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

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. © 2017 The Authors Published by S. Karger AG, Basel The azoospermia factor (AZF) locus in Yq11 was first recognised by observation of microscopically visible terminal deletions of the long arm of the Y chromosome in 6 patients with azoospermia, i.e., with no mature sperm in their ejaculate [1] . They included the complete polymorphic heterochromatin block in distal Yq (Yq12) and were assumed to also affect the neighbouring distal euchromatic Y long arm region (Yq11.23). It has been suggested that some function of the distal Yq heterochromatin blocks human male fertility despite the commonly observed polymorphism length in Yq12 [2] . Careful molecular analyses then revealed more individual breakpoints extending along the complete euchromatic long Y arm region (Yq11) in infertile men with AZFYq11 aberrations, and histological analyses of their individual testicular pathology displayed a severe disruption of spermatogenesis at different development phases [3] . This suggested an essential function of AZF during premeiotic and postmeiotic human male germ cell development, and consequently that this genetic locus should encode more than 1 Y gene functionally involved in Vogt PH (ed): Genetics of Human Infertility. Monogr Hum Genet. Basel, Karger, 2017, vol 21, pp 57–73 (DOI: 10.1159/000477278) Human Y Chromosome and Male Infertility: Forward and Back from Azoospermia Factor Chromatin Structure to Azoospermia Factor