Current relaxation of selection on the human genome: Tolerance of deleterious mutations on olfactory receptors
Graphical abstract
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)
- et al.
Evidence that natural selection acts on silent mutation
Biosystems
(1983) - et al.
Natural selection on the olfactory receptor gene family in humans and chimpanzees
Am. J. Hum. Genet.
(2003) - et al.
Comparing phylogeny and the predicted pathogenicity of protein variations reveals equal purifying selection across the global human mtDNA diversity
Am. J. Hum. Genet.
(2011) - et al.
Integrating common and rare genetic variation in diverse human populations
Nature
(2010) - et al.
SPSmart: adapting population based SNP genotype databases for fast and comprehensive web access
BMC Bioinform.
(2008) - et al.
Natural selection has driven population differentiation in modern humans
Nat. Genet.
(2008) - et al.
The role of geography in human adaptation
PLoS Genet.
(2009) - et al.
SNP uniqueness problem: a proof-of-principle in HapMap SNPs
Hum. Mutat.
(2011) - et al.
Positive and negative selection on the human genome
Genetics
(2001) - et al.
Ensembl 2011
Nucl. Acids Res.
(2011)
Impact of selection and demography on the diffusion of lactase persistence
PLoS ONE
Population differences in the human functional olfactory repertoire
Mol. Biol. Evol.
Human specific loss of olfactory receptor genes
Proc. Natl. Acad. Sci. USA
Similar numbers but different repertoires of olfactory receptor genes in humans and chimpanzees
Mol. Biol. Evol.
Cited by (22)
The repertoire of family A-peptide GPCRs in archaic hominins
2019, PeptidesCitation Excerpt :GPCRs constitute therefore one of the main target of current therapeutic drugs (30–40% of marketed medicines). Owing to their crucial role in the organism, it is not surprising to find GPCR genes located in genomic regions showing strong signature of positive selection [32], with the exception of the olfactory receptors that accumulate deleterious non-synonymous polymorphisms (nsSNP) and show relaxed negative selection [25,36]. As a correlate, mutations or deletions in the coding sequence of GPCRs are responsible for human pathologies [26,33–35].
The impact of recent population history on the deleterious mutation load in humans and close evolutionary relatives
2016, Current Opinion in Genetics and DevelopmentCitation Excerpt :They found no significant differences between European and African populations, and interpreted the pattern as indicating little or no difference in load. These studies and others [4,10,11,33–42] applied the same methodologies to subsets of non-synonymous variants classified according to their predicted severity (e.g., using computational tools that rely on phylogenetic conservation and protein structure [43]), as well as to other human populations (see also [44,45]). With few exceptions (see below), analyses relying on the Lohmueller et al. summaries found substantial differences among populations whereas those that relied on the Simons et al. and Do et al. summaries did not.
Contiguously hydrophobic sequences are functionally significant throughout the human exome
2022, Proceedings of the National Academy of Sciences of the United States of AmericaCommon homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes
2020, Proceedings of the National Academy of Sciences of the United States of America