An Estimate of the Average Number of Recessive Lethal Mutations Carried by Humans

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.

• Publication year

  2014

• Venue

  Genetics

• Publication date

  2014-07-28

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1534/genetics.114.173351arXiv 1407.7518PMID 25697177PMCID 4391560
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Population Genetics A Concise Guide

  2016influential reference
• Determinants of mutation rate variation in the human germline.

  2014cited by this paper
• R: A language and environment for statistical computing.

  2014cited by this paper
• Quantitative trait locus linkage analysis in a large Amish pedigree identifies novel candidate loci for erythrocyte traits

  2013influential reference
• The deleterious mutation load is insensitive to recent population history

  2013cited by this paper
• The zebrafish reference genome sequence and its relationship to the human genome

  2013cited by this paper
• Response to a population bottleneck can be used to infer recessive selection

  2013cited by this paper
• Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles

  2013influential reference
• Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability.

  2013cited by this paper
• Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes

  2013influential reference
• A Comparison of Models to Infer the Distribution of Fitness Effects of New Mutations

  2013cited by this paper
• Homozygous lamin A/C familial lipodystrophy R482Q mutation in autosomal recessive Emery Dreifuss muscular dystrophy.

  2013cited by this paper
• Homozygous Founder Mutation in Desmocollin-2 (DSC2) Causes Arrhythmogenic Cardiomyopathy in the Hutterite Population

  2013cited by this paper
• A shared founder mutation underlies restrictive dermopathy in Old Colony (Dutch‐German) Mennonite and Hutterite patients in North America

  2012cited by this paper
• Evaluating the Evidence for Transmission Distortion in Human Pedigrees

  2012cited by this paper
• A population-based study of autosomal-recessive disease-causing mutations in a founder population.

  2012influential reference
• Estimating human mutation rate using autozygosity in a founder population

  2012influential reference
• Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report

  2011influential reference
• Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13.

  2011cited by this paper
• TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone.

  2011cited by this paper
• A novel autosomal recessive malformation syndrome associated with developmental delay and distinctive facies maps to 16ptel in the Hutterite population

  2010cited by this paper
• Legacy of mutiny on the Bounty: founder effect and admixture on Norfolk Island

  2010influential reference
• Annotating non-coding regions of the genome

  2010cited by this paper
• A founder mutation in BBS2 is responsible for Bardet‐Biedl syndrome in the Hutterite population: utility of SNP arrays in genetically heterogeneous disorders

  2010cited by this paper
• The impact of consanguinity on neonatal and infant health.

  2010influential reference
• Consanguinity, human evolution, and complex diseases

  2010influential reference
• A founder mutation in BBS 2 is responsible for Bardet-Biedl syndrome in the Hutterite population : utility of SNP arrays in genetically heterogeneous disorders

  2010cited by this paper
• Estimating lethal allele frequencies in complex pedigrees via gene dropping approach using the example of Brown Swiss cattle.

  2009cited by this paper
• The rate of spontaneous mutation of a human gene

  2008cited by this paper
• Assessing the Evolutionary Impact of Amino Acid Mutations in the Human Genome

  2008influential reference
• Clinical genetics and the Hutterite population: A review of Mendelian disorders

  2008influential reference
• The distribution of fitness effects of new mutations

  2007cited by this paper
• The Distribution of Fitness Effects of New Deleterious Amino Acid Mutations in Humans

  2006cited by this paper
• Distribution of the strength of selection against amino acid replacements in human proteins.

  2005influential reference
• Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition

  2005cited by this paper
• How many lethal alleles?

  2003influential reference
• Inbreeding effects in wild populations.

  2002influential reference
• The effect of reproductive compensation on recessive disorders within consanguineous human populations

  2002influential reference
• A Low Genomic Number of Recessive Lethals in Natural Populations of Bluefin Killifish and Zebrafish

  2002influential reference
• Functional analysis of secreted and transmembrane proteins critical to mouse development

  2001influential reference
• Male-male competition magnifies inbreeding depression in wild house mice.

  2000cited by this paper
• SOCIODEMOGRAPHIC CORRELATES OF CONSANGUINEOUS MARRIAGE IN THE MUSLIM POPULATION OF INDIA

  2000cited by this paper
• Inbreeding effects on fertility in humans: evidence for reproductive compensation.

  1999cited by this paper
• THE PREVALENCE AND DEMOGRAPHIC CHARACTERISTICS OF CONSANGUINEOUS MARRIAGES IN PAKISTAN

  1998influential reference
• The costs of human inbreeding and their implications for variations at the DNA level

  1994influential reference
• Identification of the M1101K mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and complete detection of cystic fibrosis mutations in the Hutterite population.

  1993cited by this paper
• Genealogical analysis of cystic fibrosis families and chromosome 7q RFLP haplotypes in the Hutterite Brethren.

  1989cited by this paper
• Inbreeding in human populations: An assessment of the costs

  1988cited by this paper
• On the choice of mathematical models for the estimation of lethal gene equivalents in man

  1986cited by this paper
• Linear regressions in the calculation of lethal gene equivalents in man.

  1985influential reference
• The Meckel syndrome in the Hutterites.

  1980cited by this paper
• Human Fertility: the basic components

  1978cited by this paper
• Mutations affecting fitness in Drosophila populations.

  1977influential reference
• The age of a neutral mutant persisting in a finite population.

  1973influential reference
• Total number of individuals affected by a single deleterious mutation in a finite population.

  1972influential reference
• The genetic organization of chromosomes.

  1971cited by this paper
• The effects of parental consanguinity and inbreeding in Hirado, Japan. II. Physical development, tapping rate, blood pressure, intelligence quotient, and school performance.

  1970cited by this paper
• The effects of parental consanguinity and inbreeding in Hirado, Japan. I. Stillbirths and prereproductive mortality.

  1970cited by this paper
• The founder effect in a human isolate: evolutionary implications.

  1970cited by this paper
• The Effects of Inbreeding on Japanese Children

  1966cited by this paper
• INBREEDING AND THE MUTATIONAL AND BALANCED LOADS IN NATURAL POPULATIONS OF DROSOPHILA WILLISTONI.

  1964influential reference
• GROWTH AND INBREEDING OF A HUMAN ISOLATE.

  1964cited by this paper
• GROWTH AND INBREEDING OF A HUMAN ISOLATE.

  1964cited by this paper
• Genetics of natural populations. 32. Inbreeding and the mutational and balanced genetic loads in natural populations of Drosophila pseudoobscura.

  1963influential reference
• A Comparison of the Effect of Lethal and Detrimental Chromosomes from Drosophila Populations.

  1960cited by this paper
• AN ESTIMATE OF THE MUTATIONAL DAMAGE IN MAN FROM DATA ON CONSANGUINEOUS MARRIAGES.

  1956influential reference
• The rate of spontaneous mutation of a human gene

  1935cited by this paper
• Literature cited

  1924cited by this paper

• Insights from human NF-κB knockouts

  2025cites this paper
• The Landscape of Genetic Variation and Disease Risk in Romania: A Single-Center Study of Autosomal Recessive Carrier Frequencies and Molecular Variants

  2025influential citation
• Solones, Solo Reproduction and Vice

  2025cites this paper
• The evolution of fitness during range expansions in different dimensions

  2024influential citation
• Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings

  2024cites this paper
• The Use of Expanded Carrier Screening in Reproductive Medicine

  2024cites this paper
• Lethal phenotypes in Mendelian disorders.

  2024cites this paper
• Modern view of preconception carrier screening

  2024cites this paper
• Lethal phenotypes in Mendelian disorders

  2024cites this paper
• Constraining models of dominance for nonsynonymous mutations in the human genome

  2024influential citation
• Constraining models of dominance for nonsynonymous mutations in the human genome

  2024cites this paper
• Endogamy and high prevalence of deleterious mutations in India: evidence from strong founder events

  2024cites this paper
• Models based on best-available information support a low inbreeding load and potential for recovery in the vaquita

  2023influential citation
• The Routledge Companion to Philosophy of Medicine

  2023cites this paper
• Understanding recessive disease risk in multi‐ethnic populations with different degrees of consanguinity

  2023cites this paper
• Patterns of reproduction and autozygosity distinguish the breeding from non-breeding gray wolves of Yellowstone National Park.

  2023cites this paper
• Using Computational Simulations to Model Deleterious Variation and Genetic Load in Natural Populations

  2023influential citation
• Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

  2023cites this paper
• Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

  2023cites this paper
• Essential genes: a cross-species perspective

  2023cites this paper
• The critically endangered vaquita is not doomed to extinction by inbreeding depression

  2022cites this paper
• Interrogating the Roles of Mutation-Selection Balance, Heterozygote Advantage, and Linked Selection in Maintaining Recessive Lethal Variation in Natural Populations.

  2022cites this paper
• Using computational simulations to quantify genetic load and predict extinction risk

  2022cites this paper
• Quantifying the fraction of new mutations that are recessive lethal

  2022influential citation
• Psychosocial, ethical, legal and economic aspects of genetic screening for the carriage of variants that cause the development of monogenic recessive diseases

  2021cites this paper
• The crucial role of genome-wide genetic variation in conservation

  2021cites this paper
• Non-additive association analysis using proxy phenotypes identifies novel cattle syndromes

  2021cites this paper
• A Troublesome Subject – Exploring the possible connection between intelligence and Parkinson’s and Alzheimer's diseases

  2021cites this paper
• A genome-wide scan for candidate lethal variants in Thoroughbred horses

  2020cites this paper
• Next-generation drug repurposing using human genetics and network biology.

  2020cites this paper
• Selection and demography shape genomic variation in a Sky Island species

  2020cites this paper
• Adaptation, ancestral variation and gene flow in a ‘Sky Island’ Drosophila species

  2020cites this paper
• The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

  2020cites this paper
• Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches

  2020influential citation
• Reproductive compensation and selection among viable embryos drive the evolution of polyembryony

  2020cites this paper
• Drop of Prevalence after Population Expansion: A lower prevalence for recessive disorders in a random mating population is a transient phenomenon during and after a growth phase

  2020cites this paper
• The Reproductive Journey in the Genomic Era: From Preconception to Childhood

  2020cites this paper
• Review of the Current State of Genetic Testing-A Living Resource

  2020cites this paper
• Genetic screening for heterozygous carriage of mutations that cause the development of monogenic recessive diseases

  2020cites this paper
• From sequence to phenotype: the impact of deleterious variation in livestock

  2020influential citation
• Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective

  2019cites this paper
• [Preimplantation genetic testing].

  2019cites this paper
• Computational strategies to investigate the genetic cause of human eye disease

  2019cites this paper
• Inbreeding, Allee effects and stochasticity might be sufficient to account for Neanderthal extinction

  2019cites this paper
• The implications of rapid eco‐evolutionary processes for biological control ‐ a review

  2019cites this paper
• TRENDS IN REPRODUCTIVE MALE PARTNER TESTING WHEN FEMALE PATIENT IS IDENTIFIED TO BE A GENETIC DISEASE CARRIER By

  2019cites this paper
• Computationally Designed Recombinant-DNA-Based Compounds Production Driven in Plants During Secondary Metabolism and Their Implication in Antimalarial Therapies

  2019cites this paper
• TECHNIQUES BASED ON THE POLYMORPHISM OF MICROSATELLITE DNA AS TOOLS FOR CONSERVATION OF ENDANGERED POPULATIONS

  2019cites this paper
• Genetic Effects on Dispersion in Urinary Albumin and Creatinine in Three House Mouse (Mus musculus) Cohorts

  2019cites this paper
• Loss of function mutations in essential genes cause embryonic lethality in pigs

  2019cites this paper
• Close inbreeding and low genetic diversity in Inner Asian human populations despite geographical exogamy

  2018cites this paper
• Carrier frequency analysis of mutations causing autosomal-recessive-inherited retinal diseases in the Israeli population

  2018cites this paper
• Genomic signatures of extensive inbreeding in Isle Royale wolves, a population on the threshold of extinction

  2018cites this paper
• Are minor alleles more likely to be risk alleles?

  2018cites this paper
• Allele frequency dynamics in a pedigreed natural population

  2018cites this paper
• Cribado ampliado de portadores en un programa de donación de ovocitos: Implementación de un nuevo test y resultados tras dos años de experiencia

  2017cites this paper
• Are Lethal Alleles Too Abundant in Humans?

  2017cites this paper
• Candidate lethal haplotypes and causal mutations in Angus cattle

  2017cites this paper
• Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research

  2017cites this paper
• Lethal Haplotypes and Candidate Causal Mutations in Angus Cattle

  2017cites this paper
• Na Li and Matthew Stephens on Modeling Linkage Disequilibrium

  2016cites this paper
• NGS-based reverse genetic screen for common embryonic lethal mutations compromising fertility in livestock

  2016influential citation
• Pritchard, Stephens, and Donnelly on Population Structure

  2016cites this paper
• Human Knockout Carriers: Dead, Diseased, Healthy, or Improved?

  2016cites this paper
• Coalescent and Models of Identity by Descent

  2016cites this paper
• The Impact of Lethal Recessive Alleles on Bottlenecks with Implications for Conservation Genetics

  2016cites this paper
• The CARD-CC/Bcl10/paracaspase signaling complex is functionally conserved since the last common ancestor of Planulozoa

  2016cites this paper
• Exome Aggregation Consortium

  2016cites this paper
• Hermann Muller on Measuring Mutation Rates

  2016cites this paper
• Author ' s personal copy En Coalescent and Models of Identity by Descent

  2016cites this paper
• Studying the genetics of Mendelian and complex traits with high-throughput genotyping and sequencing in cattle

  2016cites this paper
• Obstruction of adaptation in diploids by recessive, strongly deleterious alleles

  2015cites this paper
• Health and population effects of rare gene knockouts in adult humans with related parents

  2015cites this paper
• Consanguinity and the Developmental Origins of Health and Disease

  2015cites this paper
• Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders

  2015cites this paper
• The Role of Deleterious Substitutions in Crop Genomes

  2015cites this paper
• Natural Selection at Rare Variants

  2015cites this paper
• Genomes carry a heavy burden

  2015cites this paper
• Distance from sub-Saharan Africa predicts mutational load in diverse human genomes

  2015cites this paper
• The evolution of fitness during range expansions in multiple dimensions

  year unknowncites this paper