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<p>The genetic landscape of human Mendelian diseases is shaped by mutation and selection. Although selection on heterozygotes is well-established in autosomal-dominant disorders, convincing evidence for selection in carriers of pathogenic variants associated with recessive conditions is limited. Here, we studied heterozygous pathogenic variants in 1,929 genes, which cause recessive diseases when bi-allelic, in <i>n</i> = 378,751 unrelated European individuals from the UK Biobank. We find evidence suggesting fitness effects in heterozygous carriers for recessive genes, especially for variants in constrained genes across a broad range of diseases. Our data suggest reproductive effects at the population level, and hence natural selection, for autosomal-recessive disease variants. Further, variants in genes that underlie intellectual disability are associated with lower educational attainment in carriers, and we observe an altered genetic landscape, characterized by a threefold reduction in the calculated frequency of bi-allelic intellectual disability in the population relative to other recessive disorders.</p>

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Reproductive and cognitive phenotypes in carriers of recessive pathogenic variants

  • 期刊论文

  • 发表日期：

    2025年5月15日

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  • Hila Fridman,
  • Gelana Khazeeva,
  • Ephrat Levy-Lahad,
  • Christian Gilissen,
  • Han G. Brunner

摘要

The genetic landscape of human Mendelian diseases is shaped by mutation and selection. Although selection on heterozygotes is well-established in autosomal-dominant disorders, convincing evidence for selection in carriers of pathogenic variants associated with recessive conditions is limited. Here, we studied heterozygous pathogenic variants in 1,929 genes, which cause recessive diseases when bi-allelic, in n = 378,751 unrelated European individuals from the UK Biobank. We find evidence suggesting fitness effects in heterozygous carriers for recessive genes, especially for variants in constrained genes across a broad range of diseases. Our data suggest reproductive effects at the population level, and hence natural selection, for autosomal-recessive disease variants. Further, variants in genes that underlie intellectual disability are associated with lower educational attainment in carriers, and we observe an altered genetic landscape, characterized by a threefold reduction in the calculated frequency of bi-allelic intellectual disability in the population relative to other recessive disorders.