Human Y Chromosome and Male Infertility: Forward and Back from Azoospermia Factor Chromatin Structure to Azoospermia Factor Gene Function

Abstract

In the euchromatic part of the long arm of the human Y chromosome (Yq11) at least 13 Y genes encoding proteins and expressed in male germ cells were found in 3 distinct genomic Y regions frequently deleted in infertile men with idiopathic azoospermia, i.e., for unknown reasons no mature sperm were found in their semen fluid. Accordingly, they were designated as azoospermia factor (AZF) regions: AZFa, AZFb, and AZFc. Additionally, 10 Y genes called "testis-specific transcript Y" ( TTTY ) genes were mapped in the same AZF intervals. They belong to the long non-coding RNA gene pool in human germ cells because they seem to lack any protein-coding potential. Distinct chromatin regions in Yq11 overlapping with AZFb and AZFc are supposed to be involved in the premeiotic X and Y chromosome pairing and inactivation process controlling male germ cell meiosis. It can thus be assumed that the germ line function of the AZF loci in Yq11 may be not only based on the expression of some germ cell proteins, but also on the expression of some germ cell-specific TTTY transcripts and a locally dynamic and specific chromatin folding structure probably controlled by some germ cell-specific nuclear proteins.

SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility

“…75 In addition, men with low sperm counts and a balanced reciprocal translocation have rearrangement breakpoints that sometimes cluster in distinct genomic regions, suggesting that as opposed to a nonspecific mechanism of meiotic segregation, there may be something intrinsic to these genomic regions important for fertility. 76,77 In the case of DGAP230, the structural rearrangement leads to dysregulation of SYCP2, which resides 1.5 Mb proximal to one of the rearrangement breakpoints. This cytogenomic influence on gene expression supports the finding that translocation breakpoints can influence gene expression by dysregulating genes residing within the same TAD.…”

SYCP2translocation-mediated dysregulation and frameshift variants cause human male infertility

“…While it is generally thought that balanced reciprocal translocations may reduce fertility due to production of unbalanced gametes 13 or meiotic silencing of unsynapsed chromatin 45 , this does not account for the specific phenotype of severe oligozoospermia or azoospermia because the majority of men with balanced reciprocal translocations have normal sperm counts 46 . In addition, men with low sperm counts and a balanced reciprocal translocation have rearrangement breakpoints that sometimes cluster in distinct genomic regions, suggesting that as opposed to a nonspecific mechanism of meiotic segregation, there may be something intrinsic to these genomic regions important for fertility 47,48 .…”

Consequences of Y chromosome microdeletions beyond male infertility

“…The bulk of the Y, excluding the PARs, is called the "non-recombining Y" (NRY) which is composed of the heterochromatic region (24 Mb) and the euchromatic region (30Mb) both of which lie distal to the PAR1. The euchromatic region within the NRY is also referred to as male-specific region on Y (MSY) [4][5][6][7].…”

“…Rather than being comprehensive, we will focus on the genes within the long arm of the Y chromosome in the AZF locus which are often deleted in men infertile men [1]. The roles of AZF genes in spermatogenesis and male infertility have been recently reviewed [1,4]; herein, we will present evidences that are now emerging to show the involvement of these genes beyond fertility regulation.…”