Deleterious alleles in the human genome are on average younger than neutral alleles of the same frequency.
Deleterious alleles in the human genome are on average younger than neutral alleles of the same frequency.
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DOI：
10.1371/journal.pgen.1003301
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Sunyaev SR
中科院分区：
文献类型：
--
作者：
Kiezun A;Pulit SL;Francioli LC;van Dijk F;Swertz M;Boomsma DI;van Duijn CM;Slagboom PE;van Ommen GJ;Wijmenga C;Genome of the Netherlands Consortium;de Bakker PI;Sunyaev SR
大规模的种群测序研究提供了所研究种群内人类遗传变异的完整图景。一个关键的挑战是在无数的等位基因中识别那些对分子功能、表型和生殖适合性有影响的变异。大多数非中性变异由有害等位基因组成，由于不断的突变，有害等位基因在低群体频率下分离。到目前为止，针对有害等位基因进行选择的研究一直是基于等位基因频率(检测稀有等位基因的相对过剩)或多态与分歧的比率(检测多态等位基因数量的相对增加)。在这里，从丸山的理论预测(Maruyama T(1974)，Am J Hum Genet USA 6：669-673)开始，我们设计了一种基于等位基因年龄的选择特征的方法，即(轻微的)有害等位基因平均比以相同频率分离的中性等位基因年轻。与现有方法不同，它以相同的等位基因频率比较一组中性和有害的序列变体。当应用于荷兰基因组计划的人类序列数据时，我们的方法在相同的等位基因频率下区分低频编码非同义变体和同义和非编码变体，并区分独立预测对蛋白质结构和功能有益或有害的变体集。这一结果证实了人类体内存在丰富的略微有害的编码变异。人类遗传学的一个关键挑战是，在众多个体之间的遗传差异中，找出那些对特征有影响的差异。尽管每一代人都会通过突变产生新的基因变异，但大多数变异只存在于一小部分个体中，因为它们对适应能力有轻微的负面影响。检测这种略微有害的变异是分析遗传学如何影响人类特征的关键挑战。在这篇文章中，我们检验了丸山武夫1974年的一个理论预测，即在相同的种群频率下，稍微有害的变异平均比中性(不影响适应度)的变异年轻。因此，我们的方法通过使用变种的估计年龄来检测选择。我们将我们的方法应用于荷兰基因组计划的人类数据，我们表明，它在相同的种群频率下区分了低频率的蛋白质修饰变体和沉默的变体，并区分了预测对蛋白质结构和功能有利或有害的变体集。我们的结果证实了人类体内存在丰富的略微有害的蛋白质编码变异。
Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669–673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans. A key challenge in human genetics is to identify, among the multitude of genetic differences between individuals, those that have an effect on traits. Even though new genetic variants arise through mutation in each generation, most are present only in a small proportion of individuals because they have slightly negative effects on fitness. Detecting such slightly deleterious variants is a key challenge in analyzing how genetics influence human characteristics. In this paper, we test a theoretical prediction by Takeo Maruyama from 1974 that a slightly deleterious variant is, on average, younger than a neutral (non affecting fitness) variant present at the same population frequency. Thus our method detects selection by using estimated age of variants. We applied our method to human data from the Genome of the Netherlands Project, and we show that it distinguishes low-frequency protein-modifying variants from silent variants at the same population frequency and discriminates between sets of variants predicted to be benign or damaging for protein structure and function. Our results confirm the abundance of slightly deleterious protein-coding variation in humans.
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影响因子：
5.8
作者：
Hernandez, Ryan D.
通讯作者：
Hernandez, Ryan D.
DOI：
10.1073/pnas.0812824106
发表时间：
2009-03-10
影响因子：
11.1
作者：
Kryukov, Gregory V.;Shpunt, Alexander;Sunyaev, Shamil R.
通讯作者：
Sunyaev, Shamil R.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
在人类基因组中近期阳性选择的地图。
影响因子：
9.8
作者：
Voight BF;Kudaravalli S;Wen X;Pritchard JK
通讯作者：
Pritchard JK
影响因子：
9.8
作者：
Wang, N;Akey, JM;Jin, L
通讯作者：
Jin, L