Cryptic variation in the human mutation rate.
Cryptic variation in the human mutation rate.
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DOI：
10.1371/journal.pbio.1000027
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发表时间：
2009-02-03
期刊：
影响因子：
9.8
通讯作者：
Eyre-Walker A
中科院分区：
文献类型：
--
作者：
Hodgkinson A;Ladoukakis E;Eyre-Walker A
已知突变率在人类基因组内相邻位点之间因环境而异，研究最充分的例子是CpG二核苷酸的影响。我们通过测试人类和黑猩猩是否有过多的单核苷酸多态性（SNP）位点来研究是否存在额外的变异。我们发现了一个非常显着过量的这样的网站，我们证明，这种过量是不是由于相邻的核苷酸效应，祖先的多态性，或自然选择。因此，我们推断突变率存在隐性变异。然而，尽管这种突变率的变化与相邻核苷酸无关，但我们发现，在具有重合SNP的位点的两侧延伸1080个碱基对的核苷酸存在高度非随机模式，这表明存在广泛而复杂的背景效应。最后，我们估计了产生过量的一致SNP所需的变异水平，并表明与相邻核苷酸（包括CpG效应）相比，与此隐藏过程相关的突变率的变异水平相似或更高。我们的结论是，在突变中存在着大量的变异，直到现在，这些变异一直被隐藏在视野之外。理解突变的过程是很重要的，不仅在机理上，而且因为它对序列进化和群体遗传推断的分析有影响。已知人类基因组内不同位点的突变率不同。最引人注目的例子是当C后面跟着G时; C和G核苷酸的突变率比其他位点的突变率高10到20倍。此外，已知突变率可能受该位点侧翼的核苷酸的影响。在这里，我们表明，也有很大的变化，突变率是不相关的侧翼核苷酸，或CpG效应。虽然这种变异不依赖于相邻的核苷酸，但似乎是超变的位点周围的核苷酸存在非随机模式，这表明存在影响突变率的复杂背景效应。在人类基因组中不同位点之间的突变率中观察到实质性变化，这与可变的CpG位点无关，也不是由于简单的背景效应。
The mutation rate is known to vary between adjacent sites within the human genome as a consequence of context, the most well-studied example being the influence of CpG dinucelotides. We investigated whether there is additional variation by testing whether there is an excess of sites at which both humans and chimpanzees have a single-nucleotide polymorphism (SNP). We found a highly significant excess of such sites, and we demonstrated that this excess is not due to neighbouring nucleotide effects, ancestral polymorphism, or natural selection. We therefore infer that there is cryptic variation in the mutation rate. However, although this variation in the mutation rate is not associated with the adjacent nucleotides, we show that there are highly nonrandom patterns of nucleotides that extend ∼80 base pairs on either side of sites with coincident SNPs, suggesting that there are extensive and complex context effects. Finally, we estimate the level of variation needed to produce the excess of coincident SNPs and show that there is a similar, or higher, level of variation in the mutation rate associated with this cryptic process than there is associated with adjacent nucleotides, including the CpG effect. We conclude that there is substantial variation in the mutation that has, until now, been hidden from view. Understanding the process of mutation is important, not only mechanistically, but also because it has implications for the analysis of sequence evolution and population genetic inference. The mutation rate is known to differ between sites within the human genome. The most dramatic example of this is when a C is followed by G; both the C and G nucleotides have a rate of mutation that is between 10- and 20-fold higher than the rate at other sites. In addition, is it known that the mutation rate may be influenced by the nucleotides flanking the site. Here we show that there is also very substantial variation in the mutation rate that is not associated with the flanking nucleotides, or the CpG effect. Although this variation does not depend upon the adjacent nucleotides, there are nonrandom patterns of nucleotides surrounding sites that appear to be hypermutable, suggesting there are complex context effects that influence the mutation rate. Substantial variation is seen in the rate of mutation among different sites in the human genome, which is not associated with mutable CpG sites or due to simple context effects.
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影响因子：
9.8
作者：
Akey JM;Eberle MA;Rieder MJ;Carlson CS;Shriver MD;Nickerson DA;Kruglyak L
通讯作者：
Kruglyak L
MAMUSNP：一种用于恒河猴（Macaca Mulatta）基因组学的资源。
影响因子：
3.7
作者：
Malhi, Ripan S.;Sickler, Brad;Lin, Dawei;Satkoski, Jessica;Tito, Raul Y.;George, Debbie;Kanthaswamy, Sreetharan;Smith, David Glenn
通讯作者：
Smith, David Glenn
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1101/sqb.1987.052.01.094
发表时间：
1987-01-01
期刊：
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
影响因子：
--
作者：
MIYATA, T;HAYASHIDA, H;YASUNAGA, T
通讯作者：
YASUNAGA, T
影响因子：
7
作者：
Gaffney, DJ;Keightley, PD
通讯作者：
Keightley, PD