Large scale variation in the rate of germ-line de novo mutation, base composition, divergence and diversity in humans

Smith, Thomas C A, Arndt, Peter F and Eyre-Walker, Adam (2018) Large scale variation in the rate of germ-line de novo mutation, base composition, divergence and diversity in humans. PLoS Genetics, 14 (3). e1007254. ISSN 1553-7404

[img] PDF - Published Version
Available under License Creative Commons Attribution.

Download (2MB)


It has long been suspected that the rate of mutation varies across the human genome at a large scale based on the divergence between humans and other species. However, it is now possible to directly investigate this question using the large number of de novo mutations (DNMs) that have been discovered in humans through the sequencing of trios. We investi- gate a number of questions pertaining to the distribution of mutations using more than 130,000 DNMs from three large datasets. We demonstrate that the amount and pattern of variation differs between datasets at the 1MB and 100KB scales probably as a consequence of differences in sequencing technology and processing. In particular, datasets show differ- ent patterns of correlation to genomic variables such as replication time. Never-the-less there are many commonalities between datasets, which likely represent true patterns. We show that there is variation in the mutation rate at the 100KB, 1MB and 10MB scale that can- not be explained by variation at smaller scales, however the level of this variation is modest at large scales–at the 1MB scale we infer that ~90% of regions have a mutation rate within 50% of the mean. Different types of mutation show similar levels of variation and appear to vary in concert which suggests the pattern of mutation is relatively constant across the genome. We demonstrate that variation in the mutation rate does not generate large-scale variation in GC-content, and hence that mutation bias does not maintain the isochore struc- ture of the human genome. We find that genomic features explain less than 40% of the explainable variance in the rate of DNM. As expected the rate of divergence between spe- cies is correlated to the rate of DNM. However, the correlations are weaker than expected if all the variation in divergence was due to variation in the mutation rate. We provide evidence that this is due the effect of biased gene conversion on the probability that a mutation will become fixed. In contrast to divergence, we find that most of the variation in diversity can be explained by variation in the mutation rate. Finally, we show that the correlation between divergence and DNM density declines as increasingly divergent species are considered.

Item Type: Article
Schools and Departments: School of Life Sciences > Evolution, Behaviour and Environment
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0359 Evolution
Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Depositing User: Adam Eyre-Walker
Date Deposited: 10 Apr 2018 14:39
Last Modified: 14 Sep 2018 16:42

View download statistics for this item

📧 Request an update