Beyond replication: how does parental age affect de novo mutation rates?

When it comes to the potential causes of autism spectrum disorder (ASD), it’s not just in your genes. Genomic variation beyond coding regions also plays a role, and researchers are looking more closely at short tandem repeats (STRs), a prominent source of genomic variability known for their high mutation rates. STRs are relatively understudied compared to single nucleotide variants (SNVs), the best-characterized genetic variants, and new research published by Goldberg et al. in the April issue of GENETICS explores the role of STRs in genomic evolution and the impact of parental age on de novo mutation (DNM) rates.

Historically, STR mutations were only thought to occur due to polymerase slippage during DNA replication and were therefore highly linked to paternal age. While the female germline does not replicate during the reproductive years, male germ cells continue to replicate from puberty onward, potentially leaving substantial room for error with increasing age. Indeed, a recent family study comparing children with ASD to their unaffected siblings found that STR DNMs were more common in the children with ASD.

Building on this work, Goldberg et al. studied almost 1,600 quads—families with two parents and two children, one of whom was diagnosed with ASD without prior family history—whose genomes were previously sequenced. For this new analysis, the authors performed additional filtering to account for variability in the specificity of STR genotype predictions, narrowing the starting set of de novo STR calls from 175,290 down to 56,925. They also performed additional sequencing on two of the families to help validate their approach.

When the authors analyzed DNMs at STR loci, they found that, while paternal age did play a strong role, male progenitor cells were not the sole source of mutation.

Their analysis instead highlighted a strong maternal age effect, pointing to the relevancy of a mother’s age at conception. Although there are several known hotspots for mutagenesis in the ovaries, Goldberg et al. observed maternal age effects beyond just these familiar loci, underscoring that quiescent cells—those in a state of reversible growth arrest—might also undergo DNA damage and possibly lead to mutations that contribute to developmental disorders.

Zooming in even further, nucleotide composition seemed to be significant in mothers but not fathers: the maternal age association was stronger at A/T STRs than at G/C-containing STRs. The demonstration that replication alone does not account for all STR mutations points toward quiescent cells of the human germline as a prime target for future research.