Direct estimation of de novo mutation rates in a chimpanzee parent-offspring trio by ultra-deep whole genome sequencing

Abstract

Mutations generate genetic variation and are a major driving force of evolution. Therefore, examining mutation rates and modes are essential for understanding the genetic basis of the physiology and evolution of organisms. Here, we aim to identify germline de novo mutations through the whole-genome surveyance of Mendelian inheritance error sites (MIEs), those not inherited through the Mendelian inheritance manner from either of the parents, using ultra-deep whole genome sequences (>150-fold) from a chimpanzee parent-offspring trio. We identified such 889 MIEs and classified them into four categories based on the pattern of inheritance and the sequence read depth: [i] de novo single nucleotide variants (SNVs), [ii] copy number neutral inherited variants, [iii] hemizygous deletion inherited variants, and [iv] de novo copy number variants (CNVs). From de novo SNV candidates, we estimated a germline de novo SNV mutation rate as 1.48 × 10−8 per site per generation or 0.62 × 10−9 per site per year. In summary, this study demonstrates the significance of ultra-deep whole genome sequencing not only for the direct estimation of mutation rates but also for discerning various mutation modes including de novo allelic conversion and de novo CNVs by identifying MIEs through the transmission of genomes from parents to offspring.

Reproductive longevity predicts mutation rates in primates

“…The ages at conception for all parents in all studies of the mutation rate (points in Fig. 3; Table S4) were taken from the original papers 3,11,12,[14][15][16][17]20,35,41 .…”

The germline mutational process in rhesus macaque and its implications for phylogenetic dating

“…Up until now, the germline mutation rate has only been estimated using pedigrees in few nonhuman primate species, including chimpanzee (Pan troglodytes) (Venn et al 2014;Tatsumoto et al 2017;Besenbacher et al 2019), gorilla (Gorilla gorilla) (Besenbacher et al 2019), orangutan (Pongo abelii) (Besenbacher et al 2019), African green monkey (Chlorocebus sabaeus) (Pfeifer 90 2017), owl monkey (Aotus nancymaae) (Thomas et al 2018) and recently rhesus macaque 91 (Macaca mulatta) (Wang et al 2020). The mutation rate of baboon (Papio anubis) (Wu et al 92 2019) and grey mouse lemur (Microcebus murinus) (Campbell et al 2019) have also been 93 estimated in preprinted studies.…”

“…Furthermore, the algorithms used to estimate the mutation rate should take false-negative calls into account. However, a considerable range of sequencing depth (ranging from 18X (Pfeifer 2017) to 120X (Tatsumoto et al 2017)) has been applied in many studies for estimation of mutation rate. Different filtering methods have been introduced to reduce false-positives and false-negatives but the lack of standardized methodology makes it difficult to assess whether differences in mutation rate estimates are caused by technical or biological variability.…”

Direct estimation of mutations in great apes reveals significant recent human slowdown in the yearly mutation rate

“…However, the trios used had young parents suggesting a higher yearly rate than in humans. A recent study using deeper sequencing suggests a higher rate than in humans by about 30% (14). a) The sequenced pedigrees of chimpanzee, gorilla and orangutan with names, birth years, and sequence coverage.…”