Young Candice L, Beichman Annabel C, Mas-Ponte David, Hemker Shelby L, Zhu Luke, Kitzman Jacob O, Shirts Brian H, Harris Kelley
Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195 USA.
Department of Molecular and Cellular Biology, University of Washington, 1705 NE Pacific St, Seattle, WA 98195 USA.
Genetics. 2024 Oct 15;228(4). doi: 10.1093/genetics/iyae166.
Variation in DNA repair genes can increase cancer risk by elevating the rate of oncogenic mutation. Defects in one such gene, MUTYH, are known to elevate the incidence of colorectal cancer in a recessive Mendelian manner. Recent evidence has also linked MUTYH to a mutator phenotype affecting normal somatic cells as well as the female germline. Here, we use whole genome sequencing to measure germline de novo mutation rates in a large extended family containing both mothers and fathers who are affected by pathogenic MUTYH variation. By developing novel methodology that uses siblings as "surrogate parents" to identify de novo mutations, we were able to include mutation data from several children whose parents were unavailable for sequencing. In the children of mothers affected by the pathogenic MUTYH genotype p.Y179C/V234M, we identify an elevation of the C>A mutation rate that is weaker than mutator effects previously reported to be caused by other pathogenic MUTYH genotypes, suggesting that mutation rates in normal tissues may be useful for classifying cancer-associated variation along a continuum of severity. Surprisingly, we detect no significant elevation of the C>A mutation rate in children born to a father with the same MUTYH genotype, and we similarly find that the mutator effect of the mouse homolog Mutyh appears to be localized to embryonic development, not the spermatocytes. Our results suggest that maternal MUTYH variants can cause germline mutations by attenuating the repair of oxidative DNA damage in the early embryo.
DNA修复基因的变异可通过提高致癌突变率来增加癌症风险。已知一种这样的基因MUTYH存在缺陷，会以隐性孟德尔方式提高结直肠癌的发病率。最近的证据还将MUTYH与一种影响正常体细胞以及雌性生殖系的突变体表型联系起来。在这里，我们使用全基因组测序来测量一个大家庭中的生殖系新生突变率，这个大家庭中父母双方都受到致病性MUTYH变异的影响。通过开发一种新方法，利用兄弟姐妹作为“替代父母”来识别新生突变，我们能够纳入几个父母无法进行测序的孩子的突变数据。在受致病性MUTYH基因型p.Y179C/V234M影响的母亲的孩子中，我们发现C>A突变率有所升高，但比先前报道的由其他致病性MUTYH基因型引起的突变体效应要弱，这表明正常组织中的突变率可能有助于沿着严重程度的连续体对癌症相关变异进行分类。令人惊讶的是，我们在具有相同MUTYH基因型的父亲所生的孩子中未检测到C>A突变率有显著升高，同样地，我们发现小鼠同源物Mutyh的突变体效应似乎局限于胚胎发育，而非精母细胞。我们的结果表明，母体MUTYH变异可通过减弱早期胚胎中氧化性DNA损伤的修复来导致生殖系突变。
