Mutation rate and spectrum inCaenorhabditis elegansmutation accumulation lines subjected to RNAi-induced knockdown of the mismatch repair genemsh-2

• DOI: 10.1101/2021.07.12.452034
• Publication Date: 2021-07-13T01:20:15Z
• Authors: Vaishali Katju; Anke Konrad; Thaddeus C. Deiss; Ulfar Bergthorsson
• Keywords: 0303 health sciences; 03 medical and health sciences

ABSTRACTDNA mismatch repair (MMR), an evolutionarily conserved repair pathway shared by prokaryotic and eukaryotic species alike, influences molecular evolution by detecting and correcting mismatches that escape DNA polymerase proofreading, thereby protecting genetic fidelity, reducing the mutational load, and preventing lethality. Herein we conduct the first genome-wide evaluation of the alterations to the mutation rate and spectrum under impaired activity of theMutSαhomolog,msh-2, inCaenorhabditis elegans. We performed mutation accumulation (MA) under RNAi-induced knockdown ofmsh-2for 50 generations in obligately outcrossingfog-2(lf)lines, followed by next-generation sequencing of 19 MA lines and the ancestral control.msh-2impairment substantially increased the frequency of nuclear base substitutions (∼23×) and small indels (∼328×) relative to wildtype. However, we observed no increase in the mutation rates of mtDNA, and copy-number changes of single-copy genes. There was a marked increase in copy-number variation of rDNA genes under MMR impairment. InC. elegans,msh-2repairs transitions more efficiently than transversions as well as increases the AT mutational bias relative to wildtype. The local sequence context, including sequence complexity, G+C-content, and flanking bases influenced the mutation rate. The X chromosome had a lower substitution and higher indel rate than autosomes, which can either result from sex-specific mutation rates or a nonrandom distribution of mutable sites in the genome. Comparison of MMR impairment inC. elegansto that in other species shows that the specificity of the MMR varies between taxa, and is more efficient in detecting and repairing small indels in eukaryotes relative to prokaryotes.