Alternative titles; symbols
HGNC Approved Gene Symbol: DAZ1
Cytogenetic location: Yq11.223 Genomic coordinates (GRCh38) : Y:23,129,355-23,199,094 (from NCBI)
The DAZ gene encodes an RNA-binding protein with a role in spermatogenesis (summary by Tsui et al., 2000).
Reijo et al. (1995) found that Y-chromosome deletions in 12 men with azoospermia overlapped, thus defining the locations of gene(s) required for spermatogenesis in the azoospermia factor (AZF) region (see 415000). The region contained a single-copy gene, referred to as DAZ (for 'deleted in azoospermia'), which is transcribed in the adult testis and appears to encode an RNA-binding protein. Reijo et al. (1995) found that DAZ was the only transcription factor consistently deleted in azoospermic males with de novo deletions in the euchromatic portion of Yq. The 12 men with deletions came from a series of 89 men with Sertoli cell-only syndrome or testicular maturation arrest. Some of the nondeletion cases, all of which retained the AZF region, may be found to harbor de novo mutations in DAZ.
Cooke et al. (1996) postulated that the DAZ gene product may play a role in the germ cell-specific patterns of RNA splicing and storage. The authors isolated the mouse homolog of DAZ. Cooke et al. (1996) reported that the predicted protein product of the mouse homolog is highly homologous to that of the human gene. By RT-PCR analysis, they established that transcripts occur only in mouse germ cells.
The mouse homolog of the human Y-linked DAZ gene maps to chromosome 17. Reijo et al. (1996) found that nonetheless, the predicted amino acid sequences of the mouse and human gene products are quite similar, especially in their putative RNA-binding domains, and both genes are transcribed predominantly in testes; the mouse gene is transcribed at a lower level in ovaries. Dazh transcripts were not detected in testes of mice that lacked germ cells. In testes of wildtype mice Reijo et al. (1996) detected Dazh transcription 1 day after birth (when the only germ cells are prospermatogonia). Transcription increased steadily as spermatogonial stem cells appeared, plateaued as the first wave of spermatogenic cells entered meiosis (10 days after birth), and remained at this level thereafter. This unique pattern of expression suggested to the investigators that Dazh participates in differentiation, proliferation, or maintenance of germ cell founder populations before, during, and after the pubertal onset of spermatogenesis. Such functions could readily account for the diverse spermatogenic defects observed in human males with AZF deletions.
Menke et al. (1997) reported that, on in situ hybridization of DAZ transcripts to sections of normal testes, spermatogonia were the source of the most intense signal. Their studies could not rule out the possibility that a portion of the observed signal originated from the autosomal homolog of DAZH.
Tsui et al. (2000) identified 2 proteins, DAZAP1 (607430) and DAZAP2 (607431), that bind to DAZ and DAZL (601486) mainly through the DAZ repeat region.
Kee et al. (2009) used a germ cell reporter to quantify and isolate primordial germ cells derived from both male and female human embryonic stem cells. By silencing and overexpressing genes that encode germ cell-specific cytoplasmic RNA-binding proteins (not transcription factors), Kee et al. (2009) modulated human germ cell formation and developmental progression and observed that human DAZL functions in primordial germ cell formation, whereas closely related genes DAZ and BOULE (606165) promote later stages of meiosis and development of haploid gametes.
By fluorescence in situ hybridization and characterization of BAC clones, Saxena et al. (2000) identified 4 DAZ genes in 2 clusters, each comprising an inverted pair, in the AZF region of the Y chromosome. Each of the 4 genes contains at least 7 tandem copies of a 2.4-kb repeat unit that encodes 24 amino acids, previously identified by Saxena et al. (1996). DAZ1 is paired with DAZ2 (400026), and DAZ3 (400027) is paired with DAZ4 (400048). Saxena et al. (2000) found that at least 3 of the genes, DAZ1, DAZ2, and DAZ3, are functional. They could not exclude the possibility that the DAZ4 cDNA, which encodes a predicted 579-amino acid protein with a molecular mass of 65 kD, derives from DAZ1. The approximate size of the DAZ1 gene is 65 kb and that of DAZ4, 55 kb.
See Anonymous (1995) for a diagram (provided by R. Reijo) of the Y chromosome showing the locations of genes in the pseudoautosomal and the euchromatic regions.
Cooke et al. (1996) mapped the mouse homolog of DAZ to chromosome 17 at position 25.6 cM by fluorescence in situ hybridization.
Reijo et al. (1996) mapped Dazh, the mouse homolog of DAZ, to chromosome 17 by fluorescence in situ hybridization.
Najmabadi et al. (1996) used a sequence tagged site (STS) mapping strategy to examine genomic DNA from 60 infertile men who had idiopathic azoospermia or severe oligospermia. Of the 60 subject DNAs studied with 26 STSs, 11 (18%; 10 azoospermic and 1 oligospermic) did not amplify with 1 or more STSs. Notably, 4 of 11 subjects had microdeletions outside the Yq region from which the DAZ gene was cloned.
Stuppia et al. (1996) reported molecular analysis in an oligozoospermic male and his father who presented with a morphologically identical deletion of Y:del(Y)(q11). The father had no history of subfertility. Molecular analysis revealed that the deletion in the son was larger than that present in the father. The STSs Y243 and Y269, located in zone E of interval 6 of the Y chromosome, were deleted only in the proband. Both the proband and his father retained RBM1 (400006), sY254, and Y255, which map within the DAZ region in zone D of interval 6. Stuppia et al. (1996) concluded that in oligospermic patients, genes in a region distal to DAZ and RBM1 may be involved in the spermatogenetic process. They also concluded that certain deletions may not necessarily lead to infertility but may make the Y chromosome more susceptible to a second mutation.
Moro et al. (2000) reported a partial deletion of the DAZ cluster removing all but 1 of the copies. This deletion was found in a patient affected with severe oligozoospermia who had a testicular phenotype characterized by a great quantitative reduction of germ cells (severe hypospermatogenesis). The absence of this deletion in the fertile brother of the patient suggested that this de novo mutation indeed caused the spermatogenic failure.
To clarify whether cryptorchidism might be the expression of an intrinsic congenital testicular abnormality, Foresta et al. (1999) investigated the frequency of Y chromosome long arm (Yq) microdeletions in unilateral excryptorchid subjects manifesting an important bilateral testiculopathy. Eleven of 40 (27.5%) unilateral excryptorchid patients affected by bilateral testiculopathy and 28 of 110 (25.4%) patients affected by idiopathic severe primary testiculopathy showed Yq microdeletions, whereas no microdeletions were found in all the other subjects, nor in male relatives of patients with deletions. Microdeletions were located in different parts of Yq, including known regions involved in spermatogenesis (DAZ and RBM, AZFa, b, and c) and other loci. No difference in localization of deletions was evident between cryptorchid and idiopathic patients.
Repping et al. (2004) identified the b2/b3 deletion within the AZFc region of the Y chromosome, in which 2 of the 4 copies of the DAZ gene are deleted. The b2/b3 deletion has no obvious effect on fitness.
Foresta et al. (2005) hypothesized that infertile men may be more likely than fertile men to have genetic abnormalities. They studied 750 severely oligozoospermic men who were candidates for intracytoplasmic sperm injection and 303 fertile men. Chromosomal aberrations were present in 5.6% of infertile men and 0.3% of controls, and they were in most cases alterations of the sex chromosomes. Y chromosome long-arm microdeletions were detected in 6.0% of infertile men and most frequently included the AZFc region, whereas no cases were found in controls.
Saxena et al. (1996) reported multiple copies of DAZ (more than 99% identical in DNA sequence) clustered in the AZF region, and a functional DAZ homolog, which they designated DAZH (601486), on human chromosome 3. The entire gene family appeared to be expressed in germ cells. Sequence analysis indicated that the Y-chromosome DAZ cluster arose during primate evolution by (1) transposition of the autosomal gene to the Y; (2) amplification and pruning of exons within the transposed gene; and (3) amplification of the modified gene. The authors stated that these results challenged prevailing views of sex chromosome evolution, suggesting that acquisition of autosomal fertility genes was an important process in Y chromosome evolution.
The recent transposition to the Y chromosome of the autosomal DAZLA gene (DAZL; 601486), potentially involved in germ cell development, created a unique opportunity to study the rate of Y chromosome evolution and assess the selective forces that may act upon such genes, and provided a new estimate of the male-to-male mutation rate. Agulnik et al. (1998) observed 2 different Y-located DAZ sequences in all Old World monkeys, apes, and humans. Different DAZ copies originate from independent amplification events in each primate lineage. Comparison of autosomal DAZLA and Y-linked DAZ intron sequences gave a new figure for male-to-female mutation rates of alpha(m) = 4. It was found that human DAZ exons and introns are evolving at the same rate, implying neutral genetic drift and the absence of any functional selective pressures. Agulnik et al. (1998) therefore hypothesized that Y-linked DAZ plays little, or a limited, role in human spermatogenesis. The 2 copies of DAZ in man appear to be due to a relatively recent duplication event (55,000 to 200,000 years ago). A worldwide survey of 67 men from 5 continents representing 19 distinct populations showed that most males had both DAZ variants. This implies a common origin for the Y chromosome consistent with a recent 'out of Africa' origin of the human race.
Makova and Li (2002) reported a study suggesting that mutations occur in men at a rate 5 times that in women, lending support to the idea of 'male-driven evolution.' The male bias in mutation rate had been indicated by many studies such as those comparing the substitution rate in homologous (gametologous) genes shared between X and Y and by comparison of substitution rates in a region recently transposed from the X chromosome to the Y chromosome. Makova and Li (2002) argued that the bias toward higher male mutation rate in such studies might be flawed owing to the effect of the possibility that a segment transposed to the Y chromosome might already contain polymorphic sites that distinguish it from other X-chromosome sequences. This could imply that some of the mutations interpreted as being of Y-chromosome origin could actually have arisen on the X chromosome, and were polymorphic before the transposition. The effect would be to underestimate the male excess. Makova and Li (2002) chose to study the DAZ locus, which was transposed from chromosome 3 to the Y chromosome after the split between New World and Old World monkeys. They arrived at an estimate of 5.2 for the male:female ratio, with a large 95% confidence interval (2.44 to infinity). This value was comparable to that obtained in previous comparisons of homologous X-Y genes by Shimmin et al. (1993).
Agulnik, A. I., Zharkikh, A., Boettger-Tong, H., Bourgeron, T., McElreavey, K., Bishop, C. E. Evolution of the DAZ gene family suggests that Y-linked DAZ plays little, or a limited, role in spermatogenesis but underlines a recent African origin for human populations. Hum. Molec. Genet. 7: 1371-1377, 1998. [PubMed: 9700189] [Full Text: https://doi.org/10.1093/hmg/7.9.1371]
Anonymous. A missing piece on the Y. (Editorial) Nature Genet. 10: 367-368, 1995. [PubMed: 7670479] [Full Text: https://doi.org/10.1038/ng0895-367]
Cooke, H. J., Lee, M., Kerr, S., Ruggiu, M. A murine homologue of the human DAZ gene is autosomal and expressed only in male and female gonads. Hum. Molec. Genet. 5: 513-516, 1996. [PubMed: 8845845] [Full Text: https://doi.org/10.1093/hmg/5.4.513]
Foresta, C., Garolla, A., Bartoloni, L., Bettella, A., Ferlin, A. Genetic abnormalities among severely oligospermic men who are candidates for intracytoplasmic sperm injection. J. Clin. Endocr. Metab. 90: 152-156, 2005. [PubMed: 15509635] [Full Text: https://doi.org/10.1210/jc.2004-1469]
Foresta, C., Moro, E., Garolla, A., Onisto, M., Ferlin, A. Y chromosome microdeletions in cryptorchidism and idiopathic infertility. J. Clin. Endocr. Metab. 84: 3660-3665, 1999. [PubMed: 10523011] [Full Text: https://doi.org/10.1210/jcem.84.10.6077]
Kee, K., Angeles, V. T., Flores, M., Nguyen, H. N., Reijo Pera, R. A. Human DAZL, DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation. Nature 462: 222-225, 2009. [PubMed: 19865085] [Full Text: https://doi.org/10.1038/nature08562]
Makova, K. D., Li, W.-H. Strong male-driven evolution of DNA sequences in humans and apes. Nature 416: 624-626, 2002. [PubMed: 11948348] [Full Text: https://doi.org/10.1038/416624a]
Menke, D. B., Mutter, G. L., Page, D. C. Expression of DAZ, an azoospermia factor candidate, in human spermatogonia. (Letter) Am. J. Hum. Genet. 60: 237-241, 1997. [PubMed: 8981970]
Moro, E., Ferlin, A., Yen, P. H., Franchi, P. G., Palka, G., Foresta, C. Male infertility caused by a de novo partial deletion of the DAZ cluster on the Y chromosome. J. Clin. Endocr. Metab. 85: 4069-4073, 2000. [PubMed: 11095434] [Full Text: https://doi.org/10.1210/jcem.85.11.6929]
Najmabadi, H., Huang, V., Yen, P., Subbarao, M. N., Bhasin, D, Banaag, L., Naseeruddin, S., de Kretser, D. M., Baker, H. W. G., McLachlan, R. I., Loveland, K. A., Bhasin, S. Substantial prevalence of microdeletions of the Y-chromosome in infertile men with idiopathic azoospermia and oligozoospermia detected using a sequence-tagged site-based mapping strategy. J. Clin. Endocr. Metab. 81: 1347-1352, 1996. [PubMed: 8636331] [Full Text: https://doi.org/10.1210/jcem.81.4.8636331]
Reijo, R., Lee, T.-Y., Salo, P., Alagappan, R., Brown, L. G., Rosenberg, M., Rozen, S., Jaffe, T., Straus, D., Hovatta, O., de la Chapelle, A., Silber, S., Page, D. C. Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nature Genet. 10: 383-393, 1995. [PubMed: 7670487] [Full Text: https://doi.org/10.1038/ng0895-383]
Reijo, R., Seligman, J., Dinulos, M. B., Jaffe, T., Brown, L. G., Disteche, C. M., Page, D. C. Mouse autosomal homolog of DAZ, a candidate male sterility gene in humans, is expressed in male germ cells before and after puberty. Genomics 35: 346-352, 1996. [PubMed: 8661148] [Full Text: https://doi.org/10.1006/geno.1996.0366]
Repping, S., van Daalen, S. K. M., Korver, C. M., Brown, L. G., Marszalek, J. D., Gianotten, J., Oates, R. D., Silber, S., van der Veen, F., Page, D. C., Rozen, S. A family of human Y chromosomes has dispersed throughout northern Eurasia despite a 1.8-Mb deletion in the azoospermia factor c region. Genomics 83: 1046-1052, 2004. [PubMed: 15177557] [Full Text: https://doi.org/10.1016/j.ygeno.2003.12.018]
Saxena, R., Brown, L. G., Hawkins, T., Alagappan, R. K., Skaletsky, H., Reeve, M. P., Reijo, R., Rozen, S., Dinulos, M. B., Disteche, C. M., Page, D. C. The DAZ gene cluster on the human Y chromosome arose from an autosomal gene that was transposed, repeatedly amplified and pruned. Nature Genet. 14: 292-299, 1996. [PubMed: 8896558] [Full Text: https://doi.org/10.1038/ng1196-292]
Saxena, R., de Vries, J. W. A., Repping, S., Alagappan, R. K., Skaletsky, H., Brown, L. G., Ma, P., Chen, E., Hoovers, J. M. N., Page, D. C. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome. Genomics 67: 256-267, 2000. [PubMed: 10936047] [Full Text: https://doi.org/10.1006/geno.2000.6260]
Shimmin, L. C., Chang, B. H.-J., Li, W.-H. Male-driven evolution of DNA sequences. Nature 362: 745-747, 1993. [PubMed: 8469284] [Full Text: https://doi.org/10.1038/362745a0]
Stuppia, L., Calabrese, G., Franchi, P. G., Mingarelli, R., Gatta, V., Palka, G., Dallapiccola, B. Widening of a Y-chromosome interval-6 deletion transmitted from a father to his infertile son accounts for an oligozoospermia critical region distal to the RBM1 and DAZ genes. (Letter) Am. J. Hum. Genet. 59: 1393-1395, 1996. [PubMed: 8940286]
Tsui, S., Dai, T., Roettger, S., Schempp, W., Salido, E. C., Yen, P. H. Identification of two novel proteins that interact with germ-cell-specific RNA-binding proteins DAZ and DAZL1. Genomics 65: 266-273, 2000. [PubMed: 10857750] [Full Text: https://doi.org/10.1006/geno.2000.6169]