Area of interest
I developed the nematode Caenorhabditis elegans to study telomere biology. We utilize genetics to study telomerase-mediated telomere repeat addition, which is active in 90% of all tumors, deficiency for which in humans results in transgenerational telomere erosion accompanied by lethal diseases anemia or pulmonary fibrosis. We recently defined mutations that suppress deficiency for telomerase by activating a telomerase-independent telomere lengthening pathway termed Alternative Lengthening of Telomeres, which is active in ~10% of all human tumors. We study telomere uncapping events that elicit medium- to large-scale copy number changes to the genome, which are likely common during tumor development. We recently discovered that small RNA-mediated genome silencing promotes telomere stability in the absence of telomerase.
We also study forms of transgenerational inheritance distinct from telomere shortening. We found that the Piwi/piRNA small RNA pathway represses a form of “heritable stress” that can accumulate over generations to cause reproductive arrest, similar to what occurs in response to severe exogenous stresses like starvation. We found that Piwi mutant sterility can be completely suppressed by mutation of daf-2, which results in somatic longevity, thereby creating a fascinating link to the field of aging that places stress that may be relevant to aging in the context of transgenerational inheritance. We are interested in understanding what heritable stress might be and how the organism responds to this stress, which could be relevant to human disorders that display transgenerational effects.
We recently studied 2,000 C. elegans mutants whose genomes have been completely sequenced. We utilized computational approaches to study mutant strains with long or short telomeres. We also defined de novo transposon insertions that occur as a consequence of transposon silencing defects and were able to define all genes known to silence transposons. These results convinced us that we can to use a combination of genetics and whole genome sequencing to effectively study genome stability in an unprecedented and unbiased manner. Based on our work with small RNAs in the Piwi/piRNA pathway and repetitive telomere sequences, we have developed the computational tools to study sequencing reads from repetitive sequences that have both unique and mismatched homology.
We have demonstrated that the majority of end-to-end chromosome fusions may occur as a consequence of complex genome rearrangements.