Unprecedented female mutation bias in the aye-aye, a highly unusual lemur from Madagascar

Abstract

Every mammal studied to date has been found to have a male mutation bias: male parents transmit more de novo mutations to offspring than female parents, contributing increasingly more mutations with age. Although male-biased mutation has been studied for more than 75 years, its causes are still debated. One obstacle to understanding this pattern is its near universality-without variation in mutation bias, it is difficult to find an underlying cause. Here, we present new data on multiple pedigrees from two primate species: aye-ayes (Daubentonia madagascariensis), a member of the strepsirrhine primates, and olive baboons (Papio anubis). In stark contrast to the pattern found across mammals, we find a much larger effect of maternal age than paternal age on mutation rates in the aye-aye. In addition, older aye-aye mothers transmit substantially more mutations than older fathers. We carry out both computational and experimental validation of our results, contrasting them with results from baboons and other primates using the same methodologies. Further, we analyze a set of DNA repair and replication genes to identify candidate mutations that may be responsible for the change in mutation bias observed in aye-ayes. Our results demonstrate that mutation bias is not an immutable trait, but rather one that can evolve between closely related species. Further work on aye-ayes (and possibly other lemuriform primates) should help to explain the molecular basis for sex-biased mutation.

Fig 1. Primates used in this study.

(A) Pedigree structure of aye-ayes. The 18 individuals sequenced in this study are shown: males as squares and females as circles. Two individuals (IDs 100937 and 100935) appear multiple places in the pedigree, each time connected by a dashed line. Offspring IDs in Table 1 refer to individuals here. (B) Pedigree structure of baboons. The nine individuals sequenced in this study are shown on the left hand side. The 25 individuals sequenced in Wu and colleagues [12] are shown on the right hand side. One individual (ID 1X3656; dashed gray circle) had low read-mapping and was not used here (and was not counted among the 25 individuals). Consanguineous matings are represented as double-horizontal lines, and individuals appearing in multiple places are again connected by dashed lines. Offspring IDs in Table 2 refer to individuals here.

Fig 2. Relationship between parental age and number of transmitted mutations.

(A) The number of mutations from 12 aye-aye trios assigned (“phased”) to either the female (blue) or male (red-orange) parent using the software package POOHA. The x-axis shows the age of each parent at conception, while the y-axis shows the number of inferred mutations phased for each parent. We performed a Poisson regression on the observed number of phased maternal and paternal mutations and scaled the prediction by the fraction of mutations phased to obtain the regression lines (Materials and methods). Shaded areas show 95% confidence intervals for the regression lines. (B) The number of mutations from 21 baboon trios assigned to each parent. (C) The number of mutations from 26 rhesus macaque trios assigned to each parent. Data come from Wang and colleagues [11] and Bergeron and colleagues [4]. (D) The number of mutations from 225 human trios assigned to each parent. Data come from Jónsson and colleagues [6]. The data underlying this figure can be found in S1 Data.

Fig 3. Sex-biased mutation estimated from phylogenetic comparisons.

The degree of sex-biased mutation over the long-term was calculated by comparing substitutions on the X chromosome to the autosomes (Materials and methods). Values reported for the tip branches of the tree all show α > 1, indicating a male-bias at the time of reproduction. Divergence times for the tree come from TimeTree [68]. The data underlying this figure can be found in S1 Data.