来自贝勒医学院等处的基因组学和遗传学专家指出,从进化的角度上说,在最近的五千到一万年间,编码细胞蛋白的基因有将近四分之三发生了突变。

-2013年1月10日版《自然》

中文翻译


【译文】人蛋白编码突变体的新起源

【译文】建立当代人群中分离的每个突变的时期对于完全理解我们的进化史非常重要,并将有助于新方法的开发和推动疾病相关基因发现。人群遗传变异的大范围调查已记录了近期人口爆炸性增长的信号,值得注意的是,稀有遗传突变过度出现,这表明许多突变在近期出现。为了更加定量地评估突变时期的分布,我们重测序了6515个欧裔美国人和非裔美国人祖先的15336个基因,并推断1146401个常染色体单核苷酸突变(SNVs)的时期。我们估计在过去5000-10000年间产生的约73%的蛋白编码SNV和约86%的SNV被预测为有害的。在分子通路间有害SNV的产生时间变化显著,并且疾病基因近期兴起有害突变比其他基因明显更高一些。此外,与非裔美国人相比,欧裔美国人在必要和孟德尔疾病基因中具有更多的有害突变,这与人类祖先迁出非洲之后纯化选择较弱一致。我们的结果更好的界定了人蛋白编码突变的历史细节,表明近期人类历史对从当代人群中分离的有害SNV有深刻影响,并为疾病基因发现中推导突变体发生先后次序提供了重要的实用信息。

英文原稿


[Title]: Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants

[Authors]:Wenqing Fu,1 Timothy D. O’Connor,1 Goo Jun,2 Hyun Min Kang,2 Goncalo Abecasis,2 Suzanne M. Leal,3 Stacey Gabriel,4 David Altshuler,4 Jay Shendure,1 Deborah A. Nickerson,1 Michael J.Bamshad,1, 5 NHLBI Exome Sequencing Project6 & Joshua M. Akey1

[Abstract]Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history and will help to facilitate the development of new approaches for disease-gene discovery. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth, notable for an excess of rare genetic variants, suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000–10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs than other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.

原文地址

http://www.nature.com/nature/journal/v493/n7431/full/nature11690.html

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