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. 2013 Jul 23:14:495.
doi: 10.1186/1471-2164-14-495.

Selective constraint, background selection, and mutation accumulation variability within and between human populations

Affiliations

Selective constraint, background selection, and mutation accumulation variability within and between human populations

Alan Hodgkinson et al. BMC Genomics. .

Abstract

Background: Regions of the genome that are under evolutionary constraint across multiple species have previously been used to identify functional sequences in the human genome. Furthermore, it is known that there is an inverse relationship between evolutionary constraint and the allele frequency of a mutation segregating in human populations, implying a direct relationship between interspecies divergence and fitness in humans. Here we utilise this relationship to test differences in the accumulation of putatively deleterious mutations both between populations and on the individual level.

Results: Using whole genome and exome sequencing data from Phase 1 of the 1000 Genome Project for 1,092 individuals from 14 worldwide populations we show that minor allele frequency (MAF) varies as a function of constraint around both coding regions and non-coding sites genome-wide, implying that negative, rather than positive, selection primarily drives the distribution of alleles among individuals via background selection. We find a strong relationship between effective population size and the depth of depression in MAF around the most conserved genes, suggesting that populations with smaller effective size are carrying more deleterious mutations, which also translates into higher genetic load when considering the number of putatively deleterious alleles segregating within each population. Finally, given the extreme richness of the data, we are now able to classify individual genomes by the accumulation of mutations at functional sites using high coverage 1000 Genomes data. Using this approach we detect differences between 'healthy' individuals within populations for the distributions of putatively deleterious rare alleles they are carrying.

Conclusions: These findings demonstrate the extent of background selection in the human genome and highlight the role of population history in shaping patterns of diversity between human individuals. Furthermore, we provide a framework for the utility of personal genomic data for the study of genetic fitness and diseases.

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Figures

Figure 1
Figure 1
The relationship between the average GERP score of a gene and the MAF of polymorphisms in the surrounding regions. Genes were split into quartiles based on average GERP score and the average MAF calculated in the sequences surrounding coding regions (A). The correlation between the depth of the depression in minor allele frequency and the average GERP score of genes in each of the top eight GERP score bins (B).
Figure 2
Figure 2
The relationship between effective population size (Ne) and the MAF of polymorphisms in the regions surrounding the most conserved genes. For genes with the highest GERP scores (top 10%), the average MAF scores surrounding genes in each population, with population codes shown in the corresponding colour to the right of each line (A). The correlation between Ne and the depth of depression in MAF around the most highly conserved genes for old world populations that we have Ne data (B). Population codes are as follows: Utah residents with Northern and Western European ancestry (CEU), British in England and Scotland (GBR), Toscani in Italy (TSI), Finnish from Finland (FIN), Han Chinese in Beong, China (CHB), Southern Han Chinese (CHS), Japanese in Tokyo, Japan (JPN), Yoruba in Idadan, Nigeria (YRI), Luhya in Webuye, Kenya (LWK), Americans of African Ancestry in S.W. USA (ASW), Mexican ancestry from Los Angeles, USA (MXL), Puerto Ricans from Puerto Rico (PUR) and Colombians from Medellin, Colombia (CLM).
Figure 3
Figure 3
The relationship between the average GERP score of a non-coding site that is at least 200 KB away from known genes and the MAF of polymorphisms in the surrounding regions.
Figure 4
Figure 4
The numbers and proportions of mutations that occur at nonsynonymous sites with different GERP scores for individuals in the 1000 Genomes populations. For each individual, the proportion of nonsynonymous sites carrying the minor allele that fall into each GERP score bin was found and the proportions were averaged for individuals within each population in the 1000 Genomes data (A). Similarly, the average distribution was found for each population using the absolute numbers of alleles at heterozygous (B) and homozygous derived allele (inferred from a six way primate alignment) (C) sites falling in each positive GERP bin. African populations are blue, admixed American populations are orange, European populations are red and Asian populations are green. Error bars denote 95% confidence intervals.

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