Evolutionary Genetic Signatures of Selection on Bone-Related Variation within Human and Chimpanzee Populations.

Daryn A Stover,Brian C Verrelli,Michael S Rosenberg,Anne C Stone,Genevieve Housman

doi:10.3390/genes13020183

Daryn A Stover, Brian C Verrelli + Show 3 more

Open Access

https://doi.org/10.3390/genes13020183

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Abstract

Bone strength and the incidence and severity of skeletal disorders vary significantly among human populations, due in part to underlying genetic differentiation. While clinical models predict that this variation is largely deleterious, natural population variation unrelated to disease can go unnoticed, altering our perception of how natural selection has shaped bone morphologies over deep and recent time periods. Here, we conduct the first comparative population-based genetic analysis of the main bone structural protein gene, collagen type I α 1 (COL1A1), in clinical and 1000 Genomes Project datasets in humans, and in natural populations of chimpanzees. Contrary to predictions from clinical studies, we reveal abundant COL1A1 amino acid variation, predicted to have little association with disease in the natural population. We also find signatures of positive selection associated with intron haplotype structure, linkage disequilibrium, and population differentiation in regions of known gene expression regulation in humans and chimpanzees. These results recall how recent and deep evolutionary regimes can be linked, in that bone morphology differences that developed among vertebrates over 450 million years of evolution are the result of positive selection on subtle type I collagen functional variation segregating within populations over time.

Highlights

Bone-related disorders impact more than 200 million people globally [1,2,3]
From the 1000G dataset of 5008 global gene copies, we identified 60 amino acid replacement single nucleotide polymorphism (SNP) (Table S7) to compare with the 422 disease-associated mutations (DAMs) identified from the clinical database that met the criteria of documented severity categories of 1–4 (Table S2)
Each of the 26 populations in the 1000G dataset includes at least one variant, and some include as many as seven (Table S1). These SNPs are rare in frequency (Table S8); we note that 14 of the 60 are found segregating in at least two populations, with one such variant shared across 17 populations and reaching a frequency as high as 7% (Table S7)

Summary

Introduction

Bone-related disorders impact more than 200 million people globally [1,2,3]. In addition to geographic variation in disorders such as osteoporosis, bone strength in general— measured as bone mineral density (BMD)— varies among populations, with individuals of African ancestry having better overall bone quality [4,5]. While our understanding of bone-related variation linked to osteoporotic-related disorders and fractures is incredibly robust due to high-powered GWAS in case–control cohorts [15,16], we still have a limited understanding of natural population variation unrelated to disease, and what evolutionary significance it may have [17]. We expect that bone-related phenotypes are subject to strong purifying selection, yet variation linked to bone loss is common, but has likely been segregating in the population for the past 10 Ky [18], with variation attributed to ethnicity, age, and sex [19,20,21]. The observation of alleles related to increased BMD being significantly more common in sub-Saharan African populations has been attributed to positive selection driving ethnic differences in bone strength [22]. An overlooked approach is the use of evolutionary genetics to test natural populations for signatures of adaptive functional variation in bone-related genes

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