a core rainforest area into savanna since the last glacial maximum. Our findings indicate adaptive diversification in T. affinis may be taking place along the forest-ecotone gradient during range expansions or contractions, and that refugial isolation augmented by divergent adaptation to different rainforest environments appears to play a less significant role.

Back to nature: ecological genomics of loblolly pine (Pinus taeda, Pinaceae)

Genetic variation is often arrayed in latitudinal or altitudinal clines, reflecting either adaptation along environmental gradients, migratory routes, or both. For forest trees, climate is one of the most important drivers of adaptive phenotypic traits. Correlations of single and multilocus genotypes with environmental gradients have been identified for a variety of forest trees. These correlations are interpreted normally as evidence of natural selection. Here, we use a genome-wide dataset of single nucleotide polymorphisms (SNPs) typed from 1730 loci in 682 loblolly pine (Pinus taeda L.) trees sampled from 54 local populations covering the full-range of the species to examine allelic correlations to five multivariate measures of climate. Applications of a Bayesian generalized linear mixed model, where the climate variable was a fixed effect and an estimated variance-covariance matrix controlled random effects due to shared population history, identified several well-supported SNPs associating to principal components corresponding to geography, temperature, growing degree-days, precipitation and aridity. Functional annotation of those genes with putative orthologs in Arabidopsis revealed a diverse set of abiotic stress response genes ranging from transmembrane proteins to proteins involved in sugar metabolism. Many of these SNPs also had large allele frequency differences among populations (F(ST) = 0.10-0.35). These results illustrate a first step towards a ecosystem perspective of population genomics for non-model organisms, but also highlight the need for further integration of the methodologies employed in spatial statistics, population genetics and climate modeling during scans for signatures of natural selection from genomic data.

Lineage pattern, trans-species polymorphism, and selection pressure among the major lineages of feline Mhc-DRB peptide-binding region

The long-term evolution of major histocompatibility complex (MHC) involves the birth-and-death process and independent divergence of loci during episodes punctuated by natural selection. Here, we investigated the molecular signatures of natural selection at exon-2 of MHC class II DRB gene which includes a part of the peptide-binding region (PBR) in seven of eight putative extant Felidae lineages. The DRB alleles in felids can be mainly divided into five lineages. Signatures of trans-species polymorphism among major allelic lineages indicate that balancing selection has maintained the MHC polymorphism for a long evolutionary time. Analysis based on maximum likelihood models of codon substitution revealed overall purifying selection acting on the feline DRB. Sites that have undergone positive selection and those that are under divergent selective pressure among lineages were detected and found to fall within the putative PBR. This study increased our understanding of the nature of selective forces acting on DRB during feline radiation.

Signatures of natural selection and coevolution between killer cell immunoglobulin-like receptors (KIR) and HLA class I genes

Natural killer (NK) cells are lymphocytes of the innate immune system. In humans, NK cell activities are partly controlled by the diverse killer immunoglobulin-like receptor (KIR) gene family. The importance of NK cells in both immunity to infection and reproduction makes KIR strong candidates for genes undergoing dynamic evolution in the human genome. Using high-resolution allelic typing, we investigated the potential role of natural selection in the diversification of KIR in the Irish population. Higher diversity than expected is observed at several loci, consistent with a history of balancing selection acting to maintain several allelic variants at high frequency in the population. KIR diversity is enhanced further at the haplotype level with functional polymorphisms at KIR2DL4, KIR3DL1 and KIR2DS4 defining nine 'core' haplotypes. Analysis of these core haplotypes in combination with human leukocyte antigen (HLA) class I ligands revealed several nonrandom associations. In particular, the KIR:HLA association for the core haplotype defined by KIR3DL1(*)01502 was female specific and a likely consequence of negative selection acting against KIR3DL1(*)01502 on an HLA-C1/C1 background. Many of the associations between KIR and HLA in the Irish differ from those previously reported, which argues against universal selective pressures for specific KIR:HLA combinations in diverse human populations.

Identical Skin Toxins by Convergent Molecular Adaptation in Frogs

The Tree of Life is rife with adaptive convergences at all scales and biological levels of complexity. However, natural selection is not likely to result in the independent evolution of identical gene products. Here we report such a striking example of evolutionary convergence in the toxic skin secretions of two distantly related frog lineages. Caeruleins are important decapeptides in pharmacological and clinical research [1] and are commonly believed to represent a single evolutionary class of peptides [2-4]. Instead, our phylogenetic analyses combining transcriptome and genome data reveal that independently evolved precursor genes encode identical caeruleins in Xenopus and Litoria frogs. The former arose by duplication from the cholecystokinin (cck) gene, whereas the latter was derived from the gastrin gene. These hormone genes that are involved in many physiological processes diverged early in vertebrate evolution, after a segmental duplication during the Cambrian period. Besides implicating convergent mutations of the peptide-encoding sequence, recurrent caerulein origins entail parallel shifts of expression from the gut-brain axis to skin secretory glands. These results highlight extreme structural convergence in anciently diverged genes as an evolutionary mechanism through which recurrent adaptation is attained across large phylogenetic distances.

Identifying positive selection candidate loci for high-altitude adaptation in Andean populations

High-altitude environments (>2,500 m) provide scientists with a natural laboratory to study the physiological and genetic effects of low ambient oxygen tension on human populations. One approach to understanding how life at high altitude has affected human metabolism is to survey genome-wide datasets for signatures of natural selection. In this work, we report on a study to identify selection-nominated candidate genes involved in adaptation to hypoxia in one highland group, Andeans from the South American Altiplano. We analysed dense microarray genotype data using four test statistics that detect departures from neutrality. Using a candidate gene, single nucleotide polymorphism-based approach, we identified genes exhibiting preliminary evidence of recent genetic adaptation in this population. These included genes that are part of the hypoxia-inducible transcription factor (HIF) pathway, a biochemical pathway involved in oxygen homeostasis, as well as three other genomic regions previously not known to be associated with high-altitude phenotypes. In addition to identifying selection-nominated candidate genes, we also tested whether the HIF pathway shows evidence of natural selection. Our results indicate that the genes of this biochemical pathway as a group show no evidence of having evolved in response to hypoxia in Andeans. Results from particular HIF-targeted genes, however, suggest that genes in this pathway could play a role in Andean adaptation to high altitude, even if the pathway as a whole does not show higher relative rates of evolution. These data suggest a genetic role in high-altitude adaptation and provide a basis for genotype/phenotype association studies that are necessary to confirm the role of putative natural selection candidate genes and gene regions in adaptation to altitude.

Assessing Human Variation Data for Signatures of Natural Selection

In this article, we highlight some of the different types of natural selection, their effects on patterns of DNA variation, and some of the statistical tests that are commonly used to detect such effects. We also explain some of the relative strengths and weaknesses of different strategies that can be used to detect signatures of natural selection at individual loci. These strategies are illustrated by their application to empirical data from gene variants that are often associated with differences in disease susceptibility. We briefly outline some of the methods proposed to scan the genome for evidence of selection. Finally, we discuss some of the problems associated with identifying signatures of selection and with making inferences about the nature of the selective process.

A Population Genomics Study of theArabidopsisCore Cell Cycle Genes Shows the Signature of Natural Selection

Large-scale comparison of sequence polymorphism and divergence at numerous genomic loci within and between closely related species can reveal signatures of natural selection. Here, we present a population genomics study based on direct sequencing of 61 mitotic cell cycle genes from 30 Arabidopsis thaliana accessions and comparison of the resulting data to the close relative Arabidopsis lyrata. We found that the Arabidopsis core cell cycle (CCC) machinery is not highly constrained but is subject to different modes of selection. We found patterns of purifying selection for the cyclin-dependent kinase (CDK), CDK subunit, retinoblastoma, and WEE1 gene families. Other CCC gene families often showed a mix of one or two constrained genes and relaxed purifying selection on the other genes. We found several large effect mutations in CDKB1;2 that segregate in the species. We found a strong signature of adaptive protein evolution in the Kip-related protein KRP6 and departures from equilibrium at CDKD;1 and CYCA3;3 consistent with the operation of selection in these gene regions. Our data suggest that within Arabidopsis, the genetic robustness of cell cycle-related processes is more due to functional redundancy than high selective constraint.

An Explicit Signature of Balancing Selection for Color-Vision Variation in New World Monkeys

Color vision is an important characteristic of primates and, intriguingly, Neotropical monkeys are highly polymorphic for this trait. Recent field studies have challenged the conventional view that trichromatic color vision is more adaptive than dichromatic color vision. No study has investigated the pattern of genetic variation in the long to middle wavelength-sensitive (L-M or red-green) opsin gene as compared with that of other genomic regions (neutral references) in wild populations of New World monkeys to look for the signature of natural selection. Here, we report such a study conducted on spider monkeys and capuchin monkeys inhabiting Santa Rosa National Park, Costa Rica. The nucleotide sequence of the L-M opsin gene was more polymorphic than the sequences of the neutral references, although the opsin-gene sequences were not more divergent between the two species than were the sequences of the neutral references. In a coalescence simulation that took into account the observed nucleotide diversity of the neutral references, the Tajima's D value of the L-M opsin gene deviated significantly in a positive direction from the expected range. These results are the first to statistically demonstrate balancing selection acting on the polymorphic L-M opsin gene of New World monkeys. Taking the results of behavioral and genetic studies together, the balancing selection we detected may indicate that coexistence of different color-vision types in the same population, also characteristic of humans, is adaptive.

An excess of rare genetic variation in ABCE1 among Yorubans and African-American individuals with HIV-1

Signatures of natural selection occur throughout the human genome and can be detected at the sequence level. We have re-sequenced ABCE1, a host candidate gene essential for HIV-1 capsid assembly, in European- (n=23) and African-descent (Yoruban; n=24) reference populations for genetic variation discovery. We identified an excess of rare genetic variation in Yoruban samples, and the resulting Tajima's D was low (-2.27). The trend of excess rare variation persisted in flanking candidate genes ANAPC10 and OTUD4, suggesting that this pattern of positive selection can be detected across the 184.5 kb examined on chromosome 4. Owing to ABCE1's role in HIV-1 replication, we re-sequenced the candidate gene in three small cohorts of HIV-1-infected or resistant individuals. We were able to confirm the excess of rare genetic variation among HIV-1-positive African-American individuals (n=53; Tajima's D=-2.34). These results highlight the potential importance of ABCE1's role in infectious diseases such as HIV-1.