Kai-Ning Chen

Genetic variations and DNA modification are two common dominant factors ubiquitous across the entire human genome and induce human disease, especially through static genetic variations in DNA or RNA that cause human genetic diseases. DNA N6-methyladenosine (6mA) methylation, as a new epigenetic modification mark, has been widely studied for regulatory biological processes in humans. However, the effect of DNA modification on dynamic transcriptional genetic variations from DNA to RNA has rarely been reported. Here, we identified DNA, RNA and transcriptional genetic variations from Illumina short-read sequencing data in East Asian samples (HX1 and AK1) and detected global DNA 6mA modification using single-molecule, real-time sequencing (SMRT) data. We decoded the effects of DNA 6mA modification on transcriptional genetic variations in East Asian samples and the results were extensively verified in the HeLa cell line. DNA 6mA modification had a stabilized distribution in the East Asian samples and the methylated genes were less likely to mutate than the non-methylated genes. For methylated genes, the 6mA density was positively correlated with the number of variations. DNA 6mA modification had a selective effect on transcriptional genetic variations from DNA to RNA, in which the dynamic transcriptional variations of heterozygous (0/1 to 0/1) and homozygous (1/1 to 1/1) were significantly affected by 6mA modification. The effect of DNA methylation on transcriptional genetic variations provides new insights into the influencing factors of DNA to RNA transcriptional regulation in the central doctrine of molecular biology.

The high computational cost of current assembly methods for the long, noisy single molecular sequencing (SMS) reads has prevented them from assembling large genomes. We introduce an ultra-fast alignment method based on a novel global alignment score. For large human SMS data, our method is 7X faster than MHAP for pairwise alignment and 15X faster than BLASR for reference mapping. We develop a Mapping, Error Correction and de novo Assembly Tool (MECAT) by integrating our new alignment and error correction methods, with the Celera Assembler. MECAT is capable of producing high quality de novo assembly of large genome from SMS reads with low computational cost. MECAT produces reference-quality assemblies of Saccharomyces cerevisiae , Arabidopsis thaliana , Drosophila melanogaster and reconstructs the human CHM1 genome with 15% longer NG50 in only 7600 CPU core hours using 54X SMS reads and a Chinese Han genome in 19200 CPU core hours using 102X SMS reads.