Genetics of the human Y chromosome and its association …

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Stacy Colacoet al. Reprod Biol Endocrinol. 2018.

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The human Y chromosome harbors genes that are responsible for testis development and also for initiation and maintenance of spermatogenesis in adulthood. The long arm of the Y chromosome (Yq) contains many ampliconic and palindromic sequences making it predisposed to self-recombination during spermatogenesis and hence susceptible to intra-chromosomal deletions. Such deletions lead to copy number variation in genes of the Y chromosome resulting in male infertility. Three common Yq deletions that recur in infertile males are termed as AZF (Azoospermia Factor) microdeletions viz. AZFa, AZFb and AZFc. As estimated from data of nearly 40,000 Y chromosomes, the global prevalence of Yq microdeletions is 7.5% in infertile males; however the European infertile men are less susceptible to Yq microdeletions, the highest prevalence is in Americans and East Asian infertile men. In addition, partial deletions of the AZFc locus have been associated with infertility but the effect seems to be ethnicity dependent. Analysis of > 17,000 Y chromosomes from fertile and infertile men has revealed an association of gr/gr deletion with male infertility in Caucasians and Mongolian men, while the b2/b3 deletion is associated with male infertility in African and Dravidian men. Clinically, the screening for Yq microdeletions would aid the clinician in determining the cause of male infertility and decide a rational management strategy for the patient. As these deletions are transmitted to 100% of male offspring born through assisted reproduction, testing of Yq deletions will allow the couples to make an informed choice regarding the perpetuation of male infertility in future generations. With the emerging data on association of Yq deletions with testicular cancers and neuropsychiatric conditions long term follow-up data is urgently needed for infertile men harboring Yq deletions. If found so, the information will change the current the perspective of androgenetics from infertility and might have broad implication in men health.

Keywords: AZF; AZFc; Infertility; Microdeletions; Prevalence; Spermatogenesis; Y chromosome; gr/gr deletions.

DM is scientist E and Head of Molecular Biology, Indian Council of Medical Research, National Institute for Research in Reproductive Health, Mumbai, India. SC is a post-doctoral fellow, Indian Council of Medical Research, National Institute for Research in Reproductive Health, Mumbai, India.

Not applicable as it is a review article.

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The authors declare that they have no competing interests.

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Fig. 1

Structure of the human Y

Fig. 1

Structure of the human Y chromosome. The Pseudo Autosomal Regions [PAR1 and PAR2]

Structure of the human Y chromosome. The Pseudo Autosomal Regions [PAR1 and PAR2] are located at the terminal ends of the Y chromosome. The green boxes show the genes encoded in these regions. Yp is the short arm of the Y chromosome and the genes within it are show in the peach box. The long arm, Yq, is composed of both euchromatin and the genetically inactive heterochromatin regions. This region contains the Azoospermia factors AZFa, AZFb and AZFc. The pink box shows the genes in the AZFa region. The heterochromatin is not known to harbor any known genes. The region beyond the PAR is termed as Male Specific Region on Y (MSY)

Fig. 2

Schematic organization of the AZFb

Fig. 2

Schematic organization of the AZFb and c loci depicting how the various microdeletions

Schematic organization of the AZFb and c loci depicting how the various microdeletions arise. The AZFb and c regions are located in the euchromatic region on the Yq. Both regions share a number of genes [pink box], the genes present in the AZFb region are shown in the green box while the genes present in the AZFc region are present in the blue box. The grey arrows depict the orientation of the genes and the grey bars depict the organisation of the amplicons into palindromes [P1 to P5]. The AZFb and AZFc loci are composed of numerous stretches of ampliconic sequences [block arrows] which are annotated as six colour-coded sequence families (yellow, blue, turquoise, green, red and grey) called amplicons. The size and orientation of the coloured arrows represents the length and orientation of the arrows. AZFb is defined by the P5/proximal P1 deletion (yel3/yel1) which removes 6.23Mb of DNA and AZFc by the b2/b4 deletion which removes 3.5Mb of DNA. The partial AZFc deletions b1/b3, b2/b3 and the three variations of the gr/gr deletions [g1/g2], [r1/r3] and [r2/r4] [in dotted box] remove almost half of the AZFc gene content. The shaded block depicts the exact location of the deletion. The information of the map is adapted from published data ([6, 27], and [62])

Fig. 3

Expression of RBMY during human

Fig. 3

Expression of RBMY during human spermatogenesis. Human testicular cells were separated by mild

Expression of RBMY during human spermatogenesis. Human testicular cells were separated by mild collagenase digestion, smeared on slides and fixed in acetone. The cells were probed using an antibody against human RBMY (Santacruz Biotechnology Inc., sc 14,572, USA) and detected using a FITC labeled secondary antibody. The cells were imaged under a fluorescent microscope and different stages were identified based on the cell and nuclear size. Green staining represents RBMY, red is nuclei. Bar represents 20m. For details of the methods see Abid et al. [115]

Fig. 4

World map depicting the prevalence

Fig. 4

World map depicting the prevalence of Yq microdeletions in infertile males in different

World map depicting the prevalence of Yq microdeletions in infertile males in different countries. The prevalence of Yq microdeletions in different countries of the world was estimated from published data of 40,127 Y chromosomes from infertile men. (oligozoospermic or azoospermic men). Only those articles published in English were considered and total number of infertile men studied and those having deletions were recorded along with the country. For each country data from different studies were pooled and the average estimated

Fig. 5

Prevalence of Yq microdeletions in

Fig. 5

Prevalence of Yq microdeletions in infertile men. The average prevalence of the Yq

Prevalence of Yq microdeletions in infertile men. The average prevalence of the Yq microdeletions in different continents of the world was estimated from published data of 40,127 Y chromosomes from infertile men. Infertile men could be oligozoospermic or azoospermic men. Pie chart gives distribution of Yq microdeletions in the Asian region. The numbers were estimated from the data of Asian men based on geographical. In both the cases, only those articles published in English were considered and total number of infertile men studied and those having deletions were recorded along with the country. Data from different studies from same continent were pooled and the average estimated (for details see Additional file 1: Table S1)

Fig. 6

Association of gr/gr and b2/b3

Fig. 6

Association of gr/gr and b2/b3 deletions with male infertility. Data was obtained from

Association of gr/gr and b2/b3 deletions with male infertility. Data was obtained from previous studies [105, 126, 167, 188]. Data for gr/gr is derived out of 10,978 and 6704 Y chromosomes from infertile and fertile men respectively. For b2/b3 the data is derived out of 9981 and 5990 Y chromosomes from fertile and infertile men respectively. Infertile men could be oligozoospermic or azoospermic men. Fertile men would be normozoospermic/proven fertile men with unknown sperm counts. Data was divided based on continents or by race. * indicates value significantly different form fertile counterpart

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