Population sequencing data reveal a compendium of mutational processes in the human germ line

Seplyarskiy, Vladimir B.; Soldatov, Ruslan A.; Koch, Evan; McGinty, Ryan J.; Goldmann, Jakob M.; Hernández, Ryan D.; Barnes, Kathleen C.; Correa, Adolfo; Burchard, Esteban G.; Ellinor, Patrick T.; McGarvey, Stephen T.; Mitchell, Braxton D.; Vasan, Ramachandran S.; Redline, Susan; Silverman, Edwin K.; Weiss, Scott T.; Arnett, Donna K.; Blangero, John; Boerwinkle, Eric; He, Jiang; Montgomery, Courtney G.; Rao, D. C.; Rotter, Jerome I.; Taylor, Kent D.; Brody, Jennifer A.; Chen, Yii‐Der Ida; Fuentes, Lisa de las; Hwu, Chii‐Min; Rich, Stephen S.; Manichaikul, Ani; Mychaleckyj, Josyf C.; Palmer, Nicholette D.; Smith, Jennifer A.; Kardia, Sharon L.R.; Peyser, Patricia A.; Bielak, Lawrence F.; O’Connor, Timothy D.; Emery, Leslie S.; Gilissen, Christian; Wong, Wendy S. W.; Kharchenko, Peter V.; Sunyaev, Shamil

doi:10.1126/science.aba7408

Cited by 49 publications

(82 citation statements)

References 71 publications

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“…P-values and 95% confidence intervals were computed using a Poisson test. B) Trinucleotide context plot of sSNV in schizophrenia at active TFBS and promoter sites, along with COSMIC signatures SBS17b, SBS18, and CpG transversion signature Component 11 44 . C) Proportion bar plots of the contribution of SBS17b, SBS28, along with SBS1 and SBS5, to the mutational spectrum in schizophrenia and control sSNV genome-wide and at promoter regions.…”

Section: Resultsmentioning

confidence: 99%

“…Skiagenic mutations represent a fingerprint of prenatal factors that influence risk to SCZ and promise to help further dissect and classify these factors. 44 . C) Proportion bar plots of the contribution of SBS17b, SBS28, along with SBS1 and SBS5, to the mutational spectrum in schizophrenia and control sSNV genome-wide and at promoter regions.…”

Section: Discussionmentioning

confidence: 99%

“…The higher mean VAF of CpG transversions compared to T>G mutations at active TFBS (0.09 vs 0.02) is consistent with them occurring very early in development 12 . Comparison of mosaic mutation patterns between individuals with SCZ and controls is remarkable because the overall burden in CpG transversion is higher than seen in germline in both cases and controls 44 , but the effect of TF binding is unique to individuals with neuropsychiatric disease. While we favor a model in which these SCZ-specific processes may relate to known prenatally acting risk factors, other possibilities include SCZ-specific aspects of development, such as the division rate or TF binding time, that might also lead to TFBS being enriched with damage-induced mutations 50 .…”

Section: Discussionmentioning

confidence: 99%

“…A second potential mechanism was revealed by analysis of sSNVs at CpG sites, which showed up to 61.8-fold (95% CI [7.14:245.3], p=1.04e-4, Figure 4A, Figure S3B) enrichment of CpG>GpG in active TFBS at promoters compared to the expected C>G genome-wide rate. C>G and C>A transversions at CpG contexts are characteristic of a known mutational process (Component 11, Figure 3B) 44 that reflects a footprint of enzymatic demethylation, which involves the resection of oxidated methyl-cytosine, creating an abasic site 45 (Figure 4B). If the abasic site is not repaired before replication, CpG transversions occurs 46 .…”

Section: Specific Ssnv Patterns At Tfbsmentioning

confidence: 99%

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Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites

Maury

Jones

Seplyarskiy

et al. 2022

Preprint

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Schizophrenia (SCZ) is a complex neuropsychiatric disorder in which both germline genetic mutations and maternal factors, such as infection and immune activation, have been implicated, but how these two strikingly different mechanisms might converge on the same phenotype is unknown. During development, cells accumulate somatic, mosaic mutations in ways that can be shaped by the cellular environment or endogenous processes, but these early developmental mutational patterns have not been studied in SCZ. Here we analyzed deep (267x) whole-genome sequencing (WGS) of DNA from cerebral cortical neurons isolated from 61 SCZ and 25 control postmortem brains to capture mutations occurring before or during fetal neurogenesis. SCZ cases showed a >15% increase in genome-wide sSNV compared to controls (p < 2e-10). Remarkably, mosaic T>G mutations and CpG transversions (CpG>GpG or CpG>ApG) were 79- and 62-fold enriched, respectively, at transcription factor binding sites (TFBS) in SCZ, but not in controls. The pattern of T>G mutations resembles mutational processes in cancer attributed to oxidative damage that is sterically blocked from DNA repair by transcription factors (TFs) bound to damaged DNA. The CpG transversions similarly suggest unfinished DNA demethylation resulting in abasic sites that can also be blocked from repair by bound TFs. Allele frequency analysis suggests that both localized mutational spikes occur in the first trimester. We call this prenatal mutational process skiagenesis (from the Greek skia, meaning shadow), as these mutations occur in the shadow of bound TFs. Skiagenesis reflects as-yet unidentified prenatal factors and is associated with SCZ risk in a subset (~13%) of cases. In turn, mutational disruption of key TFBS active in fetal brain is well positioned to create SCZ-specific gene dysregulation in concert with germline risk genes. Skiagenesis provides a fingerprint for exploring how epigenomic regulation and prenatal factors such as maternal infection or immune activation may shape the developmental mutational landscape of human brain.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Specific Ssnv Patterns At Tfbsmentioning

confidence: 99%

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Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites

Maury

Jones

Seplyarskiy

et al. 2022

Preprint

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“…Advances in analysis of mutation signatures are transforming genomics of cancer [ 1 – 5 ], human populations [ 6 ], and model organisms [ 7 ]. Tumor evolution is characterized by distinctive somatic mutational processes resulting from mutagen exposures (environmental or endogenous) or defects in DNA repair mechanisms that result in genome instability [ 8 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

A framework for mutational signature analysis based on DNA shape parameters

2022

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The mutation risk of a DNA locus depends on its oligonucleotide context. In turn, mutability of oligonucleotides varies across individuals, due to exposure to mutagenic agents or due to variable efficiency and/or accuracy of DNA repair. Such variability is captured by mutational signatures, a mathematical construct obtained by a deconvolution of mutation frequency spectra across individuals. There is a need to enhance methods for inferring mutational signatures to make better use of sparse mutation data (e.g., resulting from exome sequencing of cancers), to facilitate insight into underlying biological mechanisms, and to provide more accurate mutation rate baselines for inferring positive and negative selection. We propose a conceptualization of mutational signatures that represents oligonucleotides via descriptors of DNA conformation: base pair, base pair step, and minor groove width parameters. We demonstrate how such DNA structural parameters can accurately predict mutation occurrence due to DNA repair failures or due to exposure to diverse mutagens such as radiation, chemical exposure, and the APOBEC cytosine deaminase enzymes. Furthermore, the mutation frequency of DNA oligomers classed by structural features can accurately capture systematic variability in mutagenesis of >1,000 tumors originating from diverse human tissues. A nonnegative matrix factorization was applied to mutation spectra stratified by DNA structural features, thereby extracting novel mutational signatures. Moreover, many of the known trinucleotide signatures were associated with an additional spectrum in the DNA structural descriptor space, which may aid interpretation and provide mechanistic insight. Overall, we suggest that the power of DNA sequence motif-based mutational signature analysis can be enhanced by drawing on DNA shape features.

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Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes

Gillani

Camp

Han

et al. 2022

The American Journal of Human Genetics

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Population sequencing data reveal a compendium of mutational processes in the human germ line

Cited by 49 publications

References 71 publications

Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites

Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites

A framework for mutational signature analysis based on DNA shape parameters

Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes

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