165V Poster Online - Virtual Posters
Tuesday June 07, 11:00 AM - 3:00 PM

STR mutation rates do not perfectly track cell divisions but covary with maternal age


Authors:
Michael E Goldberg 1; Evan E Eichler 1,2; Kelley Harris 1,3

Affiliations:
1) Department of Genome Sciences, University of Washington, Seattle, WA; 2) Howard Hughes Medical Institute, University of Washington, Seattle, WA; 3) Computational Biology Division, Fred Hutchinson Cancer Center, Seattle, WA

Keywords:
Comparative genomics & genome evolution

Short tandem repeats (STRs) are hotspots of genomic variability because of their high mutation rates, which have long been attributed to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with the number of cell divisions in male and female germlines. In particular, STR mutation rates are not predicted to scale with the age of the mother at conception, since oocytes spend a mother’s reproductive years arrested in meiosis II and undergo a fixed number of cell divisions prior to ovulation that is independent of age. We tested this prediction using de novo mutation calls from the Simons Simplex Collection, a cohort of nearly 2300 human quad families, each consisting of two children plus parents whose ages at conception are known. Contrary to expectations, STR mutation rates covary with maternal age as well as paternal age, implying that some STR mutations are caused by DNA damage in quiescent cells rather than the classical mechanism of polymerase slippage. Our results echo the recent finding that DNA damage in quiescent oocytes is a significant source of de novo SNVs, but are especially surprising in light of the prior belief in replication slippage as the dominant mechanism of STR mutagenesis. We find that homopolymer STRs have a smaller maternal age effect than STRs of longer repeat unit lengths, and that the maternal age effect is not confined to previously discovered hotspots of oocyte mutagenesis. Our results suggest that STR mutagenesis cannot be fully explained by replication slippage, but is influenced by the DNA damage affecting quiescent cells that has recently been shown to generate a significant fraction of point mutations.