title: An estimate of the average number of recessive lethal mutations carried by humans.
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 nonconsanguineous couples, an approach that confounds socioeconomic and genetic effects of inbreeding. To overcome this limitation, we focused on a founder population that practices a communal lifestyle, for which there is almost complete Mendelian disease ascertainment and a known pedigree. Focusing on recessive lethal diseases and simulating allele transmissions, we estimated that each haploid set of human autosomes carries on average 0.29 (95% credible interval [0.10, 0.84]) recessive alleles that lead to complete sterility or death by reproductive age when homozygous. Comparison to existing estimates in humans suggests that a substantial fraction of the total burden imposed by recessive deleterious variants is due to single mutations that lead to sterility or death between birth and reproductive age. In turn, 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.
authors.affiliation: Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, Illinois 60637 ziyuegao@uchicago.edu mp3284@columbia.edu.
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois 60637 Department of Pediatrics, University of Chicago, Chicago, Illinois 60637.
authors.forename: Darrel
authors.initials: D
authors.lastname: Waggoner
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois 60637 Department of Statistics, University of Chicago, Chicago, Illinois 60637.
authors.forename: Matthew
authors.initials: M
authors.lastname: Stephens
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois 60637 Department of Obstetrics and Gynecology, University of Chicago, Chicago, Illinois 60637.
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027 Department of Systems Biology, Columbia University, New York, New York 10032 ziyuegao@uchicago.edu mp3284@columbia.edu.
authors.forename: Molly
authors.initials: M
authors.lastname: Przeworski
mesh_terms: D005787:Gene Frequency; D005804:Genes, Lethal; D005808:Genes, Recessive; D015894:Genome, Human; D006801:Humans; D008957:Models, Genetic; D010375:Pedigree
keywords: autosomal recessive disease; consanguinity; human; inbreeding; recessive lethal mutation