Loss of the Y Chromosome and Its Implications in Aging

PROJECT SUMMARY/ABSTRACT Loss of the Y chromosome (LOY) is predominantly observed in the circulating white blood cells of older men, suggesting a significant link to the aging process. LOY stands out as the most frequently observed non- physiological postzygotic chromosomal alteration in the human genome. Its profound association with age and

age-related diseases presents a critical area for in-depth study to understand the broader context of aging. In this proposal, our central focus lies in exploring the LOY-aging nexus. Utilizing both computational and hands- on experimental strategies, we aim to achieve an integrated understanding of LOY. This encompasses novel

methodological innovations, rare variant association studies, and a meticulous probe into the mechanism binding LOY with aging. By diving deep into this specific genome irregularity, we aspire to shed light on the intricate effects of genetic factors that play out as we age. Our overarching goal revolves around demystifying the

interconnections between LOY, genome instability as one ages, and the onset of age-related diseases. Our research hinges on two foundational hypotheses: first, that rare genetic variants play a pivotal role in LOY's manifestation, shaping its appearance against the backdrop of polygenic risks set by more common variants;

and second, that LOY isn't an isolated event, but a piece in the larger puzzle of age-associated genome instability. These suppositions draw strength from our preliminary data, garnered using SNP array genotyping and whole exome sequencing from the Einstein longevity cohort. This invaluable dataset previously enabled us

to identify links between rare genetic variants and exceptional human longevity. We now set forth three distinct aims: to ascertain the extent of LOY mosaicism using sequencing data; to pinpoint genes heightening LOY risk; and, most crucially, to decode the relationship between LOY and aging. We firmly believe that a holistic

understanding of LOY's genetic blueprint and the mechanics tying it to aging will serve as a gateway to understanding age-related pathology. A deeper insight into LOY will not only allow for precise quantification but also pave the way for innovative therapeutic strategies, potentially offering a novel approach to mitigate the

challenges of aging and age-associated diseases.