Science：人类健康问题的根源所在

5月17日，一项聚焦于来自世界各地的人类基因组中差异的研究披露，大多数的人类遗传变异是罕见而且不会在种群间共有的。这些发现表明，在全球人口中的罕见遗传变异要比先前的研究所提示的多得多——且它们可能在人类的健康和疾病中发挥着一种重要的作用。相关研究成果刊登在Science上。

Jacob Tennessen及其同事对2440位欧洲和非洲人的后裔的外显子组——或一个基因组中的实际编码蛋白质的基因——进行了测序。他们发现了50多万个突变，其中绝大多数是既罕见又具有人群特异性的。在另一项研究中，Matthew Nelson及其同事对1.4万多个同样为欧洲和非洲后裔的202个基因进行了测序，这些人的基因之前曾经被标为潜在的药物标靶。

他们的分析还发现了一些罕见但数量丰富的突变，这些突变看来是罕见且按地理性分布的。综合来看，这些发现提示，近来快速的人口增长与有害突变从基因组中缓慢清除的偶联导致了影响人类健康和疾病的罕见遗传变异株的积聚。这些研究还清楚地表明，将来，人们需要有大容量样本才能将这些罕见的遗传变异株与复杂的生理特征进行关联。（生物谷Bioon.com）

doi:10.1126/science.1219240
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Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes

Jacob A. Tennessen1,*, Abigail W. Bigham2,*,†, Timothy D. O’Connor1,*, Wenqing Fu1, Eimear E. Kenny3, Simon Gravel3, Sean McGee1, Ron Do4,5, Xiaoming Liu6, Goo Jun7, Hyun Min Kang7, Daniel Jordan8, Suzanne M. Leal9, Stacey Gabriel4, Mark J. Rieder1, Goncalo Abecasis7, David Altshuler4, Deborah A. Nickerson1, Eric Boerwinkle6,10, Shamil Sunyaev4,8, Carlos D. Bustamante3, Michael J. Bamshad1,2,‡, Joshua M. Akey1,‡, Broad GO, Seattle GO, on behalf of the NHLBI Exome Sequencing Project

As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human protein-coding genes to an average median depth of 111x in 2,440 individuals of European (n = 1,351) and African (n = 1,088) ancestry. We identified >500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency < 0.5%), novel (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carries were predicted to impact protein function of ~313 genes per genome, and ~95.7% of SNVs predicted to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits.