Genome-wide detection and characterization of positive selection in human populations

Abstract Despite the extreme and varying environmental conditions prevalent in the Arabian Peninsula, it has experienced several waves of human migrations following the out-of-Africa diaspora. Eventually, the inhabitants of the peninsula region adapted to the hot and dry environment. The adaptation and natural selection that shaped the extant human populations of the Arabian Peninsula region have been scarcely studied. In an attempt to explore natural selection in the region, we analyzed 662,750 variants in 583 Kuwaiti individuals. We searched for regions in the genome that display signatures of positive selection in the Kuwaiti population using an integrative approach in a conservative manner. We highlight a haplotype overlapping TNKS that showed strong signals of positive selection based on the results of the multiple selection tests conducted (integrated Haplotype Score, Cross Population Extended Haplotype Homozygosity, Population Branch Statistics, and log-likelihood ratio scores). Notably, the TNKS haplotype under selection potentially conferred a fitness advantage to the Kuwaiti ancestors for surviving in the harsh environment while posing a major health risk to present-day Kuwaitis.

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Genome-wide Characterization of Shared and Distinct Genetic Components that Influence Blood Lipid Levels in Ethnically Diverse Human Populations

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2013.04.025 ◽

2013 ◽

Vol 92 (6) ◽

pp. 904-916 ◽

Cited By ~ 81

Author(s):

Marc A. Coram ◽

Qing Duan ◽

Thomas J. Hoffmann ◽

Timothy Thornton ◽

Joshua W. Knowles ◽

...

Keyword(s):

Ethnically Diverse ◽

Blood Lipid ◽

Human Populations ◽

Lipid Levels ◽

Genetic Components ◽

Genome Wide ◽

Blood Lipid Levels

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Presence and Transmission of Mitochondrial Heteroplasmic Mutations in Human Populations of European and African Ancestry

10.1101/2020.10.13.337071 ◽

2020 ◽

Author(s):

Chunyu Liu ◽

Jessica L. Fetterman ◽

Yong Qian ◽

Xianbang Sun ◽

Kaiyu Yan ◽

...

Keyword(s):

Tyrosine Phosphatase ◽

African Ancestry ◽

Functional Characterization ◽

Nuclear Genome ◽

Human Populations ◽

Sibling Pairs ◽

Coding Regions ◽

Genome Wide ◽

A Genome

ABSTRACTWe investigated the concordance of mitochondrial DNA heteroplasmic mutations (heteroplasmies) in different types of maternal pairs (n=6,745 pairs) of European (EA, n=4,718 pairs) and African (AA, n=2,027 pairs) Americans with whole genome sequences (WGSs). The average concordance rate of heteroplasmies was highest between mother-offspring pairs, followed by sibling-sibling pairs and more distantly related maternal pairs in both EA and AA participants. The allele fractions of concordant heteroplasmies exhibited high correlation (R2=0.8) between paired individuals. Compared to concordant heteroplasmies, discordant ones were more likely to locate in coding regions, be nonsynonymous or nonsynonymous-deleterious (p<0.001). The average number of heteroplasmies per individual (i.e. heteroplasmic burden) was at a similar level until older age (70-80 years old) and increased significantly thereafter (p<0.01). The burden of deleterious heteroplasmies (combined annotation-dependent depletion score≥15), however, was significantly correlated with advancing age (20-44, 45-64, ≥65 years, p-trend=0.01). A genome-wide association analysis of the heteroplasmic burden identified many significant (P<5e-8) common variants (minor allele frequency>0.05) at 11p11.12. Many of the top SNPs act as strong long-range cis regulators of protein tyrosine phosphatase receptor type J. This study provides further evidence that mtDNA heteroplasmies may be inherited or somatic. Somatic heteroplasmic variants increase with advancing age and are more likely to have an adverse impact on mitochondrial function. Further studies are warranted for functional characterization of the deleterious heteroplasmies occurring with advancing age and the association of the 11p11.12 region of the nuclear genome with mtDNA heteroplasmy.

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Genome-wide Selection Scan in an Arabian Peninsula Population Identifies a TNKS haplotype Linked to Metabolic Traits and Hypertension

10.1101/765651 ◽

2019 ◽

Author(s):

Muthukrishnan Eaaswarkhanth ◽

Andre Luiz Campelo dos Santos ◽

Omer Gokcumen ◽

Fahd Al-Mulla ◽

Thangavel Alphonse Thanaraj

Keyword(s):

Natural Selection ◽

Positive Selection ◽

Arabian Peninsula ◽

Integrative Approach ◽

Human Populations ◽

Extended Haplotype ◽

Major Health ◽

Fitness Advantage ◽

Genome Wide ◽

Kuwaiti Population

AbstractDespite the extreme and varying environmental conditions prevalent in the Arabian Peninsula, it has experienced several waves of human migrations following the out-of-Africa diaspora. Eventually, the inhabitants of the peninsula region adapted to the hot and dry environment. The adaptation and natural selection that shaped the extant human populations of the Arabian Peninsula region have been scarcely studied. In an attempt to explore natural selection in the region, we analyzed 662,750 variants in 583 Kuwaiti individuals. We searched for regions in the genome that display signatures of positive selection in the Kuwaiti population using an integrative approach in a conservative manner. We highlight a haplotype overlapping TNKS that showed strong signals of positive selection based on the results of the multiple selection tests conducted (integrated Haplotype Score, Cross Population Extended Haplotype Homozygosity, Population Branch Statistics, and log-likelihood ratio scores). Notably, the TNKS haplotype under selection potentially conferred a fitness advantage to the Kuwaiti ancestors for surviving in the harsh environment while posing a major health risk to present-day Kuwaitis.

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Chromosome X-wide Analysis of Positive Selection in Human Populations: Common and Private Signals of Selection and its Impact on Inactivated Genes and Enhancers

Frontiers in Genetics ◽

10.3389/fgene.2021.714491 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pablo Villegas-Mirón ◽

Sandra Acosta ◽

Jessica Nye ◽

Jaume Bertranpetit ◽

Hafid Laayouni

Keyword(s):

Positive Selection ◽

X Chromosome ◽

Genetic Basis ◽

Target Genes ◽

Regulatory Elements ◽

Human Populations ◽

Third Phase ◽

Genome Wide ◽

Private Signals ◽

Sub Saharan

The ability of detecting adaptive (positive) selection in the genome has opened the possibility of understanding the genetic basis of population-specific adaptations genome-wide. Here, we present the analysis of recent selective sweeps, specifically in the X chromosome, in human populations from the third phase of the 1,000 Genomes Project using three different haplotype-based statistics. We describe instances of recent positive selection that fit the criteria of hard or soft sweeps, and detect a higher number of events among sub-Saharan Africans than non-Africans (Europe and East Asia). A global enrichment of neural-related processes is observed and numerous genes related to fertility appear among the top candidates, reflecting the importance of reproduction in human evolution. Commonalities with previously reported genes under positive selection are found, while particularly strong new signals are reported in specific populations or shared across different continental groups. We report an enrichment of signals in genes that escape X chromosome inactivation, which may contribute to the differentiation between sexes. We also provide evidence of a widespread presence of soft-sweep-like signatures across the chromosome and a global enrichment of highly scoring regions that overlap potential regulatory elements. Among these, enhancers-like signatures seem to present putative signals of positive selection which might be in concordance with selection in their target genes. Also, particularly strong signals appear in regulatory regions that show differential activities, which might point to population-specific regulatory adaptations.

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Chromosome X-wide analysis of positive selection in human populations: from common and private signals to selection impact on inactivated genes and enhancers-like signatures

10.1101/2021.05.24.445399 ◽

2021 ◽

Author(s):

Pablo Villegas Mirón ◽

Sandra Acosta ◽

Jessica Nye ◽

Jaume Bertranpetit ◽

Hafid Laayouni

Keyword(s):

Positive Selection ◽

X Chromosome ◽

Target Genes ◽

Regulatory Elements ◽

Human Populations ◽

Third Phase ◽

Recent Positive Selection ◽

Genome Wide ◽

Private Signals ◽

Sub Saharan

The ability of detecting adaptive (positive) selection in the genome has opened the possibility of understanding the genetic bases of population-specific adaptations genome-wide. Here we present the analysis of recent selective sweeps specifically in the X chromosome in different human populations from the third phase of the 1000 Genomes Project using three different haplotype-based statistics. We describe numerous instances of genes under recent positive selection that fit the regimes of hard and soft sweeps, showing a higher amount of detectable sweeps in sub-Saharan Africans than in non-Africans (Europe and East Asia). A global enrichment is seen in neural-related processes while numerous genes related to fertility appear among the top candidates, reflecting the importance of reproduction in human evolution. Commonalities with previously reported genes under positive selection are found, while particularly strong new signals are reported in specific populations or shared across different continental groups. We report an enrichment of signals in genes that escape X chromosome inactivation, which may contribute to the differentiation between sexes. We also provide evidence of a widespread presence of soft-sweep-like signatures across the chromosome and a global enrichment of highly scoring regions that overlap potential regulatory elements. Among these, enhancers-like signatures seem to present putative signals of positive selection that might be in concordance with selection in their target genes. Also, particularly strong signals appear in regulatory regions that show differential activities, which might point to population-specific regulatory adaptations.

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Mining SNPs From EST Databases

Genome Research ◽

10.1101/gr.9.2.167 ◽

1999 ◽

Vol 9 (2) ◽

pp. 167-174 ◽

Cited By ~ 12

Author(s):

Leslie Picoult-Newberg ◽

Trey E. Ideker ◽

Mark G. Pohl ◽

Scott L. Taylor ◽

Miriam A. Donaldson ◽

...

Keyword(s):

Expressed Sequence Tag ◽

De Novo ◽

Cdna Libraries ◽

Human Populations ◽

Data Sets ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

Using Data

There is considerable interest in the discovery and characterization of single nucleotide polymorphisms (SNPs) to enable the analysis of the potential relationships between human genotype and phenotype. Here we present a strategy that permits the rapid discovery of SNPs from publicly available expressed sequence tag (EST) databases. From a set of ESTs derived from 19 different cDNA libraries, we assembled 300,000 distinct sequences and identified 850 mismatches from contiguous EST data sets (candidate SNP sites), without de novo sequencing. Through a polymerase-mediated, single-base, primer extension technique, Genetic Bit Analysis (GBA), we confirmed the presence of a subset of these candidate SNP sites and have estimated the allele frequencies in three human populations with different ethnic origins. Altogether, our approach provides a basis for rapid and efficient regional and genome-wide SNP discovery using data assembled from sequences from different libraries of cDNAs.[The SNPs identified in this study can be found in the National Center of Biotechnology (NCBI) SNP database under submitter handles ORCHID (SNPS-981210-A) and debnick (SNPS-981209-A and SNPS-981209-B).]

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Exploring functional variation affecting ceRNA regulation in humans

10.1101/016865 ◽

2015 ◽

Cited By ~ 1

Author(s):

Mulin Jun Li ◽

Jiexing Wu ◽

Peng Jiang ◽

Wei Li ◽

Yun Zhu ◽

...

Keyword(s):

Genetic Effect ◽

Systematic Investigation ◽

Human Populations ◽

Functional Variation ◽

Regulatory Variants ◽

Genome Wide ◽

Competing Endogenous Rnas ◽

Mirna Sponges ◽

Cis And Trans

MicroRNA (miRNA) sponges have been shown to function as competing endogenous RNAs (ceRNAs) to regulate the expression of other miRNA targets in the network by sequestering available miRNAs. As the first systematic investigation of the genome-wide genetic effect on ceRNA regulation, we applied multivariate response regression and identified widespread genetic variations that are associated with ceRNA competition using 462 Geuvadis RNA-seq data in multiple human populations. We showed that SNPs in gene 3’UTRs at the miRNA seed binding regions can simultaneously regulate gene expression changes in both cis and trans by the ceRNA mechanism. We termed these loci as endogenous miRNA sponge expression quantitative trait loci or “emsQTLs”, and found that a large number of them were unexplored in conventional eQTL mapping. We identified many emsQTLs are undergoing recent positive selection in different human populations. Using GWAS results, we found that emsQTLs are significantly enriched in traits/diseases associated loci. Functional prediction and prioritization extend our understanding on causality of emsQTL allele in disease pathways. We illustrated that emsQTL can synchronously regulate the expression of tumor suppressor and oncogene through ceRNA competition in angiogenesis. Together these results provide a distinct catalog and characterization of functional noncoding regulatory variants that control ceRNA crosstalk.

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Resolving the insertion sites of polymorphic duplications reveals a HERC2 haplotype under selection

10.1101/488726 ◽

2018 ◽

Author(s):

M. Saitou ◽

O. Gokcumen

Keyword(s):

Phenotypic Diversity ◽

Human Populations ◽

Related Gene ◽

Partial Duplication ◽

Future Studies ◽

Evolutionary Forces ◽

Genome Wide ◽

Insertion Sites ◽

Reference Genomes

ABSTRACTPolymorphic duplications in humans have been shown to contribute to phenotypic diversity. However, the evolutionary forces that maintain variable duplications across the human genome are largely unexplored. To understand the haplotypic architecture of the derived duplications, we developed a linkage-disequilibrium based method to detect insertion sites of polymorphic duplications not represented in reference genomes. This method also allows resolution of haplotypes harboring the duplications. Using this approach, we conducted genome-wide analyses and identified the insertion sites of 22 common polymorphic duplications. We found that the majority of these duplications are intrachromosomal and only one of them is an interchromosomal insertion. Further characterization of these duplications revealed significant associations to blood and skin phenotypes. Based on population genetics analyses, we found that the partial duplication of a well-characterized pigmentation-related gene, HERC2, may be selected against in European populations. We further demonstrated that the haplotype harboring the partial duplication significantly affects the expression of the HERC2P9 gene in multiple tissues. Our study sheds light onto the evolutionary impact of understudied polymorphic duplications in human populations and presents methodological insights for future studies.

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