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。
图示：序列变异的周期性、与TCR相关联的突变
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。
The Transcript-centric Mutations in Human Genomes
Peng Cui, Qiang Lin, Feng Ding, Songnian Hu , Jun Yu
Since the human genome is mostly transcribed, genetic variations must exhibit sequence signatures reflecting the relationship between transcription processes and chromosomal structures as we have observed in unicellular organisms. In this study, a set of 646 ubiquitous expression-invariable genes (EIGs) which are present in germline cells were defined and examined based on RNA-sequencing data from multiple high-throughput transcriptomic data. We demonstrated a relationship between gene expression level and transcript-centric mutations in the human genome based on single nucleotide polymorphism (SNP) data. A significant positive correlation was shown between gene expression and mutation, where highly-expressed genes accumulate more mutations than lowly-expressed genes. Furthermore, we found four major types of transcript-centric mutations: C→T, A→G, C→G, and G→T in human genomes and identified a negative gradient of the sequence variations aligning from the 5′ end to the 3′ end of the transcription units (TUs). The periodical occurrence of these genetic variations across TUs is associated with nucleosome phasing. We propose that transcript-centric mutations are one of the major driving forces for gene and genome evolution along with creation of new genes, gene/genome duplication, and horizontal gene transfer.
文献链接：https://www.sciencedirect.com/science/article/pii/S1672022911600296
