Current relaxation of selection on the human genome: Tolerance of deleterious mutations on olfactory receptors

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Abstract

Knowledge and understanding about the selective pressures that have shaped present human genetic diversity have dramatically increased in the last few years in parallel with the availability of large genomic datasets. The release of large datasets composed of millions of SNPs across hundreds of genomes by HAPMAP, the Human Genome Diversity Panel, and other projects has led to considerable effort to detect selection signals across the nuclear genome (Coop et al., 2009, Lopez Herraez et al., 2009, Sabeti et al., 2006, Sabeti et al., 2007, Voight et al., 2006). Most of the research has focused on positive selection forces although other selective forces, such as negative selection, may have played a substantive role on the shape of our genome. Here we studied the selective strengths acting presently on the genome by making computational predictions of the pathogenicity of nonsynonymous protein mutations and interpreting the distribution of scores in terms of selection. We could show that the genetic diversity for all the major pathways is still constrained by negative selection in all 11 human populations studied. In a single exception, we observed a relaxation of negative selection acting on olfactory receptors. Since a decreased number of functioning olfactory receptors in human compared with other primates had already been shown, this suggests that the role of olfactory receptors for survival and reproductive success has decreased during human evolution. By showing that negative selection is still relaxed, the present results imply that no plateau of minimal function has yet been reached in modern humans and therefore that olfactory capability might still be decreasing. This is a first clue to present human evolution.

Highlights

► Negative selection helped shape genetic diversity in all studied populations. ► Frequencies of predicted ‘deleterious’ SNPs reveals selective constraints. ► Negative selection is relaxed on olfactory receptor genes.

Introduction

One of the constant efforts of molecular anthropology’s fathers such as Morris Goodman was to identify and describe the forces that have shaped human genome evolution (Conrad et al., 1983, Wildman et al., 2003). Based on nucleic acid and protein sequence comparisons between species, they described the evolutionary driving forces that promoted the fixation of new variants on the human lineage (positive selection), and also the forces that have limited the fixation of any new variant (negative selection). Whereas positive selection findings taught us about adaptive evolution, negative selection results taught us about physico-chemical and physiological constraints acting on proteins. Because adaption of an organism to a new environment leads to new constraints, positive selection often causes subsequent negative selection (Goodman, 1982); conversely, a new environment or new way of life can release previous negative selection.

Although positive selection, the most common focus of research on adaptive genetic variants, defines the forces leading to the frequency increase of an adaptive genetic variant, such as for allowing adults to digest milk in farmer populations (Gerbault et al., 2009), negative selection defines the forces leading to the frequency decrease of a genetic variant. For example, some variants can favor the appearance of lethal and fetal diseases, with the result that the fitness of the variant carriers will be lower than the non-carriers and consequently the frequency of this variant will decrease. Thus, knowledge of the negative selection fingerprint on our genome is crucial for understanding the constraints acting on our genome and ultimately for understanding the origin of genetic diseases.

Results involving negative selection on human populations are often based on the dN/dS ratio (reviewed in Harris, 2010). However, due to limitations of this method, other studies have proposed using algorithms predicting the potential deleterious effect, mainly based on the observed diversity in other organisms. By showing that deleterious SNPs are on average younger and/or less frequent than non-deleterious SNPs, these studies suggest that negative selection is still active on human populations, or at least was active until recently (Barreiro et al., 2008, Lohmueller et al., 2008, Pereira et al., 2011, Pierron et al., 2011). However, these studies are limited in terms of populations and groups of genes studied.

Here we have tested whether negative selection has played a significant role on current global genetic diversity observed by the HAPMAP project (Altshuler et al., 2010) by comparing the frequency of SNPs predicted as deleterious versus not deleterious. Our results confirm that the presently observed human genetic diversity is still shaped by negative selection; indeed, we could observe that the genetic diversities of all major pathways are shaped by negative selection. However, the results show an accumulation of deleterious SNPs on olfactory receptor genes in positions highly conserved relative to other primates. Because this result was observed in the 11 different human HAPMAP populations, we propose a release of negative selection on olfactory transduction on the current human population that is still going on.

Section snippets

SNP allele and genotype frequencies

Allele and genotype frequencies of 1.5 million SNPs were downloaded from the HapMap3 Public Release #28 dataset (Altshuler et al., 2010). Including the original 270 samples used in Phases I and II, the HapMap3 sample collection comprises 1,301 samples collected using two platforms: the Illumina Human1M (by the Wellcome Trust Sanger Institute) and the Affymetrix SNP 6.0 (by the Broad Institute). The samples came from 11 populations: ASW, African ancestry in Southwest USA (90 individuals); CEU,

Results

In order to study the influence of negative selection on current human genetic diversity, we have compared the frequency in 11 human populations between deleterious and non-deleterious SNPs, as described in Materials and Methods. As a result, the frequencies were available for 14,952 nsSNPs with a SIFT prediction (2550 deleterious nsSNPs, 12,402 tolerated nsSNPs) and for 15,571 nsSNPs with a POLYPHEN prediction (10,744 benign nsSNPs, 2513 possibly damaging nsSNPs, 1477 probably damaging nsSNPs).

Discussion

Our results show that negative selection still shapes the genetic diversity of modern humans and its action is strong enough to be seen in every population studied. We have shown that all the major pathways are subject to negative selection; however, some pathways, such as the olfactory transduction pathway, and specifically the olfactory receptor genes, are currently under a relaxation of this negative selection. Interestingly, previous studies had already shown a decreasing number of

Acknowledgments

This research was supported by the National Science Foundation (Grants BCS-0550209, BCS-0827546, and DBI 0965741) and Region Aquitaine Grant “projet MAGE.”.

References (29)

  • P. Gerbault et al.

    Impact of selection and demography on the diffusion of lactase persistence

    PLoS ONE

    (2009)
  • Y. Gilad et al.

    Population differences in the human functional olfactory repertoire

    Mol. Biol. Evol.

    (2003)
  • Y. Gilad et al.

    Human specific loss of olfactory receptor genes

    Proc. Natl. Acad. Sci. USA

    (2003)
  • Y. Go et al.

    Similar numbers but different repertoires of olfactory receptor genes in humans and chimpanzees

    Mol. Biol. Evol.

    (2008)
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