PDF(Pubmed)
Abstract：
Recessive alleles have been shown to directly affect both human Mendelian disease phenotypes and complex traits. Pedigree studies also suggest that consanguinity results in increased childhood mortality and adverse health phenotypes, presumably through penetrance of recessive mutations. Here, we test whether the accumulation of homozygous, recessive alleles decreases reproductive success in a human population. We address this question among the Namibian Himba, an endogamous agro-pastoralist population, who until very recently practiced natural fertility. Using a sample of 681 individuals, we show that Himba exhibit elevated levels of \"inbreeding,\" calculated as the fraction of the genome in runs of homozygosity (FROH). Many individuals contain multiple long segments of ROH in their genomes, indicating that their parents had high kinship coefficients. However, we do not find evidence that this is explained by first-cousin consanguinity, despite a reported social preference for cross-cousin marriages. Rather, we show that elevated haplotype sharing in the Himba is due to a bottleneck, likely in the past 60 generations. We test whether increased recessive mutation load results in observed fitness consequences by assessing the effect of FROH on completed fertility in a cohort of postreproductive women (n = 69). We find that higher FROH is significantly associated with lower fertility. Our data suggest a multilocus genetic effect on fitness driven by the expression of deleterious recessive alleles, especially those in long ROH. However, these effects are not the result of consanguinity but rather elevated background identity by descent.
摘要：
隐性等位基因已被证明直接影响人类孟德尔病表型和复杂性状。家谱研究还表明，血缘关系导致儿童死亡率和不良健康表型增加，大概是通过隐性突变的外显。这里,我们测试纯合的积累，隐性等位基因会降低人群的生殖成功率。我们在纳米比亚辛巴族中讨论这个问题，一夫一妻制的农牧民，直到最近才实行自然生育。使用681个人的样本，我们表明辛巴表现出更高的近亲繁殖水平，“计算为纯合性(FROH)运行中基因组的分数。许多个体在他们的基因组中含有多个长的ROH片段，表明他们的父母有很高的亲属关系系数。然而,我们没有发现证据表明这可以用表弟的血缘关系来解释，尽管有报道称社会倾向于跨堂兄婚姻。相反，我们发现Himba中单倍型共享的升高是由于瓶颈，可能在过去的60代。我们通过评估FROH对生育后妇女（n=69）的完成生育能力的影响，测试了隐性突变负荷的增加是否会导致观察到的健身后果。我们发现，较高的FROH与较低的生育率显着相关。我们的数据表明，有害隐性等位基因的表达对适应性的多基因座遗传影响，尤其是那些在长ROH。然而,这些影响不是血缘关系的结果，而是血统导致的背景认同升高。
