Alternative titles; symbols
HGNC Approved Gene Symbol: KDM5D
Cytogenetic location: Yq11.223 Genomic coordinates (GRCh38) : Y:19,703,865-19,744,726 (from NCBI)
Agulnik et al. (1994) described the isolation of a gene that mapped to the short arm of the mouse Y chromosome. They called the gene Smcy for 'selected mouse cDNA on Y.' It was clustered with the Ube1y (489000) and the Zfy1 genes (490000) in a segment of approximately 250 kb. A homologous gene, Smcx (JARID1C; 314690), was found on the X chromosome (Agulnik et al., 1994). Expression of Smcy was detected in all male tissues and expression of Smcx in all male and female tissues tested. Remarkably, the expression of both genes was detected in pools of mouse preimplantation embryos as early as the 2-cell stage. They found that Smcy, like Sry (480000) and Ube1y, has been conserved on the Y chromosome since the divergence of metatherian and eutherian mammals some 120 million years ago. Agulnik et al. (1994) isolated homologous genes from the human and horse and showed that they have similar exon/intron organizations and are more than 93% similar to each other and to Smcx at the amino acid level. Using a set of overlapping YAC clones provided by David Page, Agulnik et al. (1994) determined that the human SMCY gene maps to deletion interval 5O/5P on Yq between STS markers DYS214 and DYS215. The HYA locus maps to the same interval on the human Y chromosome.
Kent-First et al. (1996) reported the isolation and sequencing of the full-length cDNA (5.4 kb) of the human SMCY gene. They confirmed that SMCY encodes one human H-Y epitope, H-Y/HLA-B7. They also reported the pattern of the SMCY gene expression in early primary development, evolutionary sequence comparison, and, contrary to previous reports, evidence that proved SMCY is Y-linked across a broad range of species. Analysis of the consensus cDNA sequence revealed a single long open reading frame of 4,620 bp, starting at position 276 and ending with the TGA termination codon at position 4893, which encodes a 1,539-amino acid negatively charged polypeptide with an estimated molecular mass of 174 kD. Kent-First et al. (1996) found that SMCY is homologous to SMCX at the nucleotide and amino acid levels with 77% and 84.4% similarity, respectively. The human SMCY protein is 81.8% homologous to Rhesus monkey compared with 66.7% homology in mouse. SMCY/X appear to be 2 of the few early transcripts in embryos. Since SMCX escapes X-inactivation in mice and humans, the authors speculated that both copies of the SMC gene may be necessary for normal function.
Histocompatibility antigens determined by the Y chromosome were first found in the mouse (Eichwald and Silmser, 1955; Gasser and Silvers, 1972) and later in the rat, guinea pig, and many other species. Their existence in man was first shown by the fact that mouse antisera react with human male lymphocytes but not with female lymphocytes (Wachtel et al., 1974).
In the mouse, both the H-Y antigen (Hya) and the testis-determining (Tdy) genes map to the short arm of the Y chromosome. Because spermatogenesis is blocked in mice lacking the H-Y antigen, Burgoyne et al. (1986) suggested that the H-Y antigen gene or a gene closely linked to it plays a role in spermatogenesis. Simpson et al. (1993) found that of 9 azoospermic or severely oligospermic patients 7 could be tested for HYA expression; of these, 6 were H-Y positive. Of 3 patients showing Yq structural abnormalities, 2 could be tested for H-Y expression; 1 was negative, the other positive. These results showed no correlation between spermatogenic failure and the absence of HYA, thus separating the AZF locus (see 415000) from HYA.
In the mouse, Scott et al. (1995) found that Smcy encodes an H-Y epitope that is defined by the octamer peptide TENSGKDI; no similar peptide was found in Smcx. Since no similar peptide was found in the X-chromosomal homolog Smcx, it is presumably the genetic basis for the antigenic difference between males and females that contributes toward a tissue transplant rejection response. In the human, Wang et al. (1995) made comparable observations. As with other minor histocompatibility antigens, the recognition of H-Y by T lymphocytes is MHC-restricted, and some H-Y antigens are peptides derived from cellular proteins that are presented on the cell surface in association with MHC class I molecules. Wang et al. (1995) used a technique for identifying individual peptides that are bound to MHC molecules and recognized as antigens by T cells. One human H-Y antigen presented by HLA-B7 was identified as an 11-residue peptide derived from SMCY. The protein from the homologous gene on the X chromosome, SMCX, differed by 2 amino acid residues in the same region. They commented that the origin and function of H-Y antigens had eluded researchers for 40 years and suggested that the 77% DNA sequence identity between SMCY and SMCX may explain past failures to identify H-Y-encoding genes by subtractive hybridization. Both proteins show significant sequence homology to retinoblastoma binding protein-2 (RBBP2; 180202), which has been suggested to be a transcription factor.
Muller (1996) reviewed findings on the molecular nature of H-Y antigens.
Blanchard and Klassen (1997) observed that homosexual orientation in males (see 306995) correlated with the number of older brothers, with each additional older brother increasing the odds of homosexuality by 33%. The authors hypothesized that this fraternal birth order effect reflects progressive immunization of some mothers to the Y-linked minor histocompatibility antigen H-Y by each succeeding male fetus, and the concomitantly increasing effects of H-Y antibodies on the sexual differentiation of the brain in each succeeding male fetus.
By primary genomic sequencing, Shen et al. (2000) determined that the SMCY gene contains 27 exons comprising 4,620 bp of coding sequence.
Agulnik et al. (1997) noted that mammalian evolution is believed to be male-driven because the greater number of germ cell divisions per generation in males increases the opportunity for errors in DNA replication. Since the Y chromosome replicates exclusively in males, its genes should also evolve faster than X or autosomal genes. In addition, estimating the overall male-to-male mutation ratio is of great importance as a large ratio implies that replication-independent mutagenic events play a relatively small role in evolution. A small ratio suggests that the impact of these factors may, in fact, be significant. Agulnik et al. (1997) analyzed the rates of evolution in the homologous X-Y common SMCX/SMCY genes from 3 different species: mouse, human, and horse. The SMC genes were chosen because the X and Y copies are highly homologous, well conserved in evolution, and in all probability functionally interchangeable. Sequence comparisons and analysis of synonymous substitutions in approximately 1 kb of the 5-prime coding region of the SMC genes revealed that the Y-linked copies are evolving approximately 1.8 times faster than their X homologs. The male-to-female mutation ratio was estimated to be 3. Their data supported the hypothesis that mammalian evolution is male-driven. However, the ratio value was far smaller than suggested in earlier studies, implying significance of replication-independent mutagenic events in evolution also.
By use of denaturing HPLC, Shen et al. (2000) screened the SMCY, DBY (400010), DFFRY (USP9Y; 400005), and UTY1 (400009) genes for polymorphic markers in males representative of the 5 continents. Nucleotide diversity was found in the coding regions of 3 of the genes but was not observed in DBY. In agreement with most autosomal genes, diversity estimates for the noncoding regions were about 2- to 3-fold higher than those for coding regions. Pairwise nucleotide mismatch distributions dated the occurrence of population expansion to approximately 28,000 years ago.
Mendez et al. (2016) compared approximately 120 kb of exome-captured Y-chromosome DNA from a Neandertal male from Spain with orthologous chimpanzee and modern human sequences. They found support for a model that placed the Neandertal lineage as an outgroup to modern human Y chromosomes, including A00, the highly divergent basal haplogroup. The authors estimated that the time to the most recent common ancestor (TMRCA) of Neandertal and modern human Y chromosomes was approximately 588,000 years ago, approximately 2 times longer than the TMRCA of A00 and other extant modern human Y-chromosome lineages. The estimate suggested that the Y-chromosome divergence mirrored the population divergence of Neandertals, whose Y sequence is not found in modern humans, and modern human ancestors. Notable coding differences between Neandertal and modern human Y chromosomes included potentially damaging changes to PCDH11Y (400022), TMSB4Y (400017), USP9Y, and KDM5D. Three of these changes occurred in genes that produce male-specific minor histocompatibility (H-Y) antigens that may elicit a maternal immune response during gestation. The authors hypothesized that the incompatibilities at 1 or more of these genes may have played a role in the reproductive isolation of the 2 groups.
The possibility that the locus that determines heterogametic sex determination and that for the H-Y antigen were the same was suggested by Wachtel et al. (1975). The identity of the H-Y antigen and testis-determining factor was also suggested by Iwata et al. (1979), Nagai et al. (1979) and Ohno et al. (1979). However, subsequent evidence ruled out this possibility. From the study of XX males and XY females, it can be concluded that the H-Y determinant on the Y and TDF (testis-determining factor; 480000) are separate entities and not closely situated (Simpson, 1986; Simpson et al., 1987).
Wolf (1978) had proposed that the structural gene for the H-Y antigen was located on an autosome and that its expression was regulated by an X-linked repressor gene and a Y-linked inducer gene. The regulatory (suppressing) gene was thought to be located on the short arm of the X, and the Y chromosome was thought to play an antagonizing role, suppressing the X-linked suppressor or compensating for its effects (Wiberg et al., 1982).
Shapiro and Erickson (1981) presented evidence that the serologic determinant of H-Y antigen is carbohydrate.
Agulnik, A. I., Bishop, C. E., Lerner, J. L., Agulnik, S. I., Solovyev, V. V. Analysis of mutation rates in the SMCY/SMCX genes shows that mammalian evolution is male driven. Mammalian Genome 8: 134-138, 1997. [PubMed: 9060413] [Full Text: https://doi.org/10.1007/s003359900372]
Agulnik, A. I., Mitchell, M. J., Lerner, J. L., Woods, D. R., Bishop, C. E. A mouse Y chromosome gene encoded by a region essential for spermatogenesis and expression of male-specific minor histocompatibility antigens. Hum. Molec. Genet. 3: 873-878, 1994. [PubMed: 7524912] [Full Text: https://doi.org/10.1093/hmg/3.6.873]
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