Diagnostic screening of the microdeleation mutations in the azoospermia factor-gene cluster of the Y chromosome and; prostate cancer among Arabs: toward establishment of gene therapy platform in the region

Infertility is a global problem threatening with a marked downward shift in the human growth rate in the coming decades and centuries. The extant literature supports the conclusion that the problem of infertility has been underestimated and remains a neglected area in sexual and reproductive health, yet its consequences are staggering. For instance, globally, the magnitude of the infertility is estimated to impact up to 25% (200 million) of couples of reproductive age. It is associated with adverse physical and mental health outcomes, financial distress, severe social stigma, increased risk of domestic abuse, and marital instability. Furthermore, there is substantial complexity and variation in these experiences by sociodemographic and sociocultural characteristics, both within and between countries. Y chromosome is the chromosome with the least number of functional coding genes in the human genome among the global genealogical lineages. It has the least number of genes among all human chromosomes mainly consisting of the maleness sex determination and male germ cell development and maintenance. The genome size of Y chromosome is 59 Mbp with 3 Mb belonging to pseudoautosomal regions (PAR1 and PAR2 on the Yp and Yq, respectively) and 57 Mb belonging to a nonrecombining region, which can be classified into heterochromatic and euchromatic regions. The latter region is composed of 23 Mb containing all the coding genes and consisting of 8 Mb on the short arm and 14.5 Mb on the long arm Yq11. The most important region of fertility genes is located at the proximal long arm and named azoospermia factor, which is divided into subregions (AZFa, AZFb, AZFc, AZFd, AZFe) including the DAZ gene cluster, which is essential for successful spermatogenesis process to produce the sperms, that is, male gametes. Data analysis using next-generation sequencing technology and the multiplex polymerase chain reaction technology of Y chromosome revealed that any partial or complete microdeletion in the azoospermia factor (AZF) gene cluster region will cause infertility and impairment of spermatogenesis leading to infertile male as no mature healthy sperm cells will be produced. The gene therapy technology provides an alternative pioneering future platform for infertility treatment and needs to promote further research on various approaches for gene therapy future of the human male infertility. Such approaches must be explored using the available technology including viral vector, in vitro fertilization, genetically engineered human artificial chromosome, and stem cell technology. The stem cell therapy for nonobstructive azoospermia has already been explored with a highly promising future. Despite the ethical constraints and the risk of tumorigenesis, stem cells are capable of self-renewal and multidirectional differentiation, and embryonic stem cells and induced pluripotent stem cells can generate spermatozoa through differentiation. Several successful attempts have been made by many researchers using the mesenchymal stem cells, which promote spermatogenesis through paracrine activity. In conclusion, our long-standing research on the AZF gene cluster and the microsatellite STRs being correlated with prostate cancer and the haplogroups and haplotypes of Y-chromosome supports the theme that infertility is correlated to the male genealogical lineage and that the gene therapy technology provides the alternative pioneering platform for infertility treatment. There is a need to promote further research on various approaches for gene therapy of the human male infertility. The national programs for genealogical profiling of AZF will be a vital and valuable tool to promote our understanding of the infertility complexity with the prostate cancer and haplogroups of genealogical lineages worldwide to enhance the health awareness of human societies and ultimately to facilitate gene therapy practices and thus the overall management of the familial cancer disease in the region. This chapter underlines the importance of the national AZF screening programs as correlated to different haplogroups and haplotypes of Y chromosome in different Arabian tribes and ethnicity populations to establish the gene therapy platform as a pioneering therapeutic approach in the region by 2030.