Even small SNP clusters are non-randomly distributed: is this evidence of mutational non-independence?
Even small SNP clusters are non-randomly distributed: is this evidence of mutational non-independence?
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DOI：
10.1098/rspb.2009.1757
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发表时间：
2010-05-07
影响因子：
4.7
通讯作者：
Amos, William
中科院分区：
文献类型：
--
作者：
Amos, William
单核苷酸多态(SNPs)在人类基因组中的分布具有高度的非随机性，通过各种过程，从确定偏向(即在感兴趣的基因周围优先发展SNPs)到突变热点和自然选择的作用。然而，随着更系统的SNP开发，人们可能会预计SNP或多或少随机分布的比例会越来越高。在这里，我使用随机模拟来检验这个零假设，并将这一结果与另一个假设的结果进行比较，该假设认为突变更有可能发生在现有的SNPs附近，这种可能性既来自对酵母减数分裂错配修复的分子研究，也来自于数据显示SNPs聚集在杂合缺失周围。纯粹的泊松过程产生的SNP簇在不同大小的簇的频率和每个簇内的SNP密度上都与人类1号染色体上的同等数据不同，即使是只有4到5个SNP的小簇也是如此，而X染色体上的簇与常染色体上的簇不同。相比之下，适度水平的突变非独立性在集群频率和密度方面都与真实数据产生了合理的匹配，并且也展示了以“突变热点”著称的进化瞬变。因此，突变的非独立性提供了一个有趣的新假说，似乎能够解释SNPs在人类基因组中的分布。
Single nucleotide polymorphisms (SNPs) are distributed highly non-randomly in the human genome through a variety of processes from ascertainment biases (i.e. the preferential development of SNPs around interesting genes) to the action of mutation hotspots and natural selection. However, with more systematic SNP development, one might expect an increasing proportion of SNPs to be distributed more or less randomly. Here, I test this null hypothesis using stochastic simulations and compare this output with that of an alternative hypothesis that mutations are more likely to occur near existing SNPs, a possibility suggested both by molecular studies of meiotic mismatch repair in yeast and by data showing that SNPs cluster around heterozygous deletions. A purely Poisson process generates SNP clusters that differ from equivalent data from human chromosome 1 in both the frequency of different-sized clusters and the SNP density within each cluster, even for small clusters of just four or five SNPs, while clusters on the X chromosome differ from those on the autosomes. In contrast, modest levels of mutational non-independence generate a reasonable fit to the real data for both cluster frequency and density, and also exhibit the evolutionary transience noted for 'mutation hotspots'. Mutational non-independence therefore provides an interesting new hypothesis that appears capable of explaining the distribution of SNPs in the human genome.