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Mining the Genome with Deep Sequencing

By Tara Ann Cartwright and Negin Martin
March 2010

Yuan Gao, Ph.D. and Alejandro Colaneri, Ph.D.
Gao, left, posed with NIEHS scientist Alejandro Colaneri, Ph.D., a senior visiting fellow in Birnbaumer's group. There was an enthusiastic show of interest in Gao's research by a range of NIEHS investigators from various disciplines intrigued by Gao's development of comprehensive systems to analyze large volumes of data generated by his collaborators. (Photo courtesy of Steve McCaw)

On Jan. 27, guest lecturer and computational biologist Yuan Gao, Ph.D., delivered a seminar to a standing-room-only audience of NIEHS researchers. His lecture on "Illuminating the Epigenome Landscape by Deep Sequencing" was hosted by the NIEHS Laboratory of Neurobiology.

In his talk, Gao described his group's efforts to revolutionize genome sequencing by making it affordable, efficient, and accessible. "High throughput genomics," he explained, "opens the door for advanced gene expression analysis and epigenetic study of the entire organism." Ultimately, advanced genome analysis can be used to customize drug development and treatments to offer personalized medicine for each individual.   

Gao is an assistant professor in the Department of Computer Science and the Center for the Study of Biological Complexity at Virginia Commonwealth University. His primary research interests involve developing and applying new inexpensive, consistent, and simple-to-use sequence technologies to identify sequence variations within a genome and new technologies to study epigenetics.

Advanced research through team science

The enormous amount of data generated by high throughput systems has rapidly overwhelmed current acquisition and storage strategies and made data analyses inefficient and costly. New research increasingly relies on collaborations among experts from different disciplines such as bioinformaticians, computer programmers, biologists and medical scientists to solve this problem - an example of what Linda Birnbaum, Ph.D., director of NIEHS/NTP, describes as "big science."

Although Gao recognizes the uncertainty of genome sequencing and is modest about his accomplishments, he has overcome a number of challenges in sequencing strategies to produce some fascinating scientific findings. A recent collaboration on a study( Exit NIEHS with Karen Adelman, Ph.D., principal investigator of the Transcriptional Responses to the Environment Group in the Laboratory of Molecular Carcinognenesis, led to the discovery that promoter-proximal stalling of RNA polymerase II is a general feature of early elongation in Drosophila cells. Their study was selected as both a February 2010 Intramural Paper of the Month( and a 2009 Paper of the Year(

In another study, Gao and his colleagues observed gene-body methylation in the highly expressed genes of human B-lymphocytes by developing two next-generation sequencing technologies - bisulfite padlock (molecular inversion) probes (BSPP) and methyl-sensitive cut counting (MSCC). The first sequencing technology can recognize selected locations for cytosine methylation. The second utilizes the methylation- sensitive enzyme HpaII to profile methylation across the entire genome.

Gao further explained that padlock probe bisulfite sequencing also has clinical applications for identifying abnormalities of chromosomes. He and his group demonstrated that no significant global changes in methylation patterns were detected on genes of chromosome 21 after electroshock therapy. 

Potential clinical applications for deep sequencing data

Gao stressed that the ability to sequence genomes faster and more cheaply via these new sequencing technologies promises to accelerate knowledge of the molecular basis of disease states such as cancer, Alzheimer's, and autism. Additionally, such technologies could transform our understanding of epigenetic modifications, such as DNA methylation.

In addition to his work with Adelman and NIEHS Bioinformatics Information Specialist David Fargo, Ph.D., Gao collaborates with NIEHS researcher Lutz Birnbaumer, Ph.D., head of the Transmembrane Signaling Group in the Laboratory of Neurobiology. Gao encouraged scientists to use his powerful sequencing technology in their studies and said he looks forward to future collaboration with NIEHS scientists.

(Tara Ann Cartwright, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Neurobiology Membrane Signaling Group. Negin Martin, Ph.D., is a biologist in the NIEHS Laboratory of Neurobiology Viral Vector Core Facility and a 2009 Science Communication Fellow with Environmental Health Sciences.)

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