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

Alan Hodgkinson, Ferran Casals, Youssef Idaghdhour, Jean Christophe Grenier, Ryan D. Hernandez, Philip Awadalla

    Research output: Contribution to journalArticle

    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.

    Original languageEnglish (US)
    Article number495
    JournalBMC Genomics
    Volume14
    Issue number1
    DOIs
    StatePublished - Jul 23 2013

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    Genome
    Gene Frequency
    Population
    Alleles
    Human Genome
    Mutation
    Genetic Load
    Genetic Fitness
    Exome
    Inborn Genetic Diseases
    Population Density
    Mutation Accumulation
    Demography
    Genes

    ASJC Scopus subject areas

    • Biotechnology
    • Genetics

    Cite this

    Hodgkinson, A., Casals, F., Idaghdhour, Y., Grenier, J. C., Hernandez, R. D., & Awadalla, P. (2013). Selective constraint, background selection, and mutation accumulation variability within and between human populations. BMC Genomics, 14(1), [495]. https://doi.org/10.1186/1471-2164-14-495

    Selective constraint, background selection, and mutation accumulation variability within and between human populations. / Hodgkinson, Alan; Casals, Ferran; Idaghdhour, Youssef; Grenier, Jean Christophe; Hernandez, Ryan D.; Awadalla, Philip.

    In: BMC Genomics, Vol. 14, No. 1, 495, 23.07.2013.

    Research output: Contribution to journalArticle

    Hodgkinson, A, Casals, F, Idaghdhour, Y, Grenier, JC, Hernandez, RD & Awadalla, P 2013, 'Selective constraint, background selection, and mutation accumulation variability within and between human populations', BMC Genomics, vol. 14, no. 1, 495. https://doi.org/10.1186/1471-2164-14-495
    Hodgkinson, Alan ; Casals, Ferran ; Idaghdhour, Youssef ; Grenier, Jean Christophe ; Hernandez, Ryan D. ; Awadalla, Philip. / Selective constraint, background selection, and mutation accumulation variability within and between human populations. In: BMC Genomics. 2013 ; Vol. 14, No. 1.
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