Sequence effects on mutation frequencies investigated in whole-genome sequenced UK Biobank participants

UK Biobank has released whole genome sequence data for 500,000 participants, including allele counts for hundreds of millions of variants and these were considered in the context of the pentanucleotide background on which they occurred. Variants with an allele count of 25 were found to closely mirror previously reported de novo mutations (DNMs) in terms of the frequencies of variant types. Therefore these variants, referred to as AC25 variants, were used to investigate factors relevant to mutation frequency. The counts of AC25 variant types in a trinucleotide context could be well approximated by combining seven mutational signatures previously obtained from studies of cancer cells. Frequencies of variants were strongly influenced by context. C>T variants occurred more often in the CpG context but other features of the trinucleotide context also had marked effects. Although the trinucleotide context was a very strong predictor of the variant frequencies for the full pentanucleotide context, there were examples where the more distant nucleotides did have marked effects. Here, the configuration of bases two upstream or downstream could have a more than two-fold effect on variant frequencies, presumed to reflect mutation rates. For some variants frequencies varied between non-transcribed and transcribed regions and variants with higher frequencies in transcripts of protein coding genes also demonstrated strand asymmetry, being more frequent on the coding than template strand. Genes with high frequencies of these variants showed enrichment for basic cellular processes, meaning that they could have arisen as a result of transcriptional events during embryogenesis prior to entering the germline. Investigating the molecular mechanisms whereby contexts moderate mutation rates could lead to a better understanding of variant pathogenicity and how DNA fidelity is conserved in normal tissue. This research has been conducted using the UK Biobank Resource. Article summary We analysed hundreds of millions of variations in DNA code observed in 500,000 UK Biobank participants. For each change of a single DNA base, we also considered the two bases either side. We found that the set of variants which each occurred exactly 25 times in the sample, termed AC25 variants, had a frequency distribution which almost exactly matched that of a set of previously reported variants which occurred as new mutations. Therefore, we used these AC25 variants to study the effect of DNA context on mutation rates and to compare mutation types with those previously observed in cancer patients.