アブストラクト
| Date | July 3, 2006 |
| Speaker | Dr. Daniel Nilsson, Department of Cell and Molecular Biology (CMB), Programme for Genomics and Bioinformatics, Karolinska Institutet |
| Title | Genomic Feature Identification in Trypanosomatid Parasites |
| Abstract | The trypanosomatid parasites cause death and suffering, among
humans as well as livestock. These protozoans are the causative
agents of diseases such as Chagas disease, sleeping sickness and
leishmaniasis. Current drugs lack efficacy and cause severe side
effects, and no vaccines are available. Increased knowledge of the
biology of the parasites is vital for the development of new
drugs. Research on these ancient eukaryotes has also already led to
the discovery of mechanisms of broader relevance, such as RNA editing,
trans splicing and antigenic variation. Post-transcriptional
regulation is an important part of the regulatory networks of most
higher organisms, including humans. In the kinetoplastids, only a very
limited part of the control of gene expression is exerted at the
transcriptional level. Genes are expressed as long polycistronic
pre-mRNA, and individual messages are formed by trans splicing and
polyadenylation. Even genes that are not coregulated can be on the
same polycistronic pre-mRNA. The trypanosomatids can be regarded as
models for post-transcriptional regulation, in relation to the more
complex eukaryotes.
The progress of the human and other genome projects shows the opportunity provided by a complete genomic sequence to increase the efficiency of traditional molecular biology. Use of computer-aided and fully automated genome sequence analysis tools allows novel feature discovery as well as the direction of hypothesis driven experiments. We have sequenced the genome of Trypanosoma cruzi as part of a three-centre collaboration, and provided an extensive annotation that identifies biologically interesting features. To this end we have used available informatics tools where possible, and developed some new programs. Focus was on integrating current molecular biology knowledge in large scale analyses, and arriving at experimentally testable hypotheses. To produce a biologically interesting annotation, we collaborated with experts in several areas to investigate the gene content of T. cruzi, and that of two other trypanosomatid parasites, Trypanosoma brucei and Leishmania major. I will describe a program for gene-finding and annotation that we constructed for the annotation of the genome. The discovery of a global base skew feature in the genomes will also be presented. The genome project of Trypanosoma cruzi will be outlined, highlighting the genome content of surface molecules, kinases and RNA recognition motif proteins. Furthermore, two related feature identification studies will be discussed. First, a bioinformatic model of trans splicing in Trypanosoma brucei, and the application of it at the genome level, and second, we apply this trans splice model to predict message boundaries in Trypanosoma cruzi. Based on these predictions, we find that upstream open reading frames are common. We hypothesise that these generally repress translation. Finally, I will briefly sketch my part in the current collaboration on the var-gene expression of the apicomplexan parasite Plasmodium falciparum and the relation the var-genes to the rosetting of red blood cells and severity of malaria in Ugandan children. |