DNA mismatch repair preferentially protects genes from mutation

Abstract

Mutation is the source of genetic variation and fuels biological evolution. Many mutations first arise as DNA replication errors. These errors subsequently evade correction by cellular DNA repair, for example, by the well-known DNA mismatch repair (MMR) mechanism. Here, we determine the genome-wide effects of MMR on mutation. We first identify almost 9000 mutations accumulated over five generations in eight MMR-deficient mutation accumulation (MA) lines of the model plant species, We then show that MMR deficiency greatly increases the frequency of both smaller-scale insertions and deletions (indels) and of single-nucleotide variant (SNV) mutations. Most indels involve A or T nucleotides and occur preferentially in homopolymeric (poly A or poly T) genomic stretches. In addition, we find that the likelihood of occurrence of indels in homopolymeric stretches is strongly related to stretch length, and that this relationship causes ultrahigh localized mutation rates in specific homopolymeric stretch regions. For SNVs, we show that MMR deficiency both increases their frequency and changes their molecular mutational spectrum, causing further enhancement of the GC to AT bias characteristic of organisms with normal MMR function. Our final genome-wide analyses show that MMR deficiency disproportionately increases the numbers of SNVs in genes, rather than in nongenic regions of the genome. This latter observation indicates that MMR preferentially protects genes from mutation and has important consequences for understanding the evolution of genomes during both natural selection and human tumor growth.

Mutation bias shapes gene evolution inArabidopsis thaliana

“…These chromatin marks were enriched in gene bodies (Fig. 2b), and may help to explain the recent discovery that DNA mismatch repair preferentially targets genic regions -especially coding regions and introns -in A. thaliana 22 . On the other hand, cytosine methylation, more prone to spontaneous cytosine deamination 6,20,23,26,51 , was associated to high mutation rates, the heterochromatin-associated histone modification H3K9 methylation likely prevents repair machinery to be recruited and was associated to higher mutation rates 6,20,23,26,51 , while highly accessible chromatin regions (such as those with active transcription factor binding sites) have previously been shown to interfere with nucleotide excision repair, which also led to higher mutation rates 6,20,23,26,51 .…”

“…This provides an opportunity for mutation rates to evolve in beneficial directions (e.g., lower mutation rates in cytogenetic states characteristic of essential housekeeping genes where mutations are more likely to be deleterious). Indeed, processes facilitating reduced mutation rates in genic regions 22,29,33 and active genes 15,17,21,24,34 have already been documented in recent years. These discoveries are consistent with contemporary theoretical predictions from population genetics that beneficial mutation rates could readily evolve even in the face of genetic drift if mutation rates are linked to gene regulation or common sequence and epigenomic features 3,8 .…”

“…And while reports of non-random relationships between mutation rates and fitness consequences have been previously made, these have been questioned because they have largely relied on substitution rates in natural populations rather than direct measures of de novo mutations 3,9-12 .More recently though, discoveries in genome biology have inspired a reevaluation of classical theories of mutation rate evolution. It is now recognized that mutation rates across genomes are influenced by DNA sequence composition, epigenomic features, and bias in the targets of DNA repair mechanisms 5,6,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . It is also known that broad classes of genes (e.g., housekeeping genes) exist in distinct cytogenetic (DNA sequence + epigenomic) states.…”

MLH1 Promoter Methylation and Prediction/Prognosis of Gastric Cancer: A Systematic Review and Meta and Bioinformatic Analysis

“…And colorectal cancers with MSI-H have an improved prognosis 9 .MMR preferentially protects genes from mutation and has important consequences for understanding the evolution of genomes during both natural selection and human tumor growth. MMR deficiency disproportionately increases the numbers of single-nucleotide variants in genes 10 .…”

Alternative Splicing and DNA Damage Response in Plants

“…There is evidence for BER being active in chloroplasts to counter the effects of reactive oxygen species production during photosynthesis (Gutman and Niyogi, 2009). The mismatch repair (MMR) pathway is responsible for the repair of replication errors, such as mismatches and indels, UV, and oxidative damage (Li et al, 2016;Liu et al, 2017;Belfield et al, 2018). Double-strand breaks (DSBs) are repaired via non-homologous end joining (NHEJ) and homologous recombination (HR).…”