A5063124326- Cancer Genomics and Diagnostics
- DNA Repair Mechanisms
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- CRISPR and Genetic Engineering
- Chromosomal and Genetic Variations
- Carcinogens and Genotoxicity Assessment
- Epigenetics and DNA Methylation
- Genomics and Rare Diseases
- Evolution and Genetic Dynamics
- Bioinformatics and Genomic Networks
- Genomics and Phylogenetic Studies
- Fungal and yeast genetics research
- Genetic factors in colorectal cancer
- Cancer-related molecular mechanisms research
- Animal Virus Infections Studies
- Plant Disease Resistance and Genetics
- RNA Research and Splicing
- Molecular Biology Techniques and Applications
- Nutrition, Genetics, and Disease
- Lung Cancer Treatments and Mutations
- Mitochondrial Function and Pathology
- Bacteriophages and microbial interactions
- Virology and Viral Diseases
- Telomeres, Telomerase, and Senescence
Medical University of South Carolina
2022-2024
National Institute of Environmental Health Sciences
2015-2023
National Institutes of Health
2015-2021
Triangle
2021
Georgia Institute of Technology
2012-2014
Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic signature 1 . Here, as part the Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium 2 International Cancer Genome (ICGC) and The Atlas (TCGA), we characterized signatures using 84,729,690 somatic from 4,645 whole-genome 19,184 exome sequences that encompass most types cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4...
Accumulation of somatic changes, due to environmental and endogenous lesions, in the human genome is associated with aging cancer. Understanding impacts these processes on mutagenesis fundamental understanding etiology, improving prognosis prevention cancers other genetic diseases. Previous methods relying either generation induced pluripotent stem cells, or sequencing single-cell genomes were inherently error-prone did not allow independent validation mutations. In current study we...
Rubella viruses (RV) have been found in an association with granulomas children primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella (iVDRV) from diagnostic skin biopsies four patients. Sequence evolution within PID hosts was studied by comparison complete genomic sequences iVDRVs genome vaccine virus RA27/3. The degree divergence each iVDRV correlated duration persistence indicating continuous...
Genomes of tens thousands SARS-CoV2 isolates have been sequenced across the world and total number changes (predominantly single base substitutions) in these exceeds ten thousand. We compared mutational spectrum new SARS-CoV-2 mutation dataset with previously published hypermutated genomes rubella—another positive stranded (ss) RNA virus. Each rubella virus arose by accumulation hundreds mutations during propagation a subject, while represents collection events multiple from individuals...
Human skin is continuously exposed to environmental DNA damage leading the accumulation of somatic mutations over lifetime an individual. Mutagenesis in human cells can be also caused by endogenous and replication errors. The contributions these processes mutation load healthy humans has so far not been accurately assessed because low numbers from current sequencing methodologies preclude distinction between errors true genome changes. In this work, we sequenced genomes single cell-derived...
Abstract Acetaldehyde (AA), a by-product of ethanol metabolism, is acutely toxic due to its ability react with various biological molecules including DNA and proteins, which can greatly impede key processes such as replication transcription lead damage. As AA classified group 1 carcinogen by the International Agency for Research on Cancer (IARC). Previous in vitro studies have shown that generates bulky adducts DNA, signature guanine-centered (GG→TT) mutations. However, weak mutagenicity,...
Methylglyoxal (MG) is a highly reactive aldehyde that produced endogenously during metabolism and derived from exogenous sources such as sugary food items cigarette smoke. Unless detoxified by glyoxalases (Glo1 Glo2), MG can readily react with all major biomolecules, including DNA proteins, generating characteristic lesions glycation-derived by- products. As result, exposure has been linked to variety of human diseases, cancers. Prior studies show glycate DNA, preferentially on guanine...
A single cancer genome can harbor thousands of clustered mutations. Mutation signature analyses have revealed that the origin clusters are lesions in long tracts single-stranded (ss) DNA damaged by apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases, raising questions about molecular mechanisms generate ssDNA vulnerable to hypermutation. Here, we show intermediates formed during repair gamma-induced bursts double-strand breaks (DSBs) presence...
Alkylation is one of the most ubiquitous forms DNA lesions. However, motif preferences and substrates for activity major types alkylating agents defined by their nucleophilic substitution reactions (SN1 SN2) are still unclear. Utilizing yeast strains engineered large-scale production single-stranded (ssDNA), we probed substrate specificity, mutation spectra signatures associated with agents. We determined that SN1-type preferably mutagenize double-stranded (dsDNA), signature characteristic...
Redox stress is a major hallmark of cancer. Analysis thousands sequenced cancer exomes and whole genomes revealed distinct mutational signatures that can be attributed to specific sources DNA lesions. Clustered mutations discovered in several were linked single-strand (ssDNA) intermediates various processes metabolism. Previously, only one clustered signature had been clearly associated with subclass ssDNA-specific apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)...
Abstract Acetaldehyde is the primary metabolite of alcohol and present in many environmental sources including tobacco smoke. genotoxic, whereby it can form DNA adducts lead to mutagenesis. Individuals with defects acetaldehyde clearance pathways have increased susceptibility alcohol-associated cancers. Moreover, a mutation signature specific exposure widespread smoking-associated However, that repair acetaldehyde-induced damage thus prevent mutagenesis are vaguely understood. Here, we used...
Systemic sclerosis is a connective tissue disorder characterized by excessive fibrosis that primarily affects women, and can present as multisystem pathology. Roughly 4-22% of patients with systemic develop cancer, which drastically worsens prognosis. However, the mechanisms underlying initiation, propagation, cancer development are poorly understood. We hypothesize inflammation immune response associated trigger DNA damage, leading to elevated somatic mutagenesis, hallmark pre-cancerous...
Inverted repeats capable of forming hairpin and cruciform structures present a threat to chromosomal integrity. They induce double strand breaks, which lead gross rearrangements, the hallmarks cancers hereditary diseases. Secondary structure formation at this motif has been proposed be driving force for instability, albeit mechanisms leading fragility are not well-understood. We carried out genome-wide screen uncover genetic players that govern homologous homeologous Alu quasi-palindromes in...
DNA sequences capable of adopting non-canonical secondary structures have been associated with gross-chromosomal rearrangements in humans and model organisms. Previously, we shown that long inverted repeats form hairpin cruciform triplex-forming GAA/TTC induce the formation double-strand breaks which trigger genome instability yeast. In this study, demonstrate breakage at both is augmented by defects replication. Increased fragility increased mutation levels reporter genes located as far 8...
Yeast strains with low levels of the replicative DNA polymerases (alpha, delta, and epsilon) have high chromosome deletions, duplications, translocations. By examining patterns mutations induced in polymerase by human protein APOBEC3B (a that deaminates cytosine single-stranded DNA), we show dramatically elevated amounts relative to a wild-type strain. During replication, one strand (defined as leading strand) is replicated processively epsilon other (the lagging short fragments initiated...
Abstract Cancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million single nucleotide variants, short insertions/deletions, large structural variants in whole genomes from 2,642 cancer patients, employed this genomic resource study determinants of mutagenesis across 39 types. Our analyses implicate damaging a variety predisposition DNA damage response genes with specific...