Detection and Integrative Functional Characterization of DNA Modifications with Single Molecule Real-Time Sequencing
Gang Fang, Mount Sinai School of Medicine

The information content of the genetic code is not limited to the primary nucleotide sequence but is also conveyed by chemical modifications of individual bases. These modifications expand the genetic alphabet beyond the canonical deoxyribonucleotides (A, G, C and T) and provide rich additional information that is critical towards a complete understanding of the regulatory networks that modulate core cellular and biological processes under a great diversity of conditions. The most common mapping of genome-wide methylation occurs via bisulfite sequencing that specifically targets 5-methylcytosine residues. However, a variety of other chemical modifications such as 6-methyladenine, 4-methylcytosine, and 8-oxoguanine cannot be detected accurately and efficiently on a genome-wide scale using second-generation sequencing techniques, and the functional impacts of these DNA chemical modifications have not been fully explored. Recently, a third generation sequencing technique, namely Single Molecule Real-Time (SMRT) sequencing and proper statistical modeling, enabled the direct detection of and differentiation among tens of known and potentially novel DNA modifications. Some of these DNA modifications have important regulatory roles in the context of infectious diseases and genetic disorders. In recent work, we discovered methylation patterns at single base resolution in the Escherichia Coli strain that caused 2011outbreak in German and demonstrated their regulatory roles on transcription and higher order phenotypes including growth rate and virulence. We also revealed for the first time a complete map of DNA modifications for mitochondrial DNA samples isolated from human brain issue. I will highlight these works done by ourselves and others in this direction and discuss potentials for future research.

Background Review Article:

Fang, Gang, et al. "Genome-wide mapping of methylated adenine residues in pathogenic Escherichia coli using single-molecule real-time sequencing." Nature biotechnology (2012).

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