4.7 Article

Discovery of an unusually high number of de novo mutations in sperm of older men using duplex sequencing

期刊

GENOME RESEARCH
卷 32, 期 3, 页码 499-511

出版社

COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.275695.121

关键词

-

资金

  1. Austrian Science Fund (FWF)
  2. Austrian Science Fund [FWFP30867000]
  3. FWF Doctoral College NanoCell [FWFW1250]
  4. European Regional Development Fund [REGGEN ATCZ207]
  5. Linz Institute of Technology [LIT213201001]

向作者/读者索取更多资源

Researchers have discovered highly recurrent selfish mutations associated with congenital disorders in male germline. Using duplex sequencing, they examined the FGFR3 coding region and found that older donors harbor more mutations associated with congenital disorders.
De novo mutations (DNMs) are important players in heritable diseases and evolution. Of particular interest are highly recurrent DNMs associated with congenital disorders that have been described as selfish mutations expanding in the male germline, thus becoming more frequent with age. Here, we have adapted duplex sequencing (DS), an ultradeep sequencing method that renders sequence information on both DNA strands; thus, one mutation can be reliably called in millions of sequenced bases. With DS, we examined similar to 4.5 kb of the FGFR3 coding region in sperm DNA from older and younger donors. We identified sites with variant allele frequencies (VAFs) of 10(-4) to 10(-5), with an overall mutation frequency of the region of similar to 6 x 10(-7). Some of the substitutions are recurrent and are found at a higher VAF in older donors than in younger ones or are found exclusively in older donors. Also, older donors harbor more mutations associated with congenital disorders. Other mutations are present in both age groups, suggesting that these might result from a different mechanism (e.g., postzygotic mosaicism). We also observe that independent of age, the frequency and deleteriousness of the mutational spectra are more similar to COSMIC than to gnomAD variants. Our approach is an important strategy to identify mutations that could be associated with a gain of function of the receptor tyrosine kinase activity, with unexplored consequences in a society with delayed fatherhood.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据