Although sex hormones play a key role in sex differences in susceptibility, severity, outcomes, and response to therapy of different diseases, sex chromosomes are also increasingly recognized as an important factor

Y chromosome is moving out of sex determination shadow. Raheleh Heydari, Zohreh Jangravi, Samaneh Maleknia, Mehrshad Seresht-Ahmadi, Zahra Bahari, Ghasem Hosseini Salekdeh & Anna Meyfour. Cell & Bioscience volume 12, Article number: 4. January 4 2022. https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-021-00741-y

Abstract: Although sex hormones play a key role in sex differences in susceptibility, severity, outcomes, and response to therapy of different diseases, sex chromosomes are also increasingly recognized as an important factor. Studies demonstrated that the Y chromosome is not a ‘genetic wasteland’ and can be a useful genetic marker for interpreting various male-specific physiological and pathophysiological characteristics. Y chromosome harbors male‑specific genes, which either solely or in cooperation with their X-counterpart, and independent or in conjunction with sex hormones have a considerable impact on basic physiology and disease mechanisms in most or all tissues development. Furthermore, loss of Y chromosome and/or aberrant expression of Y chromosome genes cause sex differences in disease mechanisms. With the launch of the human proteome project (HPP), the association of Y chromosome proteins with pathological conditions has been increasingly explored. In this review, the involvement of Y chromosome genes in male-specific diseases such as prostate cancer and the cases that are more prevalent in men, such as cardiovascular disease, neurological disease, and cancers, has been highlighted. Understanding the molecular mechanisms underlying Y chromosome-related diseases can have a significant impact on the prevention, diagnosis, and treatment of diseases.

Conclusion

Although most sex differences in occurrence and prevalence of diseases have been associated with the function of sex hormones, molecular studies have assigned a hormone-independent role to the differential expression of genes, especially those located on sex chromosomes. Y chromosome genes independently and/or in conjunction with sex hormones, beyond their X-linked collective tasks determine the male-specific characteristics. In this review, we highlighted major recent findings on the contribution of Y chromosome genes to disease susceptibility to various human diseases and showed that how LOY and translation/function failure of Y chromosome genes can affect the pathogenesis of male-specific diseases.

Despite the vast investigation, little knowledge exists on the molecular mechanisms involved in these sex disparities. This might have been originated from the biological limitations and/or experimental issues such as low expression of MSY genes in rare organs or cell types, high similarity with their X counterparts, hormone effects on intracellular processes, and the absence of mixed-sex experimental groups in cellular, animal, and human studies. In the human Y chromosome proteome project, as a part of the Chromosome-Centric Human Proteome Project (C-HPP), the function of MSY proteins was explored in organ development by taking advantage of PSCs, which are capable of differentiation into all cell types of the human body [171]. We believe that hormone-free systems like PSC and their derivatives as well as organoids, which are in vitro generated copies of human organs, can facilitate the mechanistic studies to explore the role of Y chromosome genes in health and disease and provide novel insights into gender disparity and sex-specific therapeutic strategies for diseases.