Indian Institute of Science, Bangalore
Indian Institute of Science Education and Research Thiruvananthapuram
During meiosis, the segregation of paternal and maternal chromosomes requires formation of crossover events between them. My laboratory at IISER-Thiruvananthapuram is studying the elaborate regulatory mechanisms meiotic cells have developed to put at least one crossover on every homolog pair. Defects in this process are a leading cause for congenital birth defects observed in humans. As a high school student growing up in New Delhi, I was interested in understanding mechanisms behind biological processes and therefore decided to pursue biochemistry for my undergraduate studies at Sri Venkateswara College, Delhi University. The Biochemistry department was particularly encouraging of students who wished to go beyond the experiment’s prescribed by the course syllabus and I used to work on independent projects after college hours. These experiences further motivated me to take up research as a career. I developed my early interests in meiosis as a graduate student in Prof. M.R.S. Rao’s laboratory at the Indian Institute of Science, Bangalore. My graduate thesis was on characterization of meiotic recombination hotspots in mammalian systems (mouse and human). Meiotic hotspots serve as preferred sites for formation of crossovers. This work was challenging as very few meiotic hotspots were known in mammal’s ten years ago due to the experimental difficulties in observing recombination events in mammals. In order to get mechanistic insights into the meiotic recombination process, I turned to yeast as a model system during my postdoctoral training with Prof. Eric Alani, at Cornell University. I focussed on the role of the evolutionarily conserved proteins belonging to the prokaryotic MutS and MutL family in meiotic recombination. These proteins called MSH4, MSH5 and MLH1, MLH3 are central players in the formation of crossover products. This work allowed me to use a vast array of genetic techniques to determine the mechanisms by which the MSH4-MSH5 and MLH1-MLH3 complexes ensure crossover formation. Of particular interest for my future goals was the discovery of a series of msh4/5 hypomorphic mutants that allowed me to reduce crossover levels without changing meiotic viability. These mutants support the presence of a crossover assurance mechanism in the cell that guarantee’s every homolog pair with a crossover event. The small genome size and generation time of yeast also allowed me to use whole genome sequencing technologies to determine the stability of the eukaryotic diploid genome during successive mitotic and meiotic divisions. This work was done in collaboration with Dr. Lars Steinmetz (EMBL-Heidelberg), a pioneering expert in genomic technologies. In my own laboratory at IISER-Thiruvananthapuram I have continued this collaboration with the Steinmetz laboratory to use the power of genomic technologies to understand how crossover number and placement on homolog pairs are optimized to ensure homolog disjunction. These studies will help us identify crossover configurations that are favourable for chromosome disjunction versus those that are not. We are also working on elucidating specific mechanisms in place to protect the disjunction promoting crossovers. Although currently working with yeast, I eventually plan to extend this work into mammalian meiosis.