Genetic signatures of strong recent positive selection at the lactase gene
Genetic signatures of strong recent positive selection at the lactase gene
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DOI：
10.1086/421051
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发表时间：
2004-06-01
影响因子：
9.8
通讯作者：
Hirschhorn, JN
中科院分区：
文献类型：
--
作者：
Bersaglieri, T;Sabeti, PC;Hirschhorn, JN
在大多数人群中，消化牛奶中所含乳糖的能力通常在儿童期消失，但在欧洲来源的人群中，乳糖酶活性通常持续到成年期（Scrimshaw和Murray 1988）。有人建议（Cavalli-Sforza 1973; Hollox等，2001; Enattah等，2002; Poulter等，2003），基于乳制品中额外营养的选择优势解释了这些遗传决定的群体差异（Simoons 1970; Kretchmer 1971; Scrimshaw and Murray 1988; Enattah et al. 2002），但尚未提供正式的基于群体遗传学的选择证据。为了评估选择的群体遗传学证据，我们对乳糖酶基因周围3.2 Mb的101个单核苷酸多态性进行了分型。在来自北方欧洲的人群中，两个与乳糖酶持久性密切相关的等位基因（Enattah et al. 2002）独特地标记了一个常见的（相似度为77%）单倍型，该单倍型延伸> 1 Mb而基本上未被破坏。我们提供了两条新的遗传证据，证明这种长而常见的单倍型是由于最近的选择而迅速出现的：（1）通过使用传统的F-ST测量和基于p（过量）的新检验，我们证明了在整个单倍型中持续相关标记和侧翼标记的群体之间的较大频率差异，以及（2）我们表明单倍型异常长，因为它的出现频率很高--这是最近选择的标志。我们估计，强选择发生在过去的5000 - 10000年中，与奶牛养殖环境中乳糖酶持续性的优势一致;我们观察到的选择信号是基因组中任何基因中最强的。
In most human populations, the ability to digest lactose contained in milk usually disappears in childhood, but in European-derived populations, lactase activity frequently persists into adulthood (Scrimshaw and Murray 1988). It has been suggested (Cavalli-Sforza 1973; Hollox et al. 2001; Enattah et al. 2002; Poulter et al. 2003) that a selective advantage based on additional nutrition from dairy explains these genetically determined population differences (Simoons 1970; Kretchmer 1971; Scrimshaw and Murray 1988; Enattah et al. 2002), but formal population-genetics-based evidence of selection has not yet been provided. To assess the population-genetics evidence for selection, we typed 101 single-nucleotide polymorphisms covering 3.2 Mb around the lactase gene. In northern European-derived populations, two alleles that are tightly associated with lactase persistence ( Enattah et al. 2002) uniquely mark a common (similar to77%) haplotype that extends largely undisrupted for >1 Mb. We provide two new lines of genetic evidence that this long, common haplotype arose rapidly due to recent selection: ( 1) by use of the traditional F-ST measure and a novel test based on p(excess), we demonstrate large frequency differences among populations for the persistence-associated markers and for flanking markers throughout the haplotype, and ( 2) we show that the haplotype is unusually long, given its high frequency-a hallmark of recent selection. We estimate that strong selection occurred within the past 5,000-10,000 years, consistent with an advantage to lactase persistence in the setting of dairy farming; the signals of selection we observe are among the strongest yet seen for any gene in the genome.