Sahakyan Aleksandr B, Balasubramanian Shankar
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
BMC Genomics. 2017 Jan 13;18(1):81. doi: 10.1186/s12864-016-3440-5.
Accurate knowledge of the core components of substitution rates is of vital importance to understand genome evolution and dynamics. By performing a single-genome and direct analysis of 39,894 retrotransposon remnants, we reveal sequence context-dependent germline nucleotide substitution rates for the human genome.
The rates are characterised through rate constants in a time-domain, and are made available through a dedicated program (Trek) and a stand-alone database. Due to the nature of the method design and the imposed stringency criteria, we expect our rate constants to be good estimates for the rates of spontaneous mutations. Benefiting from such data, we study the short-range nucleotide (up to 7-mer) organisation and the germline basal substitution propensity (BSP) profile of the human genome; characterise novel, CpG-independent, substitution prone and resistant motifs; confirm a decreased tendency of moieties with low BSP to undergo somatic mutations in a number of cancer types; and, produce a Trek-based estimate of the overall mutation rate in human.
The extended set of rate constants we report may enrich our resources and help advance our understanding of genome dynamics and evolution, with possible implications for the role of spontaneous mutations in the emergence of pathological genotypes and neutral evolution of proteomes.
准确了解替代率的核心组成部分对于理解基因组进化和动态变化至关重要。通过对39,894个逆转录转座子残余物进行单基因组直接分析，我们揭示了人类基因组中依赖序列上下文的种系核苷酸替代率。
这些速率通过时域中的速率常数来表征，并通过一个专用程序（Trek）和一个独立数据库提供。由于方法设计的性质和所施加的严格标准，我们预计我们的速率常数是自发突变率的良好估计值。受益于这些数据，我们研究了人类基因组的短程核苷酸（长达7聚体）组织和种系基础替代倾向（BSP）图谱；表征了新型的、不依赖CpG的、易发生替代和抗性的基序；证实了在多种癌症类型中BSP较低部分发生体细胞突变的趋势降低；并基于Trek对人类的总体突变率进行了估计。
我们报告的扩展速率常数集可能会丰富我们的资源，并有助于推进我们对基因组动态和进化的理解，可能对自发突变在病理基因型出现和蛋白质组中性进化中的作用产生影响。
