Germline mutation rate is elevated in young and old parents in Caenorhabditis remanei

Abstract

The effect of parental age on germline mutation rate across generations is not fully understood. While some studies report a positive linear relationship of mutation rate with increasing age, others suggest that mutation rate varies with age but not in a linear fashion. We investigated the effect of parental age on germline mutations by generating replicated mutation accumulation lines in Caenorhabditis remanei at three parental ages ("Young T1" [Day 1], "Peak T2" [Day 2], and "Old T5" [Day 5] parents). We conducted whole-genome resequencing and variant calling to compare differences in mutation rates after three generations of mutation accumulation. We found that Peak T2 lines had an overall reduced mutation rate compared to Young T1 and Old T5 lines, but this pattern of the effect varied depending on the variant impact. Specifically, we found no high-impact variants in Peak T2 lines, and modifiers and up- and downstream gene variants were less frequent in these lines. These results suggest that animals at the peak of reproduction have better DNA maintenance and repair compared to young and old animals. We propose that C. remanei start to reproduce before they optimize their DNA maintenance and repair, trading the benefits of earlier onset of reproduction against offspring mutation load. The increase in offspring mutation load with age likely represents germline senescence.

Keywords: SNPs; age-related mutation rate; germline mutations; mutation accumulation; parental age effects; selection shadow.

Figure 1.

Line survival rate across generations shown for the Young T1 (orange), Peak T2 (yellow), and Old T5 (blue) mutation accumulation (MA) regimes.

Figure 2.

Mean heterozygous point mutation rates of C. remanei mutation accumulation (MA) lines in three treatment regimes: Young T1 (orange), short mutation accumulation time; Peak T2 (yellow), intermediate mutation accumulation time; and Old T5 (blue), long mutation accumulation time. N = 6 lines per regime (represented by black points). Solid vertical lines represent standard errors (s.e.).

Figure 3.

Distribution of the six types of single-nucleotide mutations of the mutation accumulation (MA) lines in three treatment regimes: Young T1 (orange), short mutation accumulation time; Peak T2 (yellow), intermediate mutation accumulation time; and Old T5 (blue), long mutation accumulation time. N = 6 lines per regime. Bars show mean % of mutations across the six lines per regime with standard error (s.e.) bars.

Figure 4.

Distribution of the consequences (a) and impact (b) of single-nucleotide mutations of the MA lines in three treatment regimes: Young T1 (orange), very young worms and short mutation accumulation time; Peak T2 (yellow), worms at the peak of their reproductive fitness and intermediate mutation accumulation time; and Old T5 (blue), old worms and long mutation accumulation time (N = 6 males from six different lines per regime).