Commentary
Harnessing genomics to identify environmental determinants of heritable disease

https://doi.org/10.1016/j.mrrev.2012.08.002Get rights and content

Abstract

Next-generation sequencing technologies can now be used to directly measure heritable de novo DNA sequence mutations in humans. However, these techniques have not been used to examine environmental factors that induce such mutations and their associated diseases. To address this issue, a working group on environmentally induced germline mutation analysis (ENIGMA) met in October 2011 to propose the necessary foundational studies, which include sequencing of parent–offspring trios from highly exposed human populations, and controlled dose–response experiments in animals. These studies will establish background levels of variability in germline mutation rates and identify environmental agents that influence these rates and heritable disease. Guidance for the types of exposures to examine come from rodent studies that have identified agents such as cancer chemotherapeutic drugs, ionizing radiation, cigarette smoke, and air pollution as germ-cell mutagens. Research is urgently needed to establish the health consequences of parental exposures on subsequent generations.

Section snippets

Commentary

Over 12,000 genes are identified in the Online Mendelian Inheritance in Man database (OMIM: www.ncbi.nlm.nih.gov/omim/); sequence variants in these genes are associated with a diverse array of genetic phenotypes. De novo mutations occur in each generation and are increasingly being recognized as contributing to a range of human disorders associated with a broad spectrum of these genes, including autism, schizophrenia, intellectual disability, and epilepsy [1], [2], [3], [4], [5]. Recent

Opportunities and challenges

Two recent studies of human families directly characterized and quantified de novo DNA mutations derived from both male and female gametes [18], [19]. Sequence and structural differences were identified by comparing whole genome sequences or copy number variants between offspring and their parents. These findings show that direct estimates of de novo mutation rates are comparable to indirect estimates from population studies [20], [21] and suggest an average mutation rate of 1 × 10−8 per

Vision and recommendations

The technologies necessary to discover the complex variables that influence germline genome stability are largely available [17]. Given this premise, the ENIGMA working group recommends a tiered plan comprised of a combination of foundational studies to accurately characterize background variability, and definitive studies designed to determine the environmental impacts on germline mutation and epigenetic variation (Fig. 1). Foundational experiments must directly determine background genomic

Author contributions

All authors listed are members of the ENIGMA working group, attended the ENIGMA workshop in October 2011, and participated in the round-table discussions. JBB was chair of the workshop. JJM, CLY, DMD, KLW and FM were on the organizing committee for the workshop. CLY drafted the manuscript, and all authors edited the manuscript. All authors approved the final manuscript.

Conflict of interest statement

There are no conflicts of interest for any of the authors.

Acknowledgements

We thank NIH/NIEHS, NIH/NCI and Health Canada for support for this workshop and for the logistical help of the Environmental Mutagen Society, under whose auspices the workshop was organized. This manuscript was reviewed by Health Canada, the National Health and Environmental Effects Research Laboratory, the United States Environmental Protection Agency, the United States Food and Drug Administration, the National Institute of Environmental Health Sciences, National Institutes of Health, and was

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