Nagashree Rachote

Amino acid homorepeats (HRs) consists of an repeats of identical amino acid (such as Polyglutamine). The preconceived notion that these are junk was contradicted during the early 1990’s, when abnormal increase in the length of HRs were implicated in several neurodegenerative and developmental disorders. Subsequent investigations probing physiological roles of HRs identified that HRs themselves participate in various molecular functions such as transcriptional regulation and subcellular localization. Similarly, on a systems-level our group has recently  shown that Essential Homorepeat containing proteins (E-HRPs) regulate larger part of the genome during key transitional switches of human brain development (Singh AK et al,  Cell Reports, 2023). Owing to their hypermutable nature, these are prone to exhibit length variability. While isolated studies link variation in HRs with different phenotypic outcomes, a comprehensive systems-wide understanding of the variability landscape of HRs in humans and their potential consequences is still lacking. Given that they are involved in brain development and lead to neurodegenerative and developmental disorders, we aim to investigate the impact of natural HR length variation on human brain development.

My Ph.D. studies involve understanding the extent and impact HR length variability in humans. I will undertake computational and experimental studies to map HR length variability landscape in humans and investigate the molecular implications of the HR length variation. With this, we will be identifying molecular players and variome landscape underlying developmental origins of brain health and disease.