Gao Ziyue, Waggoner Darrel, Stephens Matthew, Ober Carole, Przeworski Molly
Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, Illinois 60637
Department of Human Genetics, University of Chicago, Chicago, Illinois 60637 Department of Pediatrics, University of Chicago, Chicago, Illinois 60637.
Genetics. 2015 Apr;199(4):1243-54. doi: 10.1534/genetics.114.173351. Epub 2015 Feb 18.
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.
近亲繁殖对人类健康的影响严重取决于个体携带的隐性有害突变的数量和严重程度。在人类中，对这些数量的现有估计是基于近亲婚配夫妇和非近亲婚配夫妇之间的比较，这种方法混淆了近亲繁殖的社会经济和遗传效应。为了克服这一局限性，我们聚焦于一个实行集体生活方式的奠基者群体，对于该群体，几乎有完整的孟德尔疾病确诊信息且家系已知。聚焦于隐性致死性疾病并模拟等位基因传递，我们估计人类常染色体的每个单倍体组平均携带0.29个（95%可信区间[0.10, 0.84]）隐性等位基因，当这些等位基因纯合时会导致在生育年龄前完全不育或死亡。与人类现有估计的比较表明，隐性有害变异造成的总负担的很大一部分是由于导致出生至生育年龄之间不育或死亡的单基因突变。反过来，与其他真核生物的估计比较表明，在基因组大小明显不同的生物体中，隐性致死突变的平均数量出人意料地恒定。
