The mutational dynamics of short tandem repeats in large, multigenerational families.
The mutational dynamics of short tandem repeats in large, multigenerational families.
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DOI：
10.1186/s13059-022-02818-4
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发表时间：
2022-12-12
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
作者：
短串联重复序列（STR）约占基因组的3%，STR位点的突变与数十种人类疾病有关，包括肌萎缩性侧索硬化症、弗里德赖希共济失调症、亨廷顿病和脆性X综合征。提高我们对这些突变的理解将增加我们对基因组突变动力学的认识，并可能发现导致疾病的其他基因座。为了估计STR位点突变的全基因组模式，我们分析了来自29个三代CEPH家系的544个个体的血液全基因组测序数据。这些谱系包括祖父母，父母，平均每个家庭有9个孙子。我们使用HipSTR来鉴定这些谱系中第二代的新生STR突变，并需要传递到第三代进行验证。研究人员分析了大约160万个STR基因座，估计STR的经验新生突变率为每代每个基因座5.24 × 10−5个突变。完全重复序列的突变频率大约是不完全重复序列的2倍。新生str中Alu元素显著富集。大约30%的新STR突变发生在Alu元件中，仅占基因组的11%，但只有10%发生在LINE-1插入中，占基因组的17%。将这些突变分阶段转移到原生父母身上表明，父母遗传偏差在不同的家庭中有所不同。我们估计每个个体从头开始的全基因组STR突变的平均数量约为85，这与观察到的从头开始的单核苷酸变异的平均数量相似。在线版本包含补充资料，下载地址：10.1186/s13059-022-02818-4。
Short tandem repeats (STRs) compose approximately 3% of the genome, and mutations at STR loci have been linked to dozens of human diseases including amyotrophic lateral sclerosis, Friedreich ataxia, Huntington disease, and fragile X syndrome. Improving our understanding of these mutations would increase our knowledge of the mutational dynamics of the genome and may uncover additional loci that contribute to disease. To estimate the genome-wide pattern of mutations at STR loci, we analyze blood-derived whole-genome sequencing data for 544 individuals from 29 three-generation CEPH pedigrees. These pedigrees contain both sets of grandparents, the parents, and an average of 9 grandchildren per family. We use HipSTR to identify de novo STR mutations in the 2nd generation of these pedigrees and require transmission to the third generation for validation. Analyzing approximately 1.6 million STR loci, we estimate the empirical de novo STR mutation rate to be 5.24 × 10−5 mutations per locus per generation. Perfect repeats mutate about 2 × more often than imperfect repeats. De novo STRs are significantly enriched in Alu elements. Approximately 30% of new STR mutations occur within Alu elements, which compose only 11% of the genome, but only 10% are found in LINE-1 insertions, which compose 17% of the genome. Phasing these mutations to the parent of origin shows that parental transmission biases vary among families. We estimate the average number of de novo genome-wide STR mutations per individual to be approximately 85, which is similar to the average number of observed de novo single nucleotide variants. The online version contains supplementary material available at 10.1186/s13059-022-02818-4.
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影响因子：
64.5
作者：
FU, YH;KUHL, DPA;CASKEY, CT
通讯作者：
CASKEY, CT
影响因子：
9.8
作者：
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通讯作者：
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影响因子：
12.3
作者：
Dolzhenko, Egor;Bennett, Mark F.;Eberle, Michael A.
通讯作者：
Eberle, Michael A.
DOI：
10.1073/pnas.1901259116
发表时间：
2019-05-07
影响因子：
11.1
作者：
Gao, Ziyue;Moorjani, Priya;Przeworski, Molly
通讯作者：
Przeworski, Molly
DOI：
10.1073/pnas.94.3.1041
发表时间：
1997-02-04
影响因子：
11.1
作者：
Chakraborty, R;Kimmel, M;Deka, R
通讯作者：
Deka, R