Chromosome-Centric Human Proteome Project Allies with Developmental Biology: A Case Study of the Role of Y Chromosome Genes in Organ Development

Abstract

One of the main goals of Chromosome-Centric Human Proteome Project is to identify protein evidence for missing proteins (MPs). Here, we present a case study of the role of Y chromosome genes in organ development and how to overcome the challenges facing MPs identification by employing human pluripotent stem cell differentiation into cells of different organs yielding unprecedented biological insight into adult silenced proteins. Y chromosome is a male-specific sex chromosome which escapes meiotic recombination. From an evolutionary perspective, Y chromosome has preserved 3% of ancestral genes compared to 98% preservation of the X chromosome based on Ohno's law. Male specific region of Y chromosome (MSY) contains genes that contribute to central dogma and govern the expression of various targets throughout the genome. One of the most well-known functions of MSY genes is to decide the male-specific characteristics including sex, testis formation, and spermatogenesis, which are majorly formed by ampliconic gene families. Beyond its role in sex-specific gonad development, MSY genes in coexpression with their X counterparts, as single copy and broadly expressed genes, inhibit haplolethality and play a key role in embryogenesis. The role of X-Y related gene mutations in the development of hereditary syndromes suggests an essential contribution of sex chromosome genes to development. MSY genes, solely and independent of their X counterparts and/or in association with sex hormones, have a considerable impact on organ development. In this Review, we present major recent findings on the contribution of MSY genes to gonad formation, spermatogenesis, and the brain, heart, and kidney development and discuss how Y chromosome proteome project may exploit developmental biology to find missing proteins.

Y Chromosome Genes May Play Roles in Directed Differentiation of Human Embryonic Stem Cells.

“…RPS4Y1 is expressed during prenatal and infancy; indicating, it could play a critical role in early brain development (Meyfour et al, 2017b). Our results indicate a possible sex-dependent regulation of neural development that might underlie sexual dimorphism of human brain.…”

“…These studies highlighted the remarkable role of some genes that help to candidate the target genes for more investigations. Among genes of interest, theexpression of RPS4Y1 showed sexual dimorphism of the kidney, and SRY mediated kidney development and played a role in the blood pressure control in males (Meyfour et al, 2017b).…”

“…RBMY1A1 contains a conserved domain called the SRGY motif (serine, arginine, glycine, and tyrosine) that modulated its function. RBMY1 plays a signi cant role in cardiac development, spermatogenesis, infertility, prostate cancer, and hepatocellular carcinoma (HCC) (Meyfour et al, 2017b, Chua et al, 2015, Kido et al, 2020, Jangravi et al, 2013, Dasari et al, 2001.…”

“…HSFY (heat shock transcription factor, Y chromosome) is a member of HSFs and has been located in the AZFb region of the Y chromosome (Rosenfeld, 2017). This gene is associated with spermatogenic failure, infertility (Peng, 2009; Zenteno-Ruiz, 2001), varicoceles (Meyfour, 2017), maturation arrest (MA) (McCann-Crosby, 2014), sertolicell-onlysyndrome (Meyfour, 2017) and plays a crucial role in the brain and cardiac development (Meyfour et al, 2017b). SRY (sex determining region Y) encodes a transcription factor (a member of the high mobility group [HMG]-box family) (Jangravi et al, 2013) and involved in spermatogenesis, male sex determination, brain sexual differentiation, epigenetic processes, brain, cardiac and kidney development (Kamachi and Kondoh, 2013, Rosenfeld, 2017, Peng et al, 2009, Meyfour et al, 2017b.…”

Genetics of male infertility and related genes within Y chromosome

“…EIF1A protein results in azoospermia when deleted. Some studies have been investigated that deletion of DAZ1/DAZ2 but not DAZ3/DAZ4 is associated with spermatogenic failure [28,29].…”