Relating pathogenic loss-of-function mutations in humans to their evolutionary fitness costs.
Relating pathogenic loss-of-function mutations in humans to their evolutionary fitness costs.
复制标题
DOI：
10.7554/elife.83172
复制
发表时间：
2023-01-17
期刊：
影响因子：
7.7
通讯作者：
Przeworski M
中科院分区：
文献类型：
--
作者：
Agarwal I;Fuller ZL;Myers SR;Przeworski M
孟德尔和严重复杂疾病的因果性功能丧失（LOF）变体富含“突变不耐受”基因。我们展示了如何可以解释这样的观察突变选择平衡的模型，并使用该模型与LOF突变的致病后果，目前其进化的健身效果。为此，我们首先从56，855个个体的外显子组序列中推断17，318个常染色体和679个X连锁基因中LOF突变的适应性成本的后验分布。基因拷贝丢失的估计适应性成本通常在1%以上;无论是否有Y同源物，X连锁基因的适应性成本往往最大，其次是常染色体基因和假常染色体区域的基因。我们比较了所有可能的从头LOF突变的推断适应性效应与在被诊断患有六种严重、复杂疾病或发育障碍之一的个体中发现的从头突变的推断适应性效应。先证者携带过量的突变，估计适应性效应超过10%;正如我们通过模拟所示，当在群体中采样时，这种高度有害的突变通常只有几代人的年龄。此外，先证者携带的高度有害突变的比例反映了疾病发作的典型年龄。研究设计也有明显的影响：在家系中检测到的高度有害突变的比例高于病例对照研究，对于自闭症，在单一家庭中比在多重家庭中检测到的高，女性与男性先证者的比例也更高。因此，将人类遗传学中的观察锚定到群体遗传模型，使我们能够了解通过不同映射策略和不同性状识别的突变的适应性效应。
Causal loss-of-function (LOF) variants for Mendelian and severe complex diseases are enriched in 'mutation intolerant' genes. We show how such observations can be interpreted in light of a model of mutation-selection balance and use the model to relate the pathogenic consequences of LOF mutations at present to their evolutionary fitness effects. To this end, we first infer posterior distributions for the fitness costs of LOF mutations in 17,318 autosomal and 679 X-linked genes from exome sequences in 56,855 individuals. Estimated fitness costs for the loss of a gene copy are typically above 1%; they tend to be largest for X-linked genes, whether or not they have a Y homolog, followed by autosomal genes and genes in the pseudoautosomal region. We compare inferred fitness effects for all possible de novo LOF mutations to those of de novo mutations identified in individuals diagnosed with one of six severe, complex diseases or developmental disorders. Probands carry an excess of mutations with estimated fitness effects above 10%; as we show by simulation, when sampled in the population, such highly deleterious mutations are typically only a couple of generations old. Moreover, the proportion of highly deleterious mutations carried by probands reflects the typical age of onset of the disease. The study design also has a discernible influence: a greater proportion of highly deleterious mutations is detected in pedigree than case-control studies, and for autism, in simplex than multiplex families and in female versus male probands. Thus, anchoring observations in human genetics to a population genetic model allows us to learn about the fitness effects of mutations identified by different mapping strategies and for different traits.
影响因子：
--
作者：
Lee W;de Prisco N;Gennarino VA
通讯作者：
Gennarino VA
影响因子：
64.5
作者：
Smolen, Corrine;Girirajan, Santhosh
通讯作者：
Girirajan, Santhosh