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Signatures of Long-Term Balancing Selection in Human Genomes.

ABSTRACT: Balancing selection maintains advantageous diversity in populations through various mechanisms. Although extensively explored from a theoretical perspective, an empirical understanding of its prevalence and targets lags behind our knowledge of positive selection. Here, we describe the Non-central Deviation (NCD), a simple yet powerful statistic to detect long-term balancing selection (LTBS) that quantifies how close frequencies are to expectations under LTBS, and provides the basis for a neutrality test. NCD can be applied to a single locus or genomic data, and can be implemented considering only polymorphisms (NCD1) or also considering fixed differences with respect to an outgroup (NCD2) species. Incorporating fixed differences improves power, and NCD2 has higher power to detect LTBS in humans under different frequencies of the balanced allele(s) than other available methods. Applied to genome-wide data from African and European human populations, in both cases using chimpanzee as an outgroup, NCD2 shows that, albeit not prevalent, LTBS affects a sizable portion of the genome: ∼0.6% of analyzed genomic windows and 0.8% of analyzed positions. Significant windows (P < 0.0001) contain 1.6% of SNPs in the genome, which disproportionally fall within exons and change protein sequence, but are not enriched in putatively regulatory sites. These windows overlap ∼8% of the protein-coding genes, and these have larger number of transcripts than expected by chance even after controlling for gene length. Our catalog includes known targets of LTBS but a majority of them (90%) are novel. As expected, immune-related genes are among those with the strongest signatures, although most candidates are involved in other biological functions, suggesting that LTBS potentially influences diverse human phenotypes.

SUBMITTER: Bitarello BD

PROVIDER: S-EPMC5952967 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Bacterial lineages that populate the human gut microbiota contend with spatial and temporal fluctuations in numerous environmental variables, including bouts of extreme selective agents such as antibiotics. Oscillations in the adaptive landscape can impose balancing selection on populations, leaving characteristic signatures in the sequence variation of functionally significant genomic loci. Despite their potential importance for gut bacterial adaptation, the metagenomic targets of balancing selection have not been identified. Here, I present population genetic evidence that balancing selection maintains allelic diversity in multidrug efflux pumps of multiple predominant gut bacterial species. Metagenome-wide scans of 566,958 genes from 287 bacterial species represented by 118,617 metagenome-assembled genomes indicated that most genes have been conserved by purifying selection. However, dozens of core open reading frames (CORFs) displayed positive Tajima's D values that deviated significantly from their species' genomic backgrounds, indicating the action of balancing selection. Multidrug efflux pumps (MEPs) from a diversity of bacterial species were significantly enriched among the CORFs with Tajima's D values >3 in industrialized, but not nonindustrialized, human populations. The AcrB subunit of an MEP from Bacteroides dorei displayed the highest Tajima's D of any CORF. Divergent haplotypes of this CORF displayed evidence of positive selection and homology to an Escherichia coli AcrB subunit that binds tetracycline and macrolide antibiotics, suggesting functional significance and implicating medical antibiotics as an agent of selection acting on this locus. Other proteins identified as targets of balancing selection included peptidoglycan/LPS O-acetylases and ion transporters. Intriguingly, the degree of balancing selection acting on gut bacterial species was associated with species abundance in the gut based on metagenomic data, further suggesting fitness benefits of the allelic variation identified.

Project description:BackgroundBalancing selection operating for long evolutionary periods at a locus is characterized by the maintenance of distinct alleles because of a heterozygote or rare-allele advantage. The loci under balancing selection are distinguished by their unusually high polymorphism levels. In this report, we provide statistical and comparative genetic evidence suggesting that the SDHA gene is under long-term balancing selection. SDHA encodes the major catalytical subunit (flavoprotein, Fp) of the succinate dehydrogenase enzyme complex (SDH; mitochondrial complex II). The inhibition of Fp by homozygous SDHA mutations or by 3-nitropropionic acid poisoning causes central nervous system pathologies. In contrast, heterozygous mutations in SDHB, SDHC, and SDHD, the other SDH subunit genes, cause hereditary paraganglioma (PGL) tumors, which show constitutive activation of pathways induced by oxygen deprivation (hypoxia).ResultsWe sequenced the four SDH subunit genes (10.8 kb) in 24 African American and 24 European American samples. We also sequenced the SDHA gene (2.8 kb) in 18 chimpanzees. Increased nucleotide diversity distinguished the human SDHA gene from its chimpanzee ortholog and from the PGL genes. Sequence analysis uncovered two common SDHA missense variants and refuted the previous suggestions that these variants originate from different genetic loci. Two highly dissimilar SDHA haplotype clusters were present in intermediate frequencies in both racial groups. The SDHA variation pattern showed statistically significant deviations from neutrality by the Tajima, Fu and Li, Hudson-Kreitman-Aguadé, and Depaulis haplotype number tests. Empirically, the elevated values of the nucleotide diversity (% pi = 0.231) and the Tajima statistics (D = 1.954) in the SDHA gene were comparable with the most outstanding cases for balancing selection in the African American population.ConclusionThe SDHA gene has a strong signature of balancing selection. The SDHA variants that have increased in frequency during human evolution might, by influencing the regulation of cellular oxygen homeostasis, confer protection against certain environmental toxins or pathogens that are prevalent in Africa.

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Signatures of Long-Term Balancing Selection in Human Genomes.

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