Abstract
Mutations have a profound effect on human health, particularly through an increased risk of carcinogenesis and genetic disease. The strong correlation between mutagenesis and carcinogenesis has been a driving force behind genotoxicity research for more than 50 years. The stochastic and infrequent nature of mutagenesis makes it challenging to observe and to study. Indeed, decades have been spent developing increasingly sophisticated assays and methods to study these low‐frequency genetic errors, in hopes of better predicting which chemicals may be carcinogens, understanding their mode of action, and informing guidelines to prevent undue human exposure. While effective, widely used genetic selection‐based technologies have a number of limitations that have hampered major advancements in the field of genotoxicity. Emerging new tools, in the form of enhanced next‐generation sequencing platforms and methods, are changing this paradigm. In this review, we discuss rapidly evolving sequencing tools and technologies, such as error‐corrected sequencing and single cell analysis, which we anticipate will fundamentally reshape the field. In addition, we consider a variety emerging applications for these new technologies, including the detection of DNA adducts, inference of mutational processes based on genomic site and local sequence contexts, and evaluation of genome engineering fidelity, as well as other cutting‐edge challenges for the next 50 years of environmental and molecular mutagenesis research. Environ. Mol. Mutagen. 61:135–151, 2020. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.
Highlights
Exposure to environmental factors has been known to alter the genetic makeup of organisms since the seminal work by Hermann Muller in 1927 showing that Drosophila exposed to X-rays led to new heritable traits (Muller 1927)
The utility of modern sequencing platforms has expanded well beyond the initial use of sequencing DNA for genome assembly and germ line variant detection, for which they were originally developed. These technologies are ushering in a renaissance for the study of genotoxicity and somatic mutagenesis
The technologies and methods that we have described here will be deployable for direct monitoring of exposures in human populations—a concept famously envisioned by William Thilly more than three decades ago (Sattaur 1985)
Summary
Exposure to environmental factors has been known to alter the genetic makeup of organisms since the seminal work by Hermann Muller in 1927 showing that Drosophila exposed to X-rays led to new heritable traits (Muller 1927). Other environmental factors, including ultraviolet light and reactive chemicals, were reported soon after (Stadler and Sprague 1936; Auerbach et al 1947). It wasn’t until the publication of the structure of DNA in 1953, and the subsequent description of DNA polymerases that a mechanism linking environmental exposures to mutagenesis and heritable changes became fully apparent (Watson and Crick 1953; Bessman et al 1958; Lehman et al 1958). Published online 8 October 2019 in Wiley Online Library (wileyonlinelibrary.com)
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