Concurrent action of purifying selection and gene conversion results in extreme conservation of the major stress-inducible Hsp70 genes in mammals
Concurrent action of purifying selection and gene conversion results in extreme conservation of the major stress-inducible Hsp70 genes in mammals
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DOI：
10.1038/s41598-018-23508-x
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发表时间：
2018-03-23
影响因子：
4.6
通讯作者：
Nikolaidis, Nikolas
中科院分区：
文献类型：
--
作者：
Hess, Kyle;Oliverio, Ryan;Nikolaidis, Nikolas
几种进化机制根据其表现出的功能效应来改变群体内突变和基因的命运。为了了解细胞应激反应（生物体进化过程中非常保守的机制）进化的潜在机制，我们研究了自然遗传变异的模式和两个应激诱导的 Hsp70 基因多态性的功能后果。这些基因 HSPA1A 和 HSPA1B 是细胞应激反应的主要协调者，与多种人类疾病相关。我们的系统发育分析表明，HSPA1A 和 HSPA1B 的重复起源于胎盘哺乳动物的谱系，此后它们保持保守的同线性。此外，对同义和非同义变化的分析表明，纯化选择塑造了 HSPA1 基因多样化，而基因转换导致物种内的高度序列保守。在人类 HSPA1 簇中，绝大多数突变是同义的，并且特定基因区域没有突变。此外，几种人类多态性的功能表征揭示了 HSPA1A 稳定性和细胞内定位的细微差异。总的来说，HSPA1A-1B 变异的可观察模式描述了一种进化模式，其中净化选择和基因转换同时起作用，并保留了细胞应激反应的主要协调器。
Several evolutionary mechanisms alter the fate of mutations and genes within populations based on their exhibited functional effects. To understand the underlying mechanisms involved in the evolution of the cellular stress response, a very conserved mechanism in the course of organismal evolution, we studied the patterns of natural genetic variation and functional consequences of polymorphisms of two stress-inducible Hsp70 genes. These genes, HSPA1A and HSPA1B, are major orchestrators of the cellular stress response and are associated with several human diseases. Our phylogenetic analyses revealed that the duplication of HSPA1A and HSPA1B originated in a lineage proceeding to placental mammals, and henceforth they remained in conserved synteny. Additionally, analyses of synonymous and non-synonymous changes suggest that purifying selection shaped the HSPA1 gene diversification, while gene conversion resulted in high sequence conservation within species. In the human HSPA1-cluster, the vast majority of mutations are synonymous and specific genic regions are devoid of mutations. Furthermore, functional characterization of several human polymorphisms revealed subtle differences in HSPA1A stability and intracellular localization. Collectively, the observable patterns of HSPA1A-1B variation describe an evolutionary pattern, in which purifying selection and gene conversion act simultaneously and conserve a major orchestrator of the cellular stress response.