Positive Selection on the Gene RNASEL: Correlation between Patterns of Evolution and Function
Positive Selection on the Gene RNASEL: Correlation between Patterns of Evolution and Function
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DOI：
10.1093/molbev/mss123
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发表时间：
2012-10-01
影响因子：
10.7
通讯作者：
Zhang, Ya-Ping
中科院分区：
文献类型：
--
作者：
Jin, Wei;Wu, Dong-Dong;Zhang, Ya-Ping
RNASEL是干扰素诱导的2-5A系统的组成部分，是一种依赖2-5A的内切核酸酶，在干扰素的抗病毒和凋亡活性中起着至关重要的作用。在人类中，RNASEL基因中的许多多态位点与前列腺癌风险的增加有关。在这里，我们从11个灵长类动物中获得了RNASEL基因的编码序列，并发现有证据表明，正选择作用于蛋白质的C末端内切核酸酶结构域和N末端锚定蛋白重复序列结构域，这两个结构域直接与病毒相互作用(即锚定重复序列负责接收环境信号，而内切核酸酶催化对致病病毒RNA的破坏)。为了扩大这一发现，我们通过对代表四个不同群体的144个个体的等位基因进行重新排序，研究了该基因在现代人群体中的变异。有趣的是，541D等位基因的频率与全球人群前列腺癌的发病率呈负相关，包含541D多态的单倍型显示出正选择的特征。具有541D单倍型的RNASE L变异体可能具有更强的抵御病毒感染的能力，因此这种活性的丧失可能与前列腺癌的发生有关。我们提供了正选择作用于RNASEL基因的证据，其进化与其在病原体防御和癌症关联中的功能有关。
RNASEL is a 2-5A-dependent endoribonuclease that is a component of the interferon-induced 2-5A system, which plays a crucial role in the antiviral and apoptotic activities of interferons. In humans, many polymorphic sites within the RNASEL gene have been associated with an increased risk of developing prostate cancer. Here, we obtained coding sequences for the RNASEL gene from 11 primates and found evidence that positive selection has operated on the C-terminal endoribonuclease domain and the N-terminal ankyrin repeats domain of the protein, domains that directly interact with virus (i.e., ankyrin repeats are responsible for receiving environmental signals, and the endoribonuclease catalyses the destruction of the pathogenic viral RNA). To extend this finding, we studied variation within this gene in modern human populations by resequencing alleles from 144 individuals representing four separate populations. Interestingly, the frequency of the 541D allele shows a negative association with the incidence rate of prostate cancer in worldwide populations, and haplotypes containing the 541D polymorphisms demonstrate signatures of positive selection. RNASEL variants having the 541D haplotype likely have a greater ability to defend against infections by viruses, thus the loss of this activity may be associated with the development of prostate cancer. We provide evidence that positive selection has operated on the RNASEL gene, and its evolution is correlated with its function in pathogen defense and cancer association.