基因突变会导致人类疾病的产生,因此研究遗传变异的产生过程和那些能够引起疾病的突变对生命科学基础研究以及人类健康是十分关键和重要的。近日,中国科学院北京基因组研究所于军研究员带领其研究团队,在有关人类基因组中中以转录为中心的突变研究取得新进展,相关研究成果在Genomics, Proteomics & Bioinformatics杂志上发表。
该研究组崔鹏博士等人,通过对人类10种不同组织的高通量RNA测序数据和SNP(单核苷酸多态性)数据进行分析,研究了人类基因组的转录突变过程,对人类基因突变的基本法则提出了新的见解。研究结果显示,人类基因组中基因突变率与它们的表达水平成正相关。这说明突变并不是随机产生的,而更倾向于在那些表达频率更高和表达量更高的基因中产生并累积。此外,他们通过研究12种类型的核苷酸突变频率,发现C→T,A→G,C→G,和G→T是人类基因组的四种主要转录突变类型。同时,研究也表明,突变修复率从转录本的5′端到3′端呈下降趋势,并且下降幅度与基因表达水平相关,这可能与转录偶联的DNA分子修复过程有关(Transcription-coupled DNA Repair,TCR)。最后,研究还提出了人类基因组遗传变异的周期性应该是核小体定位和TCR作用的共同结果。
该研究表明人类基因组以转录为中心的突变是基因和基因组进化的主要驱动力之一,为人类基因突变研究提供了新的思路。(生物谷Bioon.com)
doi:10.1016/S1672-0229(11)60028-4
PMC:
PMID:
Distinct Contributions of Replication and Transcription to Mutation Rate Variation of Human Genomes
Peng Cuia, #, Feng Dinga, #, Qiang Lina, #, Lingfang Zhanga, Ang Lib, Zhang Zhanga, Songnian Hua, , , Jun Yua, ,
Here, we evaluate the contribution of two major biological processes—DNA replication and transcription—to mutation rate variation in human genomes. Based on analysis of the public human tissue transcriptomics data, high-resolution replicating map of Hela cells and dbSNP data, we present significant correlations between expression breadth, replication time in local regions and SNP density. SNP density of tissue-specific (TS) genes is significantly higher than that of housekeeping (HK) genes. TS genes tend to locate in late-replicating genomic regions and genes in such regions have a higher SNP density compared to those in early-replication regions. In addition, SNP density is found to be positively correlated with expression level among HK genes. We conclude that the process of DNA replication generates stronger mutational pressure than transcription-associated biological processes do, resulting in an increase of mutation rate in TS genes while having weaker effects on HK genes. In contrast, transcription-associated processes are mainly responsible for the accumulation of mutations in highly-expressed HK genes.