Subject(s)
Chromosome Deletion , Chromosomes, Human, Y , Infertility, Male/diagnosis , Infertility, Male/genetics , Deleted in Azoospermia 1 Protein , Gene Dosage , Gene Frequency , Genetic Testing , Genotype , Haplotypes , Humans , Male , Nuclear Proteins/genetics , Phenotype , RNA-Binding Proteins/geneticsABSTRACT
BACKGROUND: Complete deletion of the complete AZFc interval of the Y chromosome is the most common known genetic cause of human male infertility. Two partial AZFc deletions (gr/gr and b1/b3) that remove some copies of all AZFc genes have recently been identified in infertile and fertile populations, and an association study indicates that the resulting gene dose reduction represents a risk factor for spermatogenic failure. METHODS: To determine the incidence of various partial AZFc deletions and their effect on fertility, we combined quantitative and qualitative analyses of the AZFc interval at the DAZ and CDY1 loci in 300 infertile men and 399 control men. RESULTS: We detected 34 partial AZFc deletions (32 gr/gr deletions), arising from at least 19 independent deletion events, and found gr/gr deletion in 6% of infertile and 3.5% of control men (p>0.05). Our data provide evidence for two large AZFc inversion polymorphisms, and for relative hot and cold spots of unequal crossing over within the blocks of homology that mediate gr/gr deletion. Using SFVs (sequence family variants), we discriminate DAZ1/2, DAZ3/4, CDY1a (proximal), and CDY1b (distal) and define four types of DAZ-CDY1 gr/gr deletion. CONCLUSIONS: The only deletion type to show an association with infertility was DAZ3/4-CDY1a (p = 0.042), suggesting that most gr/gr deletions are neutral variants. We see a stronger association, however, between loss of the CDY1a SFV and infertility (p = 0.002). Thus, loss of this SFV through deletion or gene conversion could be a major risk factor for male infertility.
Subject(s)
Chromosomes, Human, Y/genetics , Gene Deletion , Nuclear Proteins/genetics , Oligospermia/genetics , RNA-Binding Proteins/genetics , Base Sequence , Chromosome Inversion , Chromosomes, Human, Y/chemistry , Deleted in Azoospermia 1 Protein , Gene Conversion , Gene Dosage , Genetic Predisposition to Disease , Genetic Variation , Humans , In Situ Hybridization, Fluorescence , Male , Polymorphism, Genetic , Recombination, GeneticSubject(s)
H-Y Antigen/genetics , Proteins/genetics , X Chromosome/genetics , Y Chromosome/genetics , Alternative Splicing , Amino Acid Sequence , Animals , Base Sequence , DNA, Complementary/genetics , Exons , Female , Genetic Variation , Histone Demethylases , Histone-Lysine N-Methyltransferase , Humans , Introns , Male , Mice , Minor Histocompatibility Antigens , Molecular Sequence Data , Oxidoreductases, N-Demethylating , Sequence Homology, Amino Acid , Species SpecificityABSTRACT
The Delta Sxrb deletion interval of the mouse Y chromosome contains Spy, a spermatogenesis factor gene(s) whose expression is essential for the postnatal development of the mitotic germ cells, spermatogonia. The boundaries of Delta Sxrb are defined by the duplicated genes Zfy1 and Zfy2 and four further genes have previously been mapped within the interval: Ube1y and Smcy, linked with Zfy1 on a contig of 250 kb, and Dffry and Uty, which were unanchored. The interval was estimated to be >450 kb. In order to identify any further gene(s) that may underlie Spy, systematic exon trapping was performed on an extended contig, anchored on Zfy1, which covers 750 kb of the Delta Sxrb interval. Exons from two novel genes were isolated and placed together with Dffry and Uty on the contig in the order Dffry-Dby-Uty-Tspy-Eif2gammay-Smcy- Ube1y-Zfy1. All the genes, with the double exception of Tspy, are X-Y homologous and produce putatively functional, spliced transcripts. The tight linkage and order of Dffry, Dby and Uty was shown to be conserved in deletion intervals 5C/5D of the human Y chromosome by the construction of a contig of human PAC and YAC clones; this represents the first example of syntenic homology between Y chromosomes from two distinct mammalian orders. Interval 5C/5D contains the distal boundary of the AZFa interval, which, like Delta Sxrb, is believed to be necessary for spermatogonial development in the prepubertal testis. Our results therefore show that AZFa and Spy may be encoded by homologous genes.
Subject(s)
Chromosome Mapping/methods , Spermatogenesis/genetics , Y Chromosome , Animals , Chromosomes, Bacterial , Chromosomes, Human , DEAD-box RNA Helicases , DNA-Binding Proteins/genetics , Exons , Female , Humans , Kruppel-Like Transcription Factors , Ligases/genetics , Male , Mice , Mice, Inbred C57BL , Minor Histocompatibility Antigens , Molecular Sequence Data , Nuclear Proteins , Proteins/genetics , Rats , Transcription Factors , Transcription, Genetic , Ubiquitin-Protein LigasesABSTRACT
DFFRY (the Y-linked homologue of the DFFRX Drosophila fat-facets related X gene) maps to proximal Yq11.2 within the interval defining the AZFa spermatogenic phenotype. The complete coding region of DFFRY has been sequenced and shows 89% identity to the X-linked gene at the nucleotide level. In common with DFFRX , the potential amino acid sequence contains the conserved Cys and His domains characteristic of ubiquitin C-terminal hydrolases. The human DFFRY mRNA is expressed in a wide range of adult and embryonic tissues, including testis, whereas the homologous mouse Dffry gene is expressed specifically in the testis. Analysis of three azoospermic male patients has shown that DFFRY is deleted from the Y chromosome in these individuals. Two patients have a testicular phenotype which resembles Sertoli cell-only syndrome, and the third diminished spermatogenesis. In all three patients, the deletions extend from close to the 3' end into the gene, removing the entire coding sequence of DFFRY. The mouse Dffry gene maps to the Sxrb deletion interval on the short arm of the mouse Y chromosome and its expression in mouse testis can first be detected between 7.5 and 10.5 days after birth when type A and B spermatogonia and pre-leptotene and leptotene spermatocytes are present.
