Global Survey of Variation in a Human Olfactory Receptor Gene Reveals Signatures of Non-Neutral Evolution.

Kara C Hoover,Aulaphan Savangsuksa,Omer Gokcumen,Hiroaki Matsunami,Zoya Qureshy,Matthew Cobb,Elise Bruguera

doi:10.1093/chemse/bjv030

Abstract

Allelic variation at 4 loci in the human olfactory receptor gene OR7D4 is associated with perceptual variation in the sex steroid-derived odorants, androstenone, and androstadienone. Androstadienone has been linked with chemosensory identification whereas androstenone makes pork from uncastrated pigs distasteful ("boar taint"). In a sample of 2224 individuals from 43 populations, we identified 45 OR7D4 single nucleotide polymorphisms. Coalescent modeling of frequency-site-spectrum-based statistics identified significant deviation from neutrality in human OR7D4; individual populations with statistically significant deviations from neutrality include Gujarati, Beijing Han, Great Britain, Iberia, and Puerto Rico. Analysis of molecular variation values indicated statistically significant population differentiation driven mainly by the 4 alleles associated with androstenone perception variation; however, fixation values were low suggesting that genetic structure may not have played a strong role in creating these group divisions. We also studied OR7D4 in the genomes of extinct members of the human lineage: Altai Neandertal and Denisovan. No variants were identified in Altai but 2 were in Denisova, one of which is shared by modern humans and one of which is novel. A functional test of modern human and a synthesized mutant Denisova OR7D4 indicated no statistically significant difference in responses to androstenone between the 2 species. Our results suggest non-neutral evolution for an olfactory receptor gene.

Highlights

Olfactory receptor genes were originally identified in rats (Buck and Axel 1991); in humans, these genes are unusually diverse and rapidly evolving (Olender et al 2004, 2012; Mainland et al 2014)
Analysis of molecular variation values indicated statistically significant population differentiation driven mainly by the 4 alleles associated with androstenone perception variation; fixation values were low suggesting that genetic structure may not have played a strong role in creating these group divisions
We identified variants in the published genomes of Altai Neandertal and Denisova from VCF files aligned to NCBI Build Human Genome Build GRCh37/hg19

Summary

Introduction

Olfactory receptor genes were originally identified in rats (Buck and Axel 1991); in humans, these genes are unusually diverse and rapidly evolving (Olender et al 2004, 2012; Mainland et al 2014). Substantial variation exists at the individual level: the difference in number of expressed olfactory receptors between any pair of individuals is at least 14% (Zhang et al 2007; Verbeurgt et al 2014) but a rate of 30% has been reported (Mainland et al 2014). Variation in olfactory receptor gene sequences among individuals is very high, second only to that seen in immune system genes (Menashe et al 2003)

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