Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population.
Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population.
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DOI：
10.1101/gr.205070.116
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发表时间：
2016-12
期刊：
影响因子：
7
通讯作者：
Bradley RK
中科院分区：
文献类型：
--
作者：
Jagannathan S;Bradley RK
破坏蛋白质编码DNA的遗传变异在人类群体中普遍存在，每个个体约有100个这样的功能丧失变异。虽然大多数功能丧失变异是罕见的，但一个子集已经上升到高频率，并在健康个体中以纯合状态发生。目前还不清楚为什么这些常见的变异是耐受良好的，即使一些影响孟德尔疾病的必需基因。在这里，我们结合联合收割机基因组，蛋白质组学和生物化学数据，以证明许多常见的无义变异不消融蛋白质生产从他们的宿主基因。我们提供了计算和实验证据的不同机制的基因拯救，包括选择性剪接，终止密码子通读，选择性翻译起始，和C-末端截短。我们的研究结果表明，许多常见的无义变体的温和的健身成本的分子解释，并表明，翻译可塑性在塑造人类遗传多样性中起着突出的作用。
Genetic variants that disrupt protein-coding DNA are ubiquitous in the human population, with about 100 such loss-of-function variants per individual. While most loss-of-function variants are rare, a subset have risen to high frequency and occur in a homozygous state in healthy individuals. It is unknown why these common variants are well tolerated, even though some affect essential genes implicated in Mendelian disease. Here, we combine genomic, proteomic, and biochemical data to demonstrate that many common nonsense variants do not ablate protein production from their host genes. We provide computational and experimental evidence for diverse mechanisms of gene rescue, including alternative splicing, stop codon readthrough, alternative translation initiation, and C-terminal truncation. Our results suggest a molecular explanation for the mild fitness costs of many common nonsense variants and indicate that translational plasticity plays a prominent role in shaping human genetic diversity.
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DOI：
10.1126/science.1215040
发表时间：
2012-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
MacArthur DG;Balasubramanian S;Frankish A;Huang N;Morris J;Walter K;Jostins L;Habegger L;Pickrell JK;Montgomery SB;Albers CA;Zhang ZD;Conrad DF;Lunter G;Zheng H;Ayub Q;DePristo MA;Banks E;Hu M;Handsaker RE;Rosenfeld JA;Fromer M;Jin M;Mu XJ;Khurana E;Ye K;Kay M;Saunders GI;Suner MM;Hunt T;Barnes IH;Amid C;Carvalho-Silva DR;Bignell AH;Snow C;Yngvadottir B;Bumpstead S;Cooper DN;Xue Y;Romero IG;1000 Genomes Project Consortium;Wang J;Li Y;Gibbs RA;McCarroll SA;Dermitzakis ET;Pritchard JK;Barrett JC;Harrow J;Hurles ME;Gerstein MB;Tyler-Smith C
通讯作者：
Tyler-Smith C
影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
64.8
作者：
通讯作者：
--
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1126/science.1260793
发表时间：
2015-02-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Battle A;Khan Z;Wang SH;Mitrano A;Ford MJ;Pritchard JK;Gilad Y
通讯作者：
Gilad Y