Genetic and chemotherapeutic influences on germline hypermutation

Kaplanis, Joanna; Ide, Benjamin; Sanghvi, Rashesh; Neville, Matthew D. C.; Danecek, Petr; Coorens, Tim; Prigmore, Elena; Short, Patrick; Gallone, Giuseppe; McRae, Jeremy F.; Carmichael, Jenny; Barnicoat, Angela; Firth, Helen V.; O’Brien, Patrick; Rahbari, Raheleh; Hurles, Matthew

doi:10.1038/s41586-022-04712-2

Cited by 74 publications

(84 citation statements)

References 72 publications

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“…Populations of great apes, mice, and yeast have similarly distinctive mutational processes (Lindsay, et al 2019;Jiang et al 2021;Goldberg and Harris 2022). It remains unclear how much these changes are due to evolution of the underlying genome-replication machinery versus changes in life history or exposure to environmental mutagens (Mathieson and Reich 2017;Macià et al 2021;Ruis, Peacock, et al 2022;Ruis, Weimann, et al 2022)-although in a few cases changes in the mutation spectrum have been linked to heritable genetic change affecting the function or expression of proteins involved in genome replication or repair (Couce et al 2013;Jiang et al 2021;Robinson, et al 2021;Kaplanis et al 2022;Sasani et al 2022). For viruses, the mutational process can also be affected by a virus's ability to evade host innate-immune proteins that mutagenize viral nucleic acids (Sadler et al 2010;De Maio et al 2021;Ratcliff and Simmonds 2021;Ringlander et al 2022).…”

Section: Introductionmentioning

confidence: 99%

Evolution of the SARS-CoV-2 mutational spectrum

Bloom

Beichman

Neher

et al. 2022

Preprint

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SARS-CoV-2 evolves rapidly in part because of its high mutation rate. Here we examine whether this mutational process itself has changed during viral evolution. To do this, we quantify the relative rates of different types of single nucleotide mutations at four-fold degenerate sites in the viral genome across millions of human SARS-CoV-2 sequences. We find clear shifts in the relative rates of several types of mutations during SARS-CoV-2 evolution. The most striking trend is a roughly two-fold decrease in the relative rate of G→T mutations in Omicron versus early clades, as was recently noted by Ruis et al (2022). There is also a decrease in the relative rate of C→T mutations in Delta, and other subtle changes in the mutation spectrum along the phylogeny. We speculate that these changes in the mutation spectrum could arise from viral mutations that affect genome replication, packaging, and antagonization of host innate-immune factors—although environmental factors could also play a role. Interestingly, the mutation spectrum of Omicron is more similar than that of earlier SARS-CoV-2 clades to the spectrum that shaped the long-term evolution of sarbecoviruses. Overall, our work shows that the mutation process is itself a dynamic variable during SARS-CoV-2 evolution, and suggests that human SARS-CoV-2 may be trending towards a mutation spectrum more similar to that of other animal sarbecoviruses.

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Section: Introductionmentioning

confidence: 99%

Evolution of the SARS-CoV-2 mutational spectrum

Bloom

Beichman

Neher

et al. 2022

Preprint

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Section: Discussionmentioning

confidence: 99%

“…Mutational signature analysis can be used to decipher the potential mutational processes underlying individual cancer or germline hypermutation [ 52 , 53 ]. A recent study has revealed genetic and environmental contributions to the germline dn SNV hypermutation [ 53 ]. Our study explored the utility of mutational signature analysis to decode potential mutational processes in the context of dn CNV hypermutation.…”

Section: Discussionmentioning

confidence: 99%

The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation

Jolly

Grochowski

et al. 2022

Genome Med

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Background The multiple de novo copy number variant (MdnCNV) phenotype is described by having four or more constitutional de novo CNVs (dnCNVs) arising independently throughout the human genome within one generation. It is a rare peri-zygotic mutational event, previously reported to be seen once in every 12,000 individuals referred for genome-wide chromosomal microarray analysis due to congenital abnormalities. These rare families provide a unique opportunity to understand the genetic factors of peri-zygotic genome instability and the impact of dnCNV on human diseases. Methods Chromosomal microarray analysis (CMA), array-based comparative genomic hybridization, short- and long-read genome sequencing (GS) were performed on the newly identified MdnCNV family to identify de novo mutations including dnCNVs, de novo single-nucleotide variants (dnSNVs), and indels. Short-read GS was performed on four previously published MdnCNV families for dnSNV analysis. Trio-based rare variant analysis was performed on the newly identified individual and four previously published MdnCNV families to identify potential genetic etiologies contributing to the peri-zygotic genomic instability. Lin semantic similarity scores informed quantitative human phenotype ontology analysis on three MdnCNV families to identify gene(s) driving or contributing to the clinical phenotype. Results In the newly identified MdnCNV case, we revealed eight de novo tandem duplications, each ~ 1 Mb, with microhomology at 6/8 breakpoint junctions. Enrichment of de novo single-nucleotide variants (SNV; 6/79) and de novo indels (1/12) was found within 4 Mb of the dnCNV genomic regions. An elevated post-zygotic SNV mutation rate was observed in MdnCNV families. Maternal rare variant analyses identified three genes in distinct families that may contribute to the MdnCNV phenomenon. Phenotype analysis suggests that gene(s) within dnCNV regions contribute to the observed proband phenotype in 3/3 cases. CNVs in two cases, a contiguous gene duplication encompassing PMP22 and RAI1 and another duplication affecting NSD1 and SMARCC2, contribute to the clinically observed phenotypic manifestations. Conclusions Characteristic features of dnCNVs reported here are consistent with a microhomology-mediated break-induced replication (MMBIR)-driven mechanism during the peri-zygotic period. Maternal genetic variants in DNA repair genes potentially contribute to peri-zygotic genomic instability. Variable phenotypic features were observed across a cohort of three MdnCNV probands, and computational quantitative phenotyping revealed that two out of three had evidence for the contribution of more than one genetic locus to the proband’s phenotype supporting the hypothesis of de novo multilocus pathogenic variation (MPV) in those families.

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“…CC-BY 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted December 17, 2022. ; https://doi.org/10.1101/2022.12.17.520885 doi: bioRxiv preprint dataset of 903,525 de novo single-nucleotide variant calls (dnSNVs) (detailed in (Kaplanis et al, 2022)). After filtering to remove 20 hyper-mutated and other outlier individuals by looking at the zscore of DNM counts, this resulted in a dataset comprising 210,918 dnSNVs called in 10,749 trios, which were then phased by parent of origin (using reads and nearby informative heterozygous sites).…”

Section: Datamentioning

confidence: 99%

Heritability of de novo germline mutation reveals a contribution from paternal but not maternal genetic factors

Hwang

Neville

Day

et al. 2022

Preprint

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De novo mutations (DNMs) in the germline have long been identified as a key element in the causes of developmental and other genetic disorders. Previous attempts to investigate genetic factors affecting DNMs have suffered from a lack of statistical power, due to the difficulty of obtaining a sufficient number of parent-offspring trios. Thus, the rare disease cohort of the UK's 100k Genomes Project (100kGP), comprising more than 10,000 trios, represents an unprecedented opportunity to investigate the genetics of germline mutation. Here we estimate SNP heritability of DNM count in offspring, as a measure of the relative contribution of genetic factors to the variance of the trait, in a PCA-selected subset of the 100kGP cohort. We estimate separate SNP heritabilities for paternally and maternally transmitted mutations (based on parentally phased DNMs in offspring), computed using parental genetic variants at a range of minimum frequencies and a variety of methodologies. We estimate a heritability of 10-20% for paternal DNMs; by contrast, for maternal DNMs we find no significant evidence for non-zero heritability. We investigated the partitioning of heritability among genes with different expression profiles in different tissue or cell states, and found a relative heritability enrichment for genes expressed in gonadal tissues, particularly testis. Among germ cells in adult testes we observed relative enrichment of heritability in genes associated with the (undifferentiated) spermatogonial stem cell state.

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Genetic and chemotherapeutic influences on germline hypermutation

Cited by 74 publications

References 72 publications

Evolution of the SARS-CoV-2 mutational spectrum

Evolution of the SARS-CoV-2 mutational spectrum

The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation

Heritability of de novo germline mutation reveals a contribution from paternal but not maternal genetic factors

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