乳糖酶持久性的分子基础:将遗传学和表观遗传学联系起来。

IF 1 4区 生物学 Q4 GENETICS & HEREDITY Annals of Human Genetics Pub Date : 2024-08-22 DOI:10.1111/ahg.12575
Céleste E Cohen, Dallas M Swallow, Catherine Walker
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引用次数: 0

摘要

乳糖酶持久性(LP)--决定乳糖酶在成年后继续表达的遗传性状--自动物驯化和乳制品业出现以来,在一些人类种群中经历了近期快速的正向选择。虽然进化论的基本解释已被广泛提出和研究,但 LP 的分子基础仍然鲜为人知。本综述将探讨 LP 的遗传学和表观遗传学基础。邻近的 MCM6 基因内含子 13 中的 LCT 增强子上的多个单核苷酸多态性(SNPs)与 LP 有关。这些单核苷酸多态性改变了转录因子(TFs)的结合,很可能阻止了与年龄相关的增强子甲基化的增加,使 LCT 的表达维持到成年,从而导致 LP。然而,LP的遗传学和表观遗传学之间的复杂关系尚未完全定性,人们对甲基化定量性状位点(meQTLs)(影响甲基化的SNPs)的作用模式普遍仍知之甚少。在这里,我们研究了已发表的 LP 数据,提出了一个模型,描述了 LCT 增强子中的甲基化是如何在 LP 成人中被阻止的。我们认为,这是通过改变 TF Oct-1(由基因 POU2F1 编码)与邻近 TF GATA-6 (GATA6)、HNF-3A (FOXA1) 和 c-Ets1 (ETS1) 的结合协同作用而发生的。因此,我们提出了LP背景下LCT下调的一个貌似合理的新模型,这对未来研究其他meQTL的机制具有更广泛的意义。
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The molecular basis of lactase persistence: Linking genetics and epigenetics.

Lactase persistence (LP) - the genetic trait that determines the continued expression of the enzyme lactase into adulthood - has undergone recent, rapid positive selection since the advent of animal domestication and dairying in some human populations. While underlying evolutionary explanations have been widely posited and studied, the molecular basis of LP remains less so. This review considers the genetic and epigenetic bases of LP. Multiple single-nucleotide polymorphisms (SNPs) in an LCT enhancer in intron 13 of the neighbouring MCM6 gene are associated with LP. These SNPs alter binding of transcription factors (TFs) and likely prevent age-related increases in methylation in the enhancer, maintaining LCT expression into adulthood to cause LP. However, the complex relationship between the genetics and epigenetics of LP is not fully characterised, and the mode of action of methylation quantitative trait loci (meQTLs) (SNPs affecting methylation) generally remains poorly understood. Here, we examine published LP data to propose a model describing how methylation in the LCT enhancer is prevented in LP adults. We argue that this occurs through altered binding of the TF Oct-1 (encoded by the gene POU2F1) and neighbouring TFs GATA-6 (GATA6), HNF-3A (FOXA1) and c-Ets1 (ETS1) acting in concert. We therefore suggest a plausible new model for LCT downregulation in the context of LP, with wider relevance for future work on the mechanisms of other meQTLs.

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来源期刊
Annals of Human Genetics
Annals of Human Genetics 生物-遗传学
CiteScore
4.20
自引率
0.00%
发文量
34
审稿时长
3 months
期刊介绍: Annals of Human Genetics publishes material directly concerned with human genetics or the application of scientific principles and techniques to any aspect of human inheritance. Papers that describe work on other species that may be relevant to human genetics will also be considered. Mathematical models should include examples of application to data where possible. Authors are welcome to submit Supporting Information, such as data sets or additional figures or tables, that will not be published in the print edition of the journal, but which will be viewable via the online edition and stored on the website.
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