An indel introduced by Neanderthal introgression, rs3835124:ATTTATT > ATT, might contribute to prostate cancer risk by regulating PDK1 expression

IF 1 4区生物学 Q4 GENETICS & HEREDITY

Annals of Human Genetics Pub Date : 2023-10-17 DOI:10.1111/ahg.12533

Ying Chen, Xin-Yi Yu, Shuang-Jia Xu, Xiao-Qian Shi, Xin-Xin Zhang, Chang Sun

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引用次数: 0

Abstract

Introduction

Prostate cancer is one of the most common cancer types in males and rs12621278:A > G has been suggested to be associated with this disease by previous genome-wide association studies. One thousand genomes project data analysis indicated that rs12621278:A > G is within two long-core haplotypes. However, the origin, causal variant(s), and molecular function of these haplotypes were remaining unclear.

Materials and Methods

Population genetics analysis and functional genomics work was performed for this locus.

Results

Phylogeny analysis verified that the rare haplotype is derived from Neanderthal introgression. Genome annotation suggested that three genetic variants in the core haplotypes, rs116108611:G > A, rs139972066:AAAAAAAA > AAAAAAAAA, and rs3835124:ATTTATT > ATT, are located in functional regions. Luciferase assay indicated that rs139972066:AAAAAAAA > AAAAAAAAA and rs116108611:G > A are not able to alter ITGA6 (integrin alpha 6) and ITGA6 antisense RNA 1 expression, respectively. In contrast, rs3835124:ATTTATT > ATT can significantly influence PDK1 (pyruvate dehydrogenase kinase 1) expression, which was verified by expression quantitative trait locus analysis. This genetic variant can alter transcription factor cut like homeobox 1 interaction efficiency. The introgressed haplotype was observed to be subject to positive selection in East Asian populations. The molecular function of the haplotype suggested that Neanderthal should be with lower PDK1 expression and further different energy homeostasis from modern human.

Conclusion

This study provided new insight into the contribution of Neanderthal introgression to human phenotypes.

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由尼安德特人渗入引入的一个indel rs3835124:ATTTATT>ATT可能通过调节PDK1的表达而增加前列腺癌症的风险。

简介：前列腺癌症是男性最常见的癌症类型之一，既往的全基因组关联研究表明rs12621278:A>G与该疾病有关。一千个基因组项目的数据分析表明rs12621278:A>G在两个长核心单倍型内。然而，这些单倍型的起源、因果变异和分子功能尚不清楚。材料和方法：对该基因座进行群体遗传学分析和功能基因组学研究。结果：系统发育分析证实该罕见单倍型来源于尼安德特人的渐渗。基因组注释表明，核心单倍型中的三个遗传变异，rs116108611:G>A，rs139972066:AAAAAAAAAAAA>AAAAAAAAA和rs3835124:ATTTATT>ATT，位于功能区。萤光素酶分析表明rs139972066:AAAAAAAAAAAA>AAAAAAAAA和rs116108611:G>A分别不能改变ITGA6（整合素α6）和ITGA6反义RNA 1的表达。相反，rs3835124:ATTTATT>ATT可以显著影响PDK1（丙酮酸脱氢酶激酶1）的表达，这通过表达定量性状基因座分析得到了验证。这种遗传变异可以改变转录因子切割样同源框1的相互作用效率。在东亚人群中观察到渐渗单倍型受到阳性选择。单倍型的分子功能表明，尼安德特人应该具有较低的PDK1表达和与现代人进一步不同的能量稳态。结论：这项研究为尼安德特人基因渗入对人类表型的贡献提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annals of Human Genetics 生物-遗传学

CiteScore

4.20

自引率

0.00%

发文量

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.