Abstract
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 investigate 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 different 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 cannot 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 structure 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 species 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.
Highlights
Until recently, the distribution of germ-line mutations across the genome was studied using patterns of nucleotide substitution between species in putatively neutral sequences, since under neutrality the rate of substitution should be equal to the mutation rate
Using a dataset of more than 130,000 de novo mutations we show that there is large-scale variation in the mutation rate at the 100KB and 1MB scales
We show that different types of mutation vary in concert and in a manner that is not expected to generate variation in base composition; mutation bias is not responsible for the large-scale variation in base composition that is observed across human chromosomes
Summary
The distribution of germ-line mutations across the genome was studied using patterns of nucleotide substitution between species in putatively neutral sequences (see [1] for review of this literature), since under neutrality the rate of substitution should be equal to the mutation rate. The sequencing of hundreds of individuals and their parents has led to the discovery of thousands of germ-line de novo mutations (DNMs) in humans [2,3,4,5,6]; it is possible to analyse the pattern of DNMs directly rather than inferring their patterns from substitutions. We use a collection of over 130,000 germ-line DNMs to address a range of questions pertaining to the large-scale distribution of DNMs. First, we quantify how much variation there is at different scales and investigate whether the variation in the mutation rate at a large-scale can be explained in terms of variation at smaller scales. We investigate to what extent the variation is correlated between different types of mutation, and to what extent it is correlated to a range of genomic variables
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have