Dr. Green is leading NISC in implementing and utilizing “next-generation” DNA sequencing technologies for myriad genome-exploration studies. He is extensively involved in projects directed towards the realization of routine whole-genome sequencing of human DNA samples.

Dr. Green’s research program focuses on the application of large-scale DNA sequencing to studying problems in human genomics, genetics, and biology. In his multiple roles as Scientific Director of NHGRI, Chief of the Genome Technology Branch, and Director of the NIH Intramural Sequencing Center (NISC), he has a fundamental interest in applying contemporary genomic technologies to diverse areas of biomedical research. All of Dr. Green’s research projects are performed in partnership with NISC.

In one area of study, Dr. Green and his colleagues are performing multi-species sequence comparisons in an effort to unravel the complexities of genome structure, function, and evolution. For these studies, genomic regions of interest are isolated from a variety of animal species, sequenced, and compared in detail. The resulting data sets provide unprecedented abilities to perform sequence comparisons of evolutionarily diverse species. In some cases, sequences conserved over tens of millions of years of evolutionary time are compared, revealing highly conserved sequences that are likely to have functional roles. In other cases, comparisons are focused on sequence differences among closely related species (such as groups of primates), revealing more recent genomic changes. In essence, Dr. Green’s group uses the detailed records of evolution embedded within all species’ DNA sequences to help decode the human genome. These efforts provided an important foundation for NHGRI’s ENCODE (Encyclopedia of DNA Elements) project, which seeks to identify all functional elements in the human genome and to facilitate the comprehensive understanding of complex genomes.

In a second area of study, Dr. Green’s efforts are aimed at understanding the molecular basis of human genetic disease. His early work led to the identification of genes associated with hereditary deafness (Pendred syndrome), vascular disease (cerebral cavernous malformations), and a neurological disorder (one form of Charcot-Marie-Tooth disease). Such discoveries provided new opportunities to study the function of individual genes and the proteins they encode, to define the pathological consequences of disease-associated mutations, and to generate animal models of these disorders. More recently, these studies have been broadened to utilize large-scale resequencing of human DNA (i.e., medical sequencing) as a general tool for studying genetic diseases. In doing so, a number of key challenges in human genetics are being addressed, including establishing the role of non-coding sequence variants in human genetic disease, as well as identifying and characterizing mutations associated with genetically complex (multigenic) disorders.