Searching for ancient balanced polymorphisms shared between Neanderthals and Modern Humans

Viscardi, Lucas Henriques; Paixão‐Côrtes, Vanessa Rodrigues; Comas, David; Salzano, Francisco M.; Rovaris, Diego Luiz; Bau, Claiton H.D.; Amorim, Carlos Eduardo G.; Bortolini, María Cátira

doi:10.1590/1678-4685-gmb-2017-0308

Cited by 10 publications

(8 citation statements)

References 97 publications

(118 reference statements)

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“…Our results show that TSPs likely maintained by LTBS have diverse functions beyond enabling a flexible immune response to pathogens. This is consistent with several recent studies of balancing selection over shorter timescales that have identified regions with functions outside the immune system (Bitarello et al, 2018; Sato & Kawata, 2018; Siewert & Voight, 2017; Viscardi et al, 2018).…”

Section: Discussionsupporting

confidence: 92%

Diverse functions associate with trans-species polymorphisms in humans

Velazquez-Arcelay

Benton

Capra

2021

Preprint

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Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. Variants shared between species, hereafter “trans-species polymorphisms” (TSPs), often result from LTBS due to host-pathogen interactions. For instance, the major histocompatibility complex (MHC) locus contains TSPs present across primates. Several hundred TSPs have been identified in humans and chimpanzees; however, because many are in non-coding regions of the genome, the functions and adaptive roles for most TSPs remain unknown. We integrated diverse genomic annotations to explore the functions of 125 previously identified non-coding TSPs that are likely under LTBS since the common ancestor of humans and chimpanzees. We analyzed genome-wide functional assays, expression quantitative trait loci (eQTL), genome-wide association studies (GWAS), and phenome-wide association studies (PheWAS). We identify functional annotations for 119 TSP regions, including 71 with evidence of gene regulatory function from GTEx or genome-wide functional genomics data and 21 with evidence of trait association from GWAS and PheWAS. TSPs in humans associate with many immune system phenotypes, including response to pathogens, but we also find associations with a range of other phenotypes, including body mass, alcohol intake, urate levels, chronotype, and risk-taking behavior. The diversity of traits associated with non-coding human TSPs suggest that functions beyond the immune system are often subject to LTBS. Furthermore, several of these trait associations provide support and candidate genetic loci for previous hypothesis about behavioral diversity in great ape populations, such as the importance of variation in sleep cycles and risk sensitivity.Significance statementMost genetic variants present in human populations are young (<100,000 years old); however, a few hundred are millions of years old with origins before the divergence of humans and chimpanzees. These trans-species polymorphisms (TSPs) were likely maintained by balancing selection—evolutionary pressure to maintain genetic diversity at a locus. However, the functions driving this selection, especially for non-coding TSPs, are largely unknown. We integrate genome-wide annotation strategies to demonstrate TSP associations with immune system function, behavior (addition, cognition, risky behavior), uric acid metabolism, and many other phenotypes. These results substantially expand our understanding of functions TSPs and suggest a substantial role for balancing selection beyond the immune system.

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“…Our results suggest that non-coding TSPs likely maintained by LTBS have diverse functions beyond enabling a flexible immune response to pathogens. This expands on several recent studies of balancing selection over shorter timescales that have identified a small number of regions with functions outside the immune system (Bitarello et al, 2018;Sato & Kawata, 2018;Siewert & Voight, 2017;Viscardi et al, 2018).…”

Section: Discussionsupporting

confidence: 52%

Diverse Functions Associate With Non-Coding Trans-species Polymorphisms in Humans

Velazquez-Arcelay

Benton

Capra

2021

Preprint

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Background: Long-term balancing selection (LTBS) can maintain allelic variation at a locus over millions of years and through speciation events. Variants shared between species, hereafter “trans-species polymorphisms” (TSPs), often result from LTBS due to host-pathogen interactions. For instance, the major histocompatibility complex (MHC) locus contains TSPs present across primates. Several hundred candidate TSPs have been identified in humans and chimpanzees; however, because many are in non-coding regions of the genome, the functions and adaptive roles for most TSPs remain unknown. Results: We integrated diverse genomic annotations, with a focus on non-coding regions, to explore the functions of 125 previously identified regions containing multiple TSPs in humans and chimpanzees. We analyzed genome-wide functional assays, expression quantitative trait loci (eQTL), genome-wide association studies (GWAS), and phenome-wide association studies (PheWAS). We identify functional annotations for 119 TSP regions, including 71 with evidence of gene regulatory function from GTEx or genome-wide functional genomics data and 21 with evidence of trait association from GWAS and PheWAS. TSPs in humans associate with many immune system phenotypes, including response to pathogens, but we also find associations with a range of other phenotypes, including body mass, alcohol intake, urate levels, chronotype, and risk-taking behavior. Conclusions: The diversity of traits associated with non-coding human TSPs further support previous hypotheses that functions beyond the immune system are subject to LTBS. Furthermore, several of these trait associations provide support and candidate genetic loci for previous hypothesis about behavioral diversity in great ape populations, such as the importance of variation in sleep cycles and risk sensitivity.

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“…The polymorphic sites indicated the differences between individuals within one species (Jaratlerdsiri et al 2014;Viscardi et al 2018;Brodetzki et al 2019;Takahashi-Kariyazono et al 2020). The research on several mitochondrial genes also showed some intra-population variation, and their differences were used as genetic markers (barcode species) (Li et al 2008;Meenakshi et al 2010;Yaacov et al 2012;Wolff et al 2014;Naim et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Molecular analysis of Taro and Bali cattle using cytochrome oxidase subunit I (COI) in Indonesia

2020

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Abstract. Susari NNW, Suastika P, Agustina KK. 2021. Molecular analysis of Taro and Bali cattle using cytochrome oxidase subunit I (COI) in Indonesia. Biodiversitas 22: 165-172. Cytochrome oxidase subunit I (COI) is one of the molecular markers often used as a differentiator with many advantages in phylogeny analysis, and it thus rarely undergoes substitution. This research was conducted to characterize the genetics of Taro and Bali (Bos javanicus) cattle. Blood from the animals was collected from the jugularis vein and amplified by PCR. The target area was COI with a primer that was successfully amplified, namely the forward BICOIF (5'-TTC-TCAACCAACCATAAAGATATTGG-3') and the reverse BICOIR fragment (5'-TAG-ACTTCGGGGTGTCCAAAGAATCA-3'). The PCR products' sequencing was carried out by phylogeny analysis using MEGA 6 software. The amplicon value that succeeded in electrophoresis was 710bp, while six polymorphic sites were obtained at base positions of 1, 300, 379, 675, 676, and 679. The haplotypes (Hap) obtained were 4, with a genetic distance that ranged from 0.000-0.001. The nitrogenous bases of the amino acid composition from the samples showed no significant difference. The phylogenetic tree (Tamura-Nei) classified the cattle into two clades with a genetic distance of 0.0005.

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“…Findings from GWAS and WGS of schizophrenia have also consistently reported signals from the HLA region on Chromosome 6 51 . A study which investigated the role of balancing selection using exome data from modern and archaic humans also found an excess of SNPs across species in a gene set associated with the immune system, of which six were located within genes previously associated with schizophrenia 52 . Another study also suggests shared genetic pathways link white blood cell indices and complex diseases such as schizophrenia, autoimmune, and coronary heart diseases 53 .…”

Section: Discussionmentioning

confidence: 99%

Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes

Mahadevan

Pathak

Vemula

et al. 2021

Preprint

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Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. We analyzed whole exome sequencing data from 80 unique individuals from India coming from families with two or more individuals with severe mental illness. We used Population Branch Statistics (PBS) to identify variants and genes under positive selection and identified 75 genes as candidates for positive selection. Of these, 20 were previously associated with Schizophrenia, Alzheimers disease and cognitive abilities in genome wide association studies. We then checked whether any of these 75 genes were involved in common biological pathways or related to specific cellular or molecular functions. We found that immune related pathways and functions related to innate immunity such as antigen binding were over-represented. We also evaluated for the presence of Neanderthal introgressed segments in these genes and found Neanderthal introgression in a single gene out of the 75 candidate genes. However, the introgression pattern indicates the region is unlikely to be the source for selection. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Further, it also provides insights into the genetic architecture of severe mental illness, such as schizophrenia and its link to immune factors.

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“…Em um trabalho recente, sugerimos que um repertório genético comum vinculado aos sistemas imunológico e comportamental foi mantido por seleção balanceada (tipo de seleção que mantém muitas variantes genéticas) por milhares de anos, tanto em humanos arcaicos como em modernos. A implicação dessa descoberta pode estar ligada ao sucesso evolutivo do gênero Homo, com sua capacidade criativa, o que é fundamental para a descoberta de inovações culturais com impacto adaptativo [27].…”

Section: Pesquisas Com Humanos Arcaicos E Primatas Não-humanosunclassified

História demográfica e evolutiva humana e de outros primatas: contribuições do laboratório de pesquisa fundado por Francisco Mauro Salzano

Bortolini

2019

Cienc. Cult.

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Searching for ancient balanced polymorphisms shared between Neanderthals and Modern Humans

Cited by 10 publications

References 97 publications

Diverse functions associate with trans-species polymorphisms in humans

Diverse Functions Associate With Non-Coding Trans-species Polymorphisms in Humans

Molecular analysis of Taro and Bali cattle using cytochrome oxidase subunit I (COI) in Indonesia

Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes

História demográfica e evolutiva humana e de outros primatas: contribuições do laboratório de pesquisa fundado por Francisco Mauro Salzano

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