There are several projects going on in the lab
(1) Molecular evolution of hepatitis B virus (HBV)
Hepatitis B virus (HBV) is one of the most common infectious agents in the world. According to world health organization (WHO), more than a third of the world’s population (2 billion people) has been infected with HBV. In Taiwan, 15-20% of the population are chronic HBV carriers which translate to 3.5-4 million people nation-wide.
We collaborate with Prof Chang, MH in Department of Pediatric, National Taiwan University Hospital, who has collected serum samples every six months from a cohort of HBV carriers for more than 17 years, beginning before the age of 10 years. For each patient, multiple full-length HBV sequences were recovered from three time points spanning the immunotolerant phase without alanine aminotransferase (ALT) elevation to the early immunoclearance phase with mild ALT elevation. We found that the interplay between viral replication and host immunity explains patterns of HBV dynamics within host during relative early stage of infection. That is, without immune selection, competition between peers increases the viral load and decreases nucleotide diversity; in contrast, host immunity accelerates viral evolution and decreases copy numbers but increases diversity (Wang et al. 2010). We are currently analyzing more individuals with different disease stages. Our observation may have important implications for studying long-term HBV adaptation and therapeutic design for chronic hepatitis infection.
(2) Quantitative trait loci (QTL) mapping of hepatitis viral susceptibility
It has been shown previously that different inbred mouse strains have different response to an engineered and replication-competent pAAV/HBV1.2 DNA. After hydrodynamical injection of pAAV/HBV1.2 DNA, the serum HBsAg level dropped faster in BALB/c mice than in C57BL/6 mice. As a result, 80% of C57BL/6 mice were still HBsAg-positive 35 days after injection, whereas none of BALB/c mice was HBsAg-positive after 28 days.
We hypothesize that genetic background of different inbred mice play a crucial role in the persistence of HBV. The ultimate goal of this study is to dissect the genetic component of HBV tolerance in mice and its possible connection with chronic HBV infection in human. To that end, we perform QTL mapping to delineate the genetic components that control viral susceptibility.
(3) Transcription regulation at incipient stage of speciation
How species forms is one of the most fascinating and mysterious question in biology. The Zimbabwe race of D. melanogaster vis-a-vis the cosmopolitan populations provides a good opportunity to study speciation at very early stage. Females from most Z lines (for Zimbabwe) do not mate with males from M lines (for melanogaster of the cosmopolitan type), whereas the reciprocal crosses experience much weaker or no isolation.
In this project, our main interest is how gene expression is regulated between different racial groups. To that end, we apply microarray and pyrosequencing technologies to study gene regulation at globally and individually. At whole genome level, we found most of genes are jointly regulated by cis- and trans-factors. In addition, cis-component increases with increase level of divergence (Wang et al 2008). We also study allelic specific expression using pyrosequencing technology. We demonstrate that gene expression is highly context-dependent, i.e. genetic background has strong influence on the expression of the gene.