Hematopoietic mosaic loss of Y chromosome: from population cohorts to pathogenic mechanisms

Abstract

Mosaic loss of Y Chromosome (mLOY) refers to genetic mosaicism in males where some somatic cells have lost the Y chromosome (ChrY) while other cells remain their ChrY. mLOY is primarily found in the blood, not only because blood cells are easily accessible, but also because hematopoietic stem cells with LOY mutation gain competitive advantages, therefore producing a large number of LOY-positive blood cells via clonal hematopoiesis. Due to the specific structures, human ChrY is prone to be missegregated during mitosis, and driving by the germline variants, environmental insults and aging microenvironments, mLOY becomes the most commonly acquired age-related mutation in male genomes. Population-based cohort studies have shown that men with a certain degree of mLOY is associated with significantly reduced life expectancy and increased risks of cancer, Alzheimer's disease, cardiovascular diseases and among others. Recent studies using mouse models have further demonstrated that mLOY is a driving factor of leukemia and cardiovascular diseases. These findings suggest that mLOY not only provides a common genetic explanation for the occurrence of many chronic diseases in men, but also provides a new kernel for studying sex differences in human lifespan and disease risk. Here, we briefly summarize the findings from the population-based cohort studies on clonal hematopoiesis driven by LOY. Subsequently we sort out the risk factors of mLOY, methods for detecting mLOY and developing mLOY mouse models, and the potential mechanisms of mLOY in promoting a myriad of chronic diseases. Finally, we provide our own forward-looking perspectives for the future challenges and opportunities in mLOY. The findings from this review provide references for studying the biological role of Y chromosome and sex difference of chronic diseases.

Keywords: Alzheimer’s disease; cardiovascular diseases; clonal hematopoiesis; leukemia; mosaic loss of Y chromosome.