Research

Our past and present areas of research are :

1. Telomeres and genomic instability: telomere maintenance in the absence of telomerase in S. cerevisiae. Telomerase negative yeast has been an excellent model for understanding the underlying genetic mechanisms leading to ALT (alternative lengthening of telomeres) tumours and associated genomic instability. We have found dramatic differences in genome stability rates between haploid and diploid cells, in the absence of telomerase. We have also shown a paradoxical role for a gene, NEJ1, which promotes DNA repair in wild type cells while protecting the telomere from end fusions in telomerase negative cells.

2. Exploiting natural variation to map quantitative trait loci (QTLs) of various telomere properties including length, silencing, ageing, and senescence. We have found dramatic differences in telomere length and telomeric transcriptional silencing in natural population. We are characterizing this variation with the aim to identify novel genes that affect telomeric properties. One of the QTL that contribute to telomere length variation is the RNA template of telomerase (hortolog of hTERT) and allelic variants of this gene are associated with telomere length variation in human populations.

3. Evolution of the RAS signalling pathway. This pathway is highly conserved in all eukaryotes and is a key regulator of cell growth and malignant transformation. We found that widespread sequence variation in this pathway regulate internal levels of cAMP and contribute to quantitative differences in ageing (chronological life span), virulence (ability to grow at high temperature) and mitochondrial genome stability. Part of the variation in the RAS signalling pathway is due to sequence polymorphisms in the IRA1 and IRA2. The IRA genes are of specific interest as they are highly conserved orthologs of the human disease gene NF1, which causes neurofibromatosis type 1, and as mutations in patients with neurofibromatosis also have similar detrimental effects on the yeast Ira1p activity.

4. Genome evolution. Our studies on genome evolution lay the foundation for understanding the population structure of Saccharomyces yeasts and highlighted how classical phylogeny is inadequate to present the true relationship between strains and species. We are also interested in the relationship between sequence divergence and meiotic sterility.

5. Population genomics. I have been part of a joint effort, the Saccharomyces Genome Resequencing Project (SGRP), involving Richard Durbin’s group at The Sanger Institute and Edward Louis’ group at Universtiy of Nottingham to sequence and release genome sequence data of 72 strains of S. cerevisiae and its closest known species S. paradoxus. This study led to a landmark paper published in March 2009 that initiate the field of population genomics and revealed the impact of human activity on the population structure of the baker’s yeast.

 

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