HGNC Approved Gene Symbol: ZFY
Cytogenetic location: Yp11.2 Genomic coordinates (GRCh38): Y:2,935,381-2,982,506 (from NCBI)
The ZFY gene is actively transcribed in males and appears to be involved in sperm or testis maturation (summary by Dorit et al., 1996).
Page et al. (1987) identified a Y-encoded zinc finger protein, designated ZFY, which they thought might represent the testis-determining factor (TDF). They cloned a 230-kb segment of the human Y chromosome thought to contain some or all of the TDF gene. The cloned region spanned the deletion in a female who carried all but 160 kb of the Y. Homologous sequences were found within this sex-determining region of the mouse Y chromosome. The nucleotide sequence of this conserved DNA on a human Y chromosome suggested that it encodes a protein with multiple 'finger' domains, as first described in frog transcription factor IIIA. The encoded protein was thought to bind to nucleic acids in a sequence-specific manner and to regulate transcription.
Using PCR, Palmer et al. (1990) showed close similarity of ZFY and ZFX (314980). They demonstrated the expression of both genes in a wide range of adult and fetal human tissues and showed that ZFX is expressed from an inactive X chromosome present in human-mouse hybrids. Palmer et al. (1989) presented genetic evidence that ZFY is not the testis-determining factor (see SRY, 480000): they observed XX males lacking ZFY. In 4 XX males lacking ZFY, they found an exchange of Y-specific sequences next to the pseudoautosomal boundary, thereby defining the region in which TDF must lie.
Muller and Schempp (1989) assigned the ZFY gene to Yp11.32 by in situ hybridization.
Models of sex determination must accommodate the finding of a ZFY-related locus on the X chromosome. The presence of similar sequences in birds suggested a possible role not only in the XX/XY sex determination system of mammals, but also in the ZZ/ZW system of birds. Mapping studies by hybridization to DNA from somatic cell hybrids containing various fragments of the X chromosome suggested that the sequence on the X chromosome maps to region Xp22.3-p21. Page et al. (1987) advanced several hypotheses to explain the existence of the X-linked locus. One hypothesis was inconsistent with the prevailing notion of a dominantly acting sex-determining factor unique to the Y chromosome. This model suggested that the X and Y loci are functionally interchangeable, that both are testis determining, and that the X locus is subject to X-chromosome inactivation. According to this model, sex is determined by the total number of expressed X and Y loci: a single dose is female-determining, while a double (or greater) dose is male-determining. The addition of an X-derived transgene to the genome of an XX embryo should result in testis differentiation, as long as that transgene is not subject to X inactivation. Increased expression of the X-chromosomal locus could explain the presence of testicular tissue in XX hermaphrodites and the rare Y-negative XX males, who lack the TDF locus of the Y chromosome. Although some XY females lack TDF as judged by Y-DNA analysis, others do not have discernible deletions. These unexplained XY females may have point mutations in TDF or in genes that function in conjunction with or downstream of TDF. The model mentioned above suggests that mutation in the X-chromosomal locus (at Xp22.3-p21) could cause XY embryos to develop as females.
Sinclair et al. (1988) showed that in marsupials sequences homologous to ZFY (and ZFX) map not to the X and Y but to autosomes. This implies that ZFY is not the primary sex-determining gene in marsupials.
Mahaffey et al. (1997) concluded that the human ZFY gene has 2 mouse homologs, designated Zfy1 and Zfy2, which apparently arose by an intrachromosomal duplication of an ancestral gene on the Y chromosome. Zambrowicz et al. (1994) characterized the promoters of the murine Zfy1 and Zfy2 genes.
Dorit et al. (1995) found no polymorphism of the 729-bp intron located immediately upstream of the ZFY zinc finger exon in a sample of 38 individuals chosen to represent a cross-section of geographic origins. This was surprising to the authors because interspecific comparisons with other nonhuman primates revealed phylogenetically informative sequence changes. The invariance likely resulted from either a recent selective sweep, a recent origin for modern homo sapiens, recurrent male population bottlenecks, or historically small affected male population sizes. Fu and Li (1996) used what they called a more rigorous method and showed that the most recent common ancestor of present humans may have been only half as long ago as the estimate made by Dorit et al. (1995): 270,000 years, with 95% confidence limits of 0 to 800,000. Three other groups (Donnelly et al., 1996; Weiss and von Haeseler, 1996; and Rogers et al., 1996) also commented on the question of the age of the most recent common ancestor (MRCA), and Dorit et al. (1996) offered a response. They commented that, given the small number of changes taking place along the branches and nodes of this gene tree, their original data should not be used as a 'molecular clock.'
Genes located on the mammalian Y chromosome outside the pseudoautosomal region do not recombine with those on the X chromosome and are predicted to either undergo selection for male function or gradually degenerate because of an accumulation of deleterious mutations. Slattery et al. (2000) performed phylogenetic analyses of X-Y homologs Zfx and Zfy among 26 felid species, which indicated 2 ancestral episodes of directed genetic exchange (ectopic gene conversion) from X to Y: once during the evolution of the pallas cat and once in a common predecessor of ocelot lineage species. Replacement of the more rapidly evolving Y homolog with the evolutionarily constrained X copy may represent a mechanism for adaptive editing of functional genes on the nonrecombining region of the mammalian Y chromosome.
Donnelly, P., Tavare, S., Balding, D. J., Griffiths, R. C. Estimating the age of the common ancestor of men from the ZFY intron. (Letter) Science 272: 1357-1359, 1996. [PubMed: 8650551] [Full Text: https://doi.org/10.1126/science.272.5266.1357]
Dorit, R. L., Akashi, H., Gilbert, W. Absence of polymorphism at the ZFY locus on the human Y chromosome. Science 268: 1183-1185, 1995. [PubMed: 7761836] [Full Text: https://doi.org/10.1126/science.7761836]
Dorit, R. L., Akashi, H., Gilbert, W. Estimating the age of the common ancestor of men from the ZFY intron. (Letter) Science 272: 1361-1362, 1996. [PubMed: 17832185] [Full Text: https://doi.org/10.1126/science.272.5266.1361]
Fu, Y.-X., Li, W.-H. Estimating the age of the common ancestor of men from the ZFY intron. (Letter) Science 272: 1356-1357, 1996. [PubMed: 8650550] [Full Text: https://doi.org/10.1126/science.272.5266.1356]
Mahaffey, C. L., Bayleran, J. K., Yeh, G. Y., Lee, T. C., Page, D. C., Simpson, E. M. Intron/exon structure confirms that mouse Zfy1 and Zfy2 are members of the ZFY gene family. Genomics 41: 123-127, 1997. [PubMed: 9126493] [Full Text: https://doi.org/10.1006/geno.1997.4611]
Muller, G., Schempp, W. Mapping the human ZFX locus to Xp21.3 by in situ hybridization. Hum. Genet. 82: 82-84, 1989. [PubMed: 2497060] [Full Text: https://doi.org/10.1007/BF00288279]
Page, D. C., Mosher, R., Simpson, E. M., Fisher, E. M. C., Mardon, G., Pollack, J., McGillivray, B., de la Chapelle, A., Brown, L. G. The sex-determining region of the human Y chromosome encodes a finger protein. Cell 51: 1091-1104, 1987. [PubMed: 3690661] [Full Text: https://doi.org/10.1016/0092-8674(87)90595-2]
Palmer, M. S., Berta, P., Sinclair, A. H., Pym, B., Goodfellow, P. N. Comparison of human ZFY and ZFX transcripts. Proc. Nat. Acad. Sci. 87: 1681-1685, 1990. [PubMed: 2308929] [Full Text: https://doi.org/10.1073/pnas.87.5.1681]
Palmer, M. S., Sinclair, A. H., Berta, P., Ellis, N. A., Goodfellow, P. N., Abbas, N. E., Fellous, M. Genetic evidence that ZFY is not the testis-determining factor. Nature 342: 937-939, 1989. [PubMed: 2594087] [Full Text: https://doi.org/10.1038/342937a0]
Rogers, J., Samollow, P. B., Comuzzie, A. G. Estimating the age of the common ancestor of men from the ZFY intron. (Letter) Science 272: 1360-1361, 1996. [PubMed: 8650553] [Full Text: https://doi.org/10.1126/science.272.5266.1360]
Sinclair, A. H., Foster, J. W., Spencer, J. A., Page, D. C., Palmer, M., Goodfellow, P. N., Graves, J. A. M. Sequences homologous to ZFY, a candidate human sex-determining gene, are autosomal in marsupials. Nature 336: 780-783, 1988. [PubMed: 3144651] [Full Text: https://doi.org/10.1038/336780a0]
Slattery, J. P., Sanner-Wachter, L., O'Brien, S. J. Novel gene conversion between X-Y homologues located in the nonrecombining region of the Y chromosome in Felidae (mammalia). Proc. Nat. Acad. Sci. 97: 5307-5312, 2000.
Weiss, G., von Haeseler. Estimating the age of the common ancestor of men from the ZFY intron. (Letter) Science 272: 1359-1360, 1996. [PubMed: 8650552] [Full Text: https://doi.org/10.1126/science.272.5266.1359]
Zambrowicz, B. P., Findley, S. D., Simpson, E. M., Page, D. C., Palmiter, R. D. Characterization of the murine Zfy1 and Zfy2 promoters. Genomics 24: 406-408, 1994. [PubMed: 7698773] [Full Text: https://doi.org/10.1006/geno.1994.1641]