Effects of parental age and polymer composition on short tandem repeat de novo mutation rates.
Effects of parental age and polymer composition on short tandem repeat de novo mutation rates.
复制标题
父母年龄和聚合物组成对短串联重复从头突变率的影响。
DOI：
10.1101/2023.12.22.573131
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Harris,Kelley
中科院分区：
文献类型：
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作者：
Goldberg,MichaelE;Noyes,MichelleD;Eichler,EvanE;Quinlan,AaronR;Harris,Kelley
短串联重复序列 (STR) 是人类种系基因组变异的热点，因为它们的突变率很高，长期以来，这主要归因于 DNA 复制过程中聚合酶的滑移。该模型表明，STR 突变率应与父亲的年龄呈线性关系，因为祖细胞在青春期后不断分裂。相比之下，它表明 STR 突变率不应该随着母亲受孕时的年龄而变化，因为卵母细胞在母亲的生育年龄中处于减数分裂 II 期，并经历与排卵年龄无关的固定次数的细胞分裂。然而，与最近的研究结果相呼应，我们发现 STR 突变率随父亲和母亲的年龄而变化，这意味着一些 STR 突变是由静止细胞中的 DNA 损伤引起的，而不是由复制祖细胞中的聚合酶滑移引起的。这些结果与最近的发现相呼应，即卵母细胞中的 DNA 损伤是从头单核苷酸变异的重要来源，并证实了有丝分裂后细胞中 STR 扩增的证据。然而，我们发现母亲年龄的影响并不局限于已知的卵母细胞突变热点，合子后突变也不会产生显着影响。 STR 核苷酸组成显示出对不同性别的新生突变 (DNM) 率的不同影响。与父系谱系不同，A/T STR 中源自母系的 DNM 与母体年龄的相关性显着高于含 G/C STR 中的 DNM。这些观察结果可能表明某些 STR 突变的机制和发育时间，并与先前将复制滑移作为 STR 突变的主要机制的归因相矛盾。
Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with a father's age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mother's age at her child's conception, since oocytes spend a mother's reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation. Yet, mirroring recent findings, we find that STR mutation rates covary with paternal and maternal age, implying that some STR mutations are caused by DNA damage in quiescent cells rather than polymerase slippage in replicating progenitor cells. These results echo the recent finding that DNA damage in oocytes is a significant source of de novo single nucleotide variants and corroborate evidence of STR expansion in postmitotic cells. However, we find that the maternal age effect is not confined to known hotspots of oocyte mutagenesis, nor are postzygotic mutations likely to contribute significantly. STR nucleotide composition demonstrates divergent effects on de novo mutation (DNM) rates between sexes. Unlike the paternal lineage, maternally derived DNMs at A/T STRs display a significantly greater association with maternal age than DNMs at G/C-containing STRs. These observations may suggest the mechanism and developmental timing of certain STR mutations and contradict prior attribution of replication slippage as the primary mechanism of STR mutagenesis.