CommentaryHarnessing genomics to identify environmental determinants of heritable disease
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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