Increased homozygosity due to endogamy results in fitness consequences in a human population.
Increased homozygosity due to endogamy results in fitness consequences in a human population.
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由于内婚导致的纯合性增加导致了人群的健康后果。
DOI：
10.1073/pnas.2309552120
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发表时间：
2023-10-24
影响因子：
11.1
通讯作者：
Henn, B. M.
中科院分区：
文献类型：
--
作者：
Swinford, N. A.;Prall, S. P.;Gopalan, S.;Williams, C. M.;Sheehama, J.;Scelza, B. A.;Henn, B. M.
人类群体的突变负荷不同--基因组中突变的累积;这些突变的突变率取决于它们的隐性、显性或加性状态。然而，突变负荷的大多数估计都是理论上的，并且与进化适应度无关（即，繁殖成功）。在这里，我们评估运行的纯合性对健身在自然生育能力的人口从北方纳米比亚的影响。随着基因组纯合部分的增加，雌性生育力显著降低。这表明多基因座遗传效应的健康驱动的有害隐性等位基因的表达。有趣的是，尽管辛巴族的文化倾向于近亲结婚，但我们发现这种婚姻很少发生在近亲之间。隐性等位基因已被证明直接影响人类孟德尔疾病表型和复杂性状。系谱研究还表明，血缘关系导致儿童死亡率增加和不利的健康表型，可能是通过隐性突变的遗传。在这里，我们测试是否积累纯合子，隐性等位基因减少人类群体的繁殖成功。我们在纳米比亚辛巴族中讨论这个问题，他们是一个同族通婚的农牧人口，直到最近还实行自然生育。使用681个个体的样本，我们表明，辛巴表现出升高水平的“近亲繁殖”，计算为纯合性（FROH）运行的基因组的分数。许多个体的基因组中含有多个ROH长片段，表明其父母具有较高的亲缘系数。然而，我们没有发现证据表明这可以用表兄弟血缘来解释，尽管有报道称社会偏好表兄弟婚姻。相反，我们表明，Himba的单倍型共享升高是由于瓶颈，可能在过去的60代。我们测试是否增加隐性突变负荷的结果，在观察健身的后果，通过评估FROH完成生育能力的影响，在一个队列中的postreproductive妇女（n = 69）。我们发现较高的FROH与较低的生育率显著相关。我们的数据表明，多位点的遗传效应对健身驱动的有害隐性等位基因的表达，特别是那些在长ROH。然而，这些影响并不是血缘关系的结果，而是由于血统而提高的背景认同。
Human populations have been shown to differ in their mutation load—the accumulation of mutations in their genomes; the penetrance of these mutations will depend on their recessive, dominant, or additive states. However, most estimates of mutation load are theoretical and have not been associated with evolutionary fitness (i.e., reproductive success). Here, we assess the effect of runs of homozygosity on fitness in a natural fertility population from northern Namibia. As the homozygous fraction of the genome increases, female fertility is significantly reduced. This suggests a multilocus genetic effect on fitness driven by the expression of deleterious recessive alleles. Interestingly, despite a cultural preference for consanguineous marriage in the Himba, we find that such marriages rarely occur between close biological kin. 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.
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