Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.01.21.427090

Diverse functions associate with trans-species polymorphisms in humans

Velazquez-Arcelay, K.·Benton, M. L.·Capra, J. A.
View original source ↗Export metadata ↓

Abstract

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.

Source connections

Explore related subjects

evolutionary biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Velazquez-Arcelay, K., Benton, M. L., Capra, J. A.. 2021-01-22. Diverse functions associate with trans-species polymorphisms in humans. https://doi.org/10.1101/2021.01.21.427090

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Ocean current models predict spatial structure for coastal biodiversity

Genomic diversity provides the raw material through which all evolutionary processes occur. Accurately describing how environmental features affect patterns of diversity shows promise in predicting the resilience of populations and entire communities to dynamic environments and novel stressors. Identifying the contribution of purely neutral responses to environmental effects can be difficult, especially across large spatial ranges with many covarying environmental features. Using an individual-based model of larvae carried by ocean currents, we predict patterns of neutral genomic diversity in a passively dispersed coastal species, suggesting large geographic regions of relative homogeneity with ancestry determined by the nearest "upstream" population with limited larval input. The genomic identity that dominates each region sharply transitions at the next such interruption, generating hierarchical structure and violating assumptions of isolation-by-distance. We call these upstream populations "lineage source regions" (LSRs), and we find strong concordance between LSR model predictions and an empirical population genomic survey of a keystone salt marsh mussel (Geukensia demissa). We quantitatively validate model performance and goodness-of-fit, updating baseline predictions of genomic diversity patterns from the classic isolation-by-distance model to this LSR framework. This spatially explicit coastal ancestry model has potential for generalization across passive dispersing species.

evolutionary biology↗
bioRxiv2026

TaxaAudit: A statistical model of consensus in phylogenetics identifies non-monophyletic taxa

Interpreting variation in genes and traits across species requires understanding their evolutionary relationships. Taxonomic hierarchies provide a practical approximation of the tree of life, with the NCBI taxonomy linking this framework directly to public sequence data. Some named groups, however, are not evolutionary clades, and recognizing these exceptions requires knowledge scattered across the phylogenetics literature. Here we introduce TaxaAudit, a statistical model that identifies taxonomic groups whose monophyly is repeatedly contradicted by published phylogenies. The model accounts for background taxonomic conflict and the ability of each study's species sampling to expose non-monophyly. Applied to 5,865 molecular phylogenies from TimeTree, TaxaAudit flagged 516 NCBI taxa at family rank and below for significant recurrent contradiction of monophyly. Excluding these taxa's monophyly requirements improved the taxonomy's agreement with independent phylogenomic reference trees and phylogenies withheld from discovery. Flagged taxa were also 3.61 times as likely as matched controls to have their monophyly challenged in publications outside the discovery set. In tree-inference experiments, excluding these monophyly constraints improved agreement with reference phylogenies relative to enforcing the unmodified taxonomy. By identifying groups whose monophyly should not be assumed, TaxaAudit lets researchers draw on published phylogenetic knowledge without reviewing the specialist literature for every taxon. This supports broader use of the NCBI taxonomy as an evolutionary framework for biological comparisons.

evolutionary biology↗
bioRxiv2026

Shared landscape, divergent genomes: Comparative population genomics of co-occurring flora in an isolated Australian mountain range

Understanding how landscape heterogeneity shapes genomic variation is key to conserving biodiversity and evolutionary potential. Yet conservation genomics is typically conducted at the single species level, limiting our ability to identify shared genomic patterns or understand how co-occurring taxa differ in their response to common environmental gradients. We assessed spatial patterns of genomic variation and their associations with geographic and environmental features among populations of nine co-existing plant species with contrasting life-histories and ecological traits across Gariwerd, a threatened biodiversity hotspot in south-eastern Australia. All species exhibited weak overall genetic structure, although the magnitude and spatial distribution of differentiation varied among species. Despite this variation, broadly consistent spatial trends were apparent, with higher genomic divergence largely concentrated in central zones and higher genomic diversity localised in southern regions of the landscape. Significant associations between genetic differentiation and geographic distance were observed in three species, while another species showed associations with environmental distance. These findings demonstrate that coexisting species can show overlapping spatial patterns in genomic variation while differing markedly in their associations with geographic and environmental variation across the same landscape. This comparative approach provides a basis for spatial prioritisation and conservation planning, while highlighting the complex eco-evolutionary processes operating across heterogeneous landscapes.

evolutionary biology↗