Biology subjects

Aylwyn Scally

Publications and source records attributed to Aylwyn Scally.

3 recordsLinked to original sources

bioRxiv2016

The mutation rate in human evolution and demographic inference

The germline mutation rate has long been a major source of uncertainty in human evolutionary and demographic analyses based on genetic data, but estimates have improved substantially in recent years. I discuss our current knowledge of the mutation rate in humans and the underlying biological factors affecting it, which include generation time, parental age and other developmental and reproductive timescales. There is good evidence for a slowdown in mean mutation rate during great ape evolution, but not for a more recent change within the timescale of human genetic diversity. Hence, pending evidence to the contrary, it is reasonable to use a present-day rate of approximately 0.5 x 10-9 bp-1 yr-1 in all human or hominin demographic analyses.

Evolutionary Biology↗

bioRxiv2016

A direct multi-generational estimate of the human mutation rate from autozygous segments seen in thousands of parentally related individuals

Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations (DNMs) across multiple generations. Using exome sequences from 3,222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1. 45 {+/-} 0.05 x 10-8 per base pair per generation in autosomal coding sequence, with a corresponding noncrossover gene conversion rate of 8.75 {+/-} 0.05 x 10-6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germline mutation rate. We found frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5 CCG 3 [->] 5 CTG 3 context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.

Genomics↗

bioRxiv2015

Mutation rates and the evolution of germline structure

Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities with our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our longstanding model of spermatogenesis. I consider possible explanations for these differences, including evolutionary changes in life history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and variation in cellular mutation rates at different stages of the germline. I suggest a revised model of stem cell state transitions during spermatogenesis, in which dark gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates.

Genetics↗