Research Projects

Our computational biology research is focused on the identification and characterization of regulatory sequences controlling the transcription of genes. Cells respond to diverse stimuli by altering gene activity. Subtle alterations of the regulatory network can produce dramatic phenotypic consequences. Over time the group has explored a variety of topics linked to the central goals of understanding how genes are regulated and learning how to apply this knowledge to advance biomedical research. You can learn about many of our projects via our group homepage at http://www.cisreg.ca/.

IDENTIFICATION AND ANALYSIS OF SEQUENCES REGULATING TRANSCRIPTION

Regulatory sequence analysis is complicated by a signal-to-noise problem. Transcription is regulated at one level by proteins that bind to short segments of DNA. These transcription factors activate or suppress gene activity by modulating the recruitment of RNA polymerase enzymes to the beginning of genes. As the target sequences for transcription factors are short, and in addition the transcription factors are tolerant of considerable variation in the sequences to they bind, it is extremely difficult to distinguish functional binding sites in the ocean of the human genome.

Much of our research has focused on how to circumvent this signal-to-noise problem for both pattern discovery and pattern discrimination. It is convenient to divide the problems we address into these categories. For pattern discovery, we start with an observation of a set of genes which appear to be co-expressed (across cell types and/or changing conditions). Working under the hypothesis that the genes are co-regulated by a common transcription factor, we apply computational methods to identify sequence patterns that are enriched in the DNA sequences of the set of genes. This process requires no a priori knowledge of the sequence pattern. For pattern discrimination we start with the sequence pattern to which a transcription factor binds and seek to specify the locations of additional target sites in a DNA sequence. Over time we have developed diverse algorithms and methods addressing the above problems. As biological knowledge advances and technology provides new types of data, we are constantly pushing to improve our ability to define the regulatory sequences governing gene expression. For example, we study combinatorial interactions between patterns, the evolutionary retention of patterns across similar species and the accessibility of sequences within the three dimensional nucleus. Our efforts have been aided by the tremendous advances in DNA sequencing and the availability of high-throughput microarray techniques for measuring gene expression and chromatin properties.

APPLIED BIOINFORMATICS

At the CMMT we maintain a strong link between research and application. We work closely with our collaborators to impact human health. At present we are engineering regulatory sequences to direct gene expression selectively to regions of the brain in the Pleiades Promoter Project. Working with diverse groups, we identify regulatory sequences in human genes in order to understand how mutations in transcription factor binding sites can alter phenotype. At a ground level, we are working on the GATC Project to identify children at risk for adverse reactions to pharmaceuticals and consult with the Biomarkers in Transplantation Project to identify transplant patients at risk for organ rejection.

NOTICE FOR POTENTIAL APPLICANTS

Our team is constantly changing. The students and post-docs in the group have historically done well, with alumni working in both industry and academia. We take pride in teamwork and maintaining a positive research environment. Opportunities are always available for exceptional students and post-docs. Computer programming skills are essential—we work in a linux environment and develop our own software.

Post-doc candidates with good publication records are strongly encouraged to apply. Graduate students should consider the UBC-SFU Bioinformatics Training Program, although on occasion we directly accept students with demonstrated interest in our research. Motivated undergraduate students with strong computer skills are welcomed, particularly during the summer (May-August). In all cases early contact is best—it gives us time to plan for space, resources and the scientific project.