生物谷报道：南京大学田大成课题组20日在顶级杂志nature在线发表研究论文“Single-nucleotide mutation rate increases close to insertions/deletions in eukaryotes”。这是南京大学首次作为通信单位发表nature论文。
变异热点常见于遗传序列和人体特定疾病发生的位点，但是这种现象发生的机理并不十分明确。南京大学科学家通过对六种独立物种基因组的研究，加入或剪切单个核苷酸后比较发现，在单个核苷酸插入或剪切位点附近100个核苷酸也较易发生改变。结果表明单个核苷酸插入或剪切会使其临近序列也具有很高的变异率。
田大成解释说，基因突变主要是指DNA中核苷酸顺序、种类和数量的改变，而DNA序列中普遍存在的点（碱基）突变是遗传变异的基本来源。点突变又分为自发突变和诱发突变。长期以来，学术界对自发突变机制的经典认识是，自发突变受一系列因素的影响，是一系列变化的结果，具有随机性和稀有性。但随着上个世纪90年代以来DNA测序技术的突破性进展，研究者们对自发突变在基因组中的数量和分布有了精确估计，并普遍认为“自发突变在基因组中不是随机分布的，突变热点普遍存在于基因组中”。这一结论对传统的自发突变随机性和稀有性的认识形成巨大挑战，而这种现象也引起了各国科学家的极大关注，但遗憾的是始终没有找到一种普遍的机制来解释这一重大的科学疑问。
田大成等发现的遗传突变新机制具有重大科学意义，成功破解了生物遗传学上的很多悬念：第一，基因组各区域的突变率很不相同，自发突变的数量是由Indel的数量和密度所决定，自发突变的数量在Indel附近并不稀有，远离Indel的区域是稀有的，但Indel本身是一种点突变，其发生有一定的随机性，因而其诱发的突变也有一定的随机性；第二，找到了多数自发突变的发生根源，也就是说，生物多样性的最初变异来源，主要是由Indel诱导产生；第三，自然选择在很大程度上是通过对Indel的选择而实现，而自发突变率的高低很大程度上也是自然选择的结果；第四，生物通过调节自身变异能力而适应环境的能力，比人们原先想象的要大得多，即突变在进化中的作用相当巨大。（生物谷Bioon.com）
推荐阅读：人民的科学家——生物谷专访南大教授田大成
生物谷推荐原始出处：
Nature , | doi:10.1038/nature07175; Received 19 January 2008; Accepted 17 June 2008; Published online 20 July 2008
Single-nucleotide mutation rate increases close to insertions/deletions in eukaryotes
Dacheng Tian1,4, Qiang Wang1,4, Pengfei Zhang1, Hitoshi Araki1,2, Sihai Yang1, Martin Kreitman3, Thomas Nagylaki3, Richard Hudson3, Joy Bergelson1,3 & Jian-Qun Chen1
State Key Laboratory of Pharmaceutical Biotechnology, Department of Biology, Nanjing University, Nanjing 210093, China
Department of Fish Ecology and Evolution, EAWAG Center of Ecology, Evolution and Biogeochemistry, 6047 Kastanienbaum, Switzerland
Department of Ecology & Evolution, University of Chicago, Chicago, Illinois 60637, USA
These authors contributed equally to this work.
Abstract
Mutation hotspots are commonly observed in genomic sequences and certain human disease loci1, 2, 3, 4, 5, 6, 7, but general mechanisms for their formation remain elusive7, 8, 9, 10, 11. Here we investigate the distribution of single-nucleotide changes around insertions/deletions (indels) in six independent genome comparisons, including primates, rodents, fruitfly, rice and yeast. In each of these genomic comparisons, nucleotide divergence (D) is substantially elevated surrounding indels and decreases monotonically to near-background levels over several hundred bases. D is significantly correlated with both size and abundance of nearby indels. In comparisons of closely related species, derived nucleotide substitutions surrounding indels occur in significantly greater numbers in the lineage containing the indel than in the one containing the ancestral (non-indel) allele; the same holds within species for single-nucleotide mutations surrounding polymorphic indels. We propose that heterozygosity for an indel is mutagenic to surrounding sequences, and use yeast genome-wide polymorphism data to estimate the increase in mutation rate. The consistency of these patterns within and between species suggests that indel-associated substitution is a general mutational mechanism.
