Consequences of Y chromosome microdeletions beyond male infertility

Abstract

Purpose: The human Y chromosome plays a central role in sex determination and spermatogenesis. The azoospermia factor (AZF) loci on the Y chromosome contain genes that were thought to be testis specific with their deletions leading to spermatogenic failure. However, beyond the testis, the AZF genes (mainly those in AZFa and AZFb loci) are widely expressed in multiple tissues. Further, these genes are predicted to play roles in processes such as gene regulation and protein synthesis. These observations suggest that the AZF genes may have functions beyond regulation of fertility.

Results: Three major areas have emerged where alternations in AZF genes have effects beyond infertility. (1) Poor-quality embryos are generated in assisted reproduction when sperm from men harboring Y chromosome microdeletions are used, (2) a higher preponderance of neuropsychiatry disorders is observed in men with deletions in AZF genes, and (3) copy number variations and altered expression of AZF genes are found in several cancers.

Conclusion: While our data is preliminary and observational in nature, systematic studies are required to address how genetic alterations in the Y chromosome can affect the health of men beyond infertility. This information will provide a different perspective in the area of androgenetics and have implications in devising strategies for maintaining the overall well-being of infertile males.

Keywords: AZF; Brain; Cancer; Embryo; Extra-gonadal; Gonads; Infertility; Microdeletions; Testis; Y chromosome.

Fig. 1

Transcribing genes within the AZF loci of the human Y chromosome, their biological processes and molecular functions. A. Transcribing genes in the AZF loci of the human Y chromosome where each block represents the three AZF clusters. The genes in the yellow overlaid block are ubiquitously transcribed while those in the blue block are generally testis-enriched. The associated phenotypic manifestations due to loss or gain of these gene/gene families is depicted by the lilac bars to the extreme left of the image. Tissue expression of the genes has been labelled adjacent to the boxes. B. Biological processes and C. Molecular functions of the transcribing genes within the AZF loci as predicted by Uniprot (https://www.uniprot.org, accessed on 15 Nov 2018). t a. T is depicted. lilac extreme b.c.

Fig. 2

Tissue distribution of the AZF genes. The legend depicts normalized RPKM values from the HPA dataset (source protein atlas). The pale blue color correlates with an RPKM value of 0.01 to 1. Blocks with no color have RPKM values < 0.01