An estimate of the average number of recessive lethal mutations carried by humans

TL;DR

This study estimates that each human haploid genome carries approximately 0.29 recessive lethal alleles, highlighting the genetic burden of such mutations and their impact on human health, with implications for understanding inbreeding effects.

Contribution

The paper provides a novel estimate of recessive lethal mutations in humans using a founder population with complete disease data, avoiding confounding factors of previous methods.

Findings

Average of 0.29 recessive lethal alleles per haploid genome

Substantial fraction of deleterious burden due to single mutations causing early death

Constancy of recessive lethal mutation rate across diverse eukaryotes

Abstract

The effects of inbreeding on human health depend critically on the number and severity of recessive, deleterious mutations carried by individuals. In humans, existing estimates of these quantities are based on comparisons between consanguineous and non-consanguineous couples, an approach that confounds socioeconomic and genetic effects of inbreeding. To circumvent this limitation, we focused on a founder population with almost complete Mendelian disease ascertainment and a known pedigree. By considering all recessive lethal diseases reported in the pedigree and simulating allele transmissions, we estimated that each haploid set of human autosomes carries on average 0.29 (95% credible interval [0.10, 0.83]) autosomal, recessive alleles that lead to complete sterility or severe disorders at birth or before reproductive age when homozygous. Comparison to existing estimates of the deleterious effects of all recessive alleles suggests that a substantial fraction of the burden of autosomal, recessive variants is due to single mutations that lead to death between birth and reproductive age. In turn, the comparison to estimates from other eukaryotes points to a surprising constancy of the average number of recessive lethal mutations across organisms with markedly different genome sizes.