Florian Eichler

Florian Eichler, a neurologist, leverages the biology of single gene disorders affecting the nervous system to develop treatments for leukodystrophies and hereditary neuropathies.  Among his scientific contributions, Dr. Eichler has […]

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Yulia Grishchuk

Dr. Grishchuk obtained her Ph.D. in Molecular Biology from Engelhardt Institute of Molecular Biology in Moscow, Russia. During her post-doctoral training at the Brain Mind Institute, EPFL, and University of […]

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Stephen J. Haggarty

Dr. Stephen J. Haggarty is an Associate Professor of Neurology at Harvard Medical School, an Associate Neuroscientist at Massachusetts General Hospital, and Director of the MGH Chemical Neurobiology Laboratory. Dr. […]

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Sekar Kathiresan

Sekar Kathiresan, a physician scientist and a human geneticist, leverages human genetics to understand the root causes of heart attack and to improve preventive cardiac care.  Among his scientific contributions, […]

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Christopher D. Anderson

Dr. Anderson is a Neurocritical Care physician with research expertise in the medical genetics of complex diseases, specifically ischemic and hemorrhagic stroke. His career research goal is to use computational, […]

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Daniel MacArthur, PhD, Jose C. Florez, MD, PhD, Sekar Kathiresan, MD, Benjamin Neale, PhD, Aarno Palotie, MD, PhD, Mark Daly, PhD
Analysis of protein-coding genetic variation in 60,706 humans

Nature. 2016 Aug 18;536(7616):285-91. doi: 10.1038/nature19057.

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human ‘knockout’ variants in protein-coding genes.

Vamsi K. Mootha, MD
Hypoxia as a therapy for mitochondrial disease

Science. 2016 Apr 1;352(6281):54-61. doi: 10.1126/science.aad9642. Epub 2016 Feb 25.

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.