Mammalian Genome 3: $289-$293, 1992
eHollle 9 Springer-VerlagNew York Inc. 1992
Mouse Y Chromosome Colin E. Bishop Department of Obstetrics and Gynecology, University of Tennessee, Division of Reproductive Genetics, 711 Jefferson Avenue, Memphis, Tennessee 38105, U S A Received February 17, 1992
Introduction
Molecular characteristics
The Y Chromosome (Chr) is the most specialized of mouse chromosomes, being involved almost exclusively in controlling primary sex determination, spermatogenesis, and fertility. Unlike autosomes, which can pair and recombine along their entire length during meiosis, X-Y recombination is restricted to the tiny pairing/exchange or pseudoautosomal region located at the Yq telomere. This makes normal meiotic mapping impossible outside this region. The localization of genes/functions/DNA probes (with the exception of pseudoautosomally located Sts and movl5) is due to a combination of direct in situ hybridization to metaphase spreads and/or the use of rearranged Y Chrs--in particular the sex-reversed mouse mutanl Sxr (see below). This first Y Chr committee report will concentrate on a description of functional genes mapped to the Y, establishment of a preliminary deletion map, and the placement of these genes on it. A description of the many anonymous DNA fragments and viral integration sites can be found in the appropriate references, and a full list can be found in the mouse database or Eppig (1991). It is hoped that probes will all be assigned DY numbers and map posilions by the next report.
At the molecular level the majority of the Y Chr consists of highly repeated DNA sequences of no obvious function. These include Murvy (murine repeated virus-Y linked; Eicher and Washburn 1986; Eicher et al. 1989) and a large number of random repeated DNA probes isolated by several laboratories (Lamar and Palmer 1984; Bishop et al. 1985; Baron et al. 1986; Nallaseth and Dewey 1986; Nishioka and Lamoth 1986; Harbers et al. 1986; Bishop et al. 1987; Avner et al. 1987; Garchon et al. 1989; Nishioka 1989; Tucker et al. 1989). The pericentric region of the Y is characterized by a high concentration of simple repeat sequences ([GATA]n/[GACA]n) originally isolated from the banded krait minor satellite DNA fraction (Bkm; Jones and Singh 1981; Singh and Jones 1982; Schafer et at. 1986; Epplen et at. 1988). To date no random DNA probes have been directly isolated from the pseudoautosomal region. Isolation of DNA flanking an experimentally induced fortuitous integration of Mov15 (Moloney leukemia virus-15) in this region has produced only highly repeated sequences (Harbers et al. 1986). Several other loci can be defined on the Y by sites of viral integration: endogenous xenotropic murine leukemia viruses, Xmv-7,40,11 (Frankel et al. 1989a) and X m m v - Y (Blattet at. 1983); polytropic mu-
Table
1. Locus Li*tfor mouse Chr Y.
New Locus
Ge~e name Yqinked zinc finger protein- 1 Y-linked zinc finger protein-2 Y-linked Hi~ompatibility antigen Sdma Yoliakedserologically defined male antigen Spy Y-linked Spermatogenesis U~ly Y-linked Ubiquitin activating enzyme El homolog (fo~,nerlyShy o~A ls9Y- 1) sty Y-lir,ked S~x d~enninmg r~ Y-linked primary testis determining Ss~y Y-linltedspermiogenesis specific transcript (fo~erly pYMT2/B) Stsy Y-linked Steroid sulfatase Zfy-I Zfy-2 Hya
* *
*
Map position S:~r/Yp Sxr/Yp Sxr/Yp Sxr/Yp Sxr/Yp Sxr/Yp
Deletion interval 3/2 (or 1/2)junction 1/2 (or 3t2) junction
T D,B D,B
Method I,D,P I,D,P
2 2
B B
D D
ZFy ZFy HYA gDMA (?)
2 2
B D
D D,P
NONE NONE
S~r/Yp Sxr/Yp Yq
3 1 or 3 4,5,6
D,V,B D,P
Yq (Psendoautosomal)7
It. symbol
H. location Ypll.2-pter Ypll.2-pter Yq Yq(?)
Reference 55,42 55,42 44,56 23 9 47,33
B
D
gRY TDy
D
D
NONE
YpI 1.2-pter 24,3~ Ypl 1.2-pter 24,36 5
B
L
STs-Y
Yq
34,35A9
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C.E. Bishop: Mouse Y Chr
fine virus, Pmv-34 (Frankel et al. 1989b); mammary tumor virus Mtv-31 and Moloney leukemia virus Mov24 (Soriano et al. 1987). The precise localization of most of these loci is not known except that they all lie on the Y outside the pseudoautosomal region.
Genes mapped to the Y Chr
At present almost all the genetic functions of the Y (listed in Table 1) have been mapped to its minute short arm (Fig. 1) by use of the sex-reversed mouse. These include Hya, the structural or controlling gene for expression of the male specific minor histocompatibility antigen H-Y as defined by killer or proliferative T helper cells (Roberts et al. 1988; McLaren et al. 1988); Sdma, a gene controlling the expression of the serologically defined male antigen SDMA (which may or may not be identical to H-Y; Goldberg et al. 1991); Spy, a gene controlling spermatogonial proliferation and/or survival (Burgoyne et al. 1986); Zfy-I and Zfy2, genes encoding DNA-binding proteins/transcription factors of the zinc finger type (Page et al. 1987; Mardon et al. 1989); Ubely, a Y-linked homolog of the X-linked, ubiquitin-activating enzyme E1 (Mitchell et al. 1991; Kay et al. 1991), which has been proposed as a good candidate for Spy; and Sry, which is almost certainly identical to Tdy (Gubbay et al. 1990; Koopman et al. 1991). It has been shown that a 14-kb DNA fragment containing Sry can induce male development in XX + Sry transgenic mice (Koopman et al. 1991). It thus seems proven that Sry is the long-sought-after, primary testis-determining gene Tdy. Zfy-1/2 have a closely related X-linked homolog Zfx in the mouse and a pseudogene Zfa on Chr 10 (Mitchell et al. 1989; Mardon et al. 1989). A single X and Y homolog exists in the human (ZFX and ZFY). Using repeated probe pY353, Bishop and Hatat (1987) detected a testis-specific transcript. The corresponding cDNA (pYMT2) was sequenced and shown to contain an open reading frame of 696 bp, which is expressed only in round spermatids and from multiple loci (Burgoyne, personal communication; Bishop, un-
YP i ~
r!
Yq
A B c
D E Fig. 1. The mouse Y is the smallest mouse chromosome (approximately 50-60 Mb), representing some 2% of the haploid genome. It is composed of a minute short arm (Yp), a centromeric region, a long arm (Yq), and a small X-Y homologous pairing/recombination or pseudoautosomal region, located at the Yq telomere. The Y can be distinguished from other mouse chromosomes by its characteristic G banding pattern, which produces five resolvable bands on Yq (A-E) and by the presence of the short arm visible only in good preparations.
published results). Although no function can as yet be attributed to this transcript, it has been given a preliminary gene symbol Ssty (Spermiogenesis specific transcript from the Y). The only gene to be definitively mapped to the pseudoautosomal region is steroid sulfatase (Sts), which carries active copies on the X and Y Chrs (Keitges et al. 1985). The observed Sts recombination frequency with respect to sex (Tdy) is 50%, and thus it must map very close to the Yq telomere. Using Sxr to mark the telomere, Nagamine and colleagues (1987a) obtained a recombination frequency of 1%, wheras Keitges and co-workers (1987) reported a 9.8% recombination frequency in a nearly identical cross. Further, a double recombinant between Tdy, Sts, and Sxr was reported. Sts is located distally to the Mov-15 integration site in the pseudoautosomal region, and double recombinants between Tdy, Mov-15, and Sts have been described (Soriano et al. 1987). This contrasts with the situation in the human, where double crossover events have not been found in the pseudoautosomal region.
Y Chr rearrangements
Sex reversed The most useful rearrangement for mapping is the sexreversed mutation Sxr, first described by Cattanach and colleagues (1971). Sxr, or [Tp(Y)ICt] as it is more properly termed, is a small fragment of the Y Chr short arm, transposed distal to the pairing/recombination region of the Y in XYSxr mutant mice (Singh and Jones 1982; Roberts et al. 1988; McLaren et al. 1988). As Sxr is distal to the X-Y recombination region in these carrier males, four types of sperm are produced in equal proportions during male meiosis: X and YSxr sperm derived from the unrecombined chromatids, and XSxr and Y sperm derived from the recombinant chromarids. Thus four types of offspring are produced, mimicking an autosomal inheritance pattern: XX fertile females, XXSxr sterile males, XY fertile males, and XYSxr fertile carrier males. Viable XSxrO male mice can be produced by mating XO females with XYSxr carrier males. These XSxrO males have Sxr attached distally to their single paternal X chromosome. By comparing XSxrO males with normal XY males, one can determine which Y-linked functions are provided by Sxr and which are not. As both XXSxr and XSxrO mice are male and express the minor transplantation antigen H-Y (McLaren et al. 1984; Simpson et al. 1984), the Sxr region must carry the primary testisdetermining gene Tdy and the structural/controlling gene for H-Y antigen expression, Hya. It has been shown that XO germ cells in XO/XY mosaics never progress beyond meiotic prophase owing to the lack of a Y Chr-located spermatogenesis gene termed Spy (Levy and Burgoyne 1986). Since XSxrO germ cells are not subject to this block (Cattanach et al. 1971), the Sxr region must also encode Spy.
C.E. Bishop: Mouse Y Chr
In 1984 McLaren and co-workers described a deletion variant of Sxr termed Sxr' (now referred to as Sxr b and the original Sxr as Sxra). Sex-reversed mice carrying Sxr b were male but were found to be H-Y negative (McLaren et al. 1984; Simpson et al. 1986), and an analysis of the germ cells in XSxrbO testis showed them to be blocked prior to the first meiotic metaphase (Burgoyne et al. 1986; Sutcliffe and Burgoyne 1989). This further localized Hya and Spy to the Sxr a DNA deleted in Sxr b. It has recently been shown that Sxr a mice are SDMA positive and Sxr b mice SDMA negative, thus placing Sdma in the deletion (Goldberg et al. 1991). Recent evidence has shown that the S x r b deletion breakpoints lie within the Zfy-1/Zfy-2 genes (Simpson and Page 1991). Thus in Sxr ~ a fusion gene comprising the promoter region of Zfy-2 linked in frame to the coding region of Zfy-1 has been produced with the deletion of the intervening DNA. This now allows the gene order Zfy-2, [Hya, Sdma, Spy], Ubety, Zfy-1 to be determined, although orientation with respect to the centromere is unknown. It can be shown from physical mapping that the deletion is greater than 900 kb and Ubely is located 30 kb 5' of Zfy- ! (Mitchell and Bishop 1992; Bishop et al. unpublished). With a synthetic oligonucleotide telomere probe, restriction fragment length polymorphisms (RFLPs) identifing the telomeric region of Yp and Yq have been reported (Elliott and Yen 1991). Unusual pairing and recombination have been reported involving the YSxr ~ Chr (Chandley and Speed 1987; Roberts et al. 1988; McLaren et al. 1988). A low frequency of back-pairing and recombination can occur between Yp and Sxr ~, resulting in the transfer of Yp material to Sxr ~. When Sxr a is carried on the X Chr, X-Y pairing and exchange can occur between Sxr ~ and Yp in addition to normal pseudoautosomal exchange (Cattanach 1991). It should be noted that XSxr"O males are sterile, producing abnormal germ cells, especially with regard to sperm head morphology. Eicher and Washburn (1986) have, therefore, suggested that there is a sperm morphogenesis gene located outside the Sxr a region on the long arm of the Y. In this respect the testis-specific transcript detected by repeated Y probe pY353 is a good candidate for this proposed gene (P.S. Burgoyne, personal communication). Y* Chr
This is a complex Y Chr rearrangement first reported by Eicher and co-workers (1986). Recombination between Y* and the X produces two recombinant products: X Y* and a Y*• X Y* consists of almost the entire Y attached to the X Chr, wheras y . X consists of most of the pseudoautosomal region attached to a non-Y centromere and lacks any Y-specific DNA (Eicher et al. 1991; Hale et al. 1991). Two large, visible interstitial deletions of Yq
These have been described, one derived from the B10.BR strain (Styrna et al. 1991), the other from RIII,
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which has now been transferred to the B10 background B10SmY (small Y; P.S. Burgoyne, personal communication). Both strains show an increased frequency of abnormal sperm heads, supporting the view that gene(s) necessary for the proper development of the sperm head are located there. About half of the repeated sequences defined by pY353 are deleted in the StaY Chr.
Deletion map of the mouse Y Chr
A preliminary deletion map comprising seven intervals can now be constructed for the mouse Y Chr with these rearranged Y Chrs and is shown in Fig. 2.
Other traits assigned to the Y
It has been shown that the Y carries gene(s) influencing a variety of sperm head abnormalities (KryzaYpTel
Zfy-2
YpTel---I~
Sdma Hya Spy Ubely Zfy-1
Sx rb - 4 ~ Sxrb
>900kb [30kb
Sty [Tdy]
B10SmY---~'-
i=iliSperm head
B10SmY--ID,-
ov-15
[ ~ 1
Sts
u
Fig. 2. Interval 1, containing the Yp telomere, can be defined by the telomeric RFLP described by Elliot and co-workers (1991); interval 2 is comprised of the Sxr ~ DNA deleted from Sxr b, the breakpoints lying within the Zfy genes, as described by Simpson and colleagues (1991). Interval 3 would comprise the rest of the nondeleted Sxr ~ Yp DNA. On Yq, interval 5 is defined by the Y DNA deleted from the Stay Chr, and interval 4 as the DNA lying between it and the Sxr ~ break. Interval 6 is the region lying between the distal break in interval 5. The pseudoautosomal region is interval 7 and contains Mov-15, Sts and the Yq telomere RFLPs. Tdy (Sry) can be placed in interval 1 or 3, and the orientation of interval 2 is not known. Boundaries between the intervals are indicated by arrows. Physical distances are based on cosmid/phage and YAC contigs (Mitchell and Bishop 1992; C.E. Bishop et al., unpublished observations).
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nowska 1969, 1976, 1986; Eicher et al. 1982): testis weight (Hayward and Shire 1974; Herrick and Wolfe 1977); a gene(s) (provisionally termed Yaa) involved in the acceleration of a lupus-like autoimmune syndrome in recombinant inbred BXSB mice and their Fl hybrids with NZB or NZW strains (Hudgins et al. I985; Izui et al. 1988); Y-controlled chemosensory cues similar to those mapped to the major histocompatibility complex (MHC) playing a role in individual recognition, mate selection, and aggressive interactions (Yamazaki et al. 1990; Maxon 1990); gene(s) influencing pubertal (but not adult) testosterone levels (Jutley and Stewart 1986); and glucose intolerance (Leiter 1988). M.m. domesticus/musculus polymorphisms
With RFLPs it has been shown that the Y Chr in the majority of inbred laboratory strains is of M.m. musculus origin, not M.m. domesticus, as indicated by mitochondrial and protein polymorphisms (Bishop et al. 1985). Data are consistent when repeated or singlecopy probes are used (Nishioka 1987; Mardon et al. 1989). It is most probable that the Y has been introduced by interbreeding with the very closely related Asiatic subspecies M . m . molossinus (Bonhomme 1986; Boursot et al. 1989). Common strains carrying a domesticus type Y include: AKR/J, BFM/2, BUB/ BnJ, FUB/N, IS/CamEl, Ma/MyJ, NCS, PL/J, RF/J, SJL/J, St/bJ, SWR/J, and SWV; those carrying a musculus type Y include: 129/J, A/J, AEJ/GnLe, BALB/c, BDP/J, CBA/FaCam, CE/J, C3H/HeJ, C3H/An, C57BL/6J, DA/HuSn, DBA/I, DBA/2J, I/LnJ, NZB/ Scr, NZB/BINJ, NZW/LacJ,P/J, RIIIS/J, SB/Le, SEA/GnJ, SECflReJ, SF/CamEi, SM/J, WB/ReJ, and YBR/Ei. The introduction of certain domesticus type Y Chrs into the C57BL/6 genome can lead to sex reversal, generating XY females and hermaphrodites (Eicher et al. 1982; Eicher and Washburn 1986; Nagamine et al. 1987b). Y-linked RFLP's have been found Within M.m. domesticus strains, which may correlate with the degree of sex reversal they induce (Bishop et al. 1987; Biddle et al. 1991).
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56.
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63. 64.
65. 66.
Smith, M.A., and Bishop, C.E. Localization of murine X and autosomal sequences homologous to the Y located zinc finger domain. Genetics 121: 803-809, 1989. Mitchell, M.J., Woods, D.R., Tucker, P.K., Opp, J.S., and Bishop, C.E.: Homology of a candidate spermatogenesis gene from the mouse Y chromosome to the ubiquitin-activating enzyme El. Nature 354: 483--486, 1991. Mitchell, M.J. and Bishop, C.E.: A structural analysis of the Sxr region of the mouse Y chromosome. Genomics 12: 26-34, 1992. Nagamine, C.M., Michot, J.L., Roberts, C., Gurnet, J.-L., and Bishop, C.E.: Linkage of the murine steroid sulphatase locus, Sts to sex reversed, Sxr: a genetic and molecular analysis. Nucleic Acids Res 15: 9227-9238, 1987a. Nagamine, C.M., Taketo, T., and Koo, G.C.: Studies on the genetics of tda-1 XY sex reversal in the mouse. Differentiation 33: 223-230, 1987b. Nallaseth, F.S. and Dewey, M.J.: Moderately repeated mouse Y chromosomal sequence families present distinct types of organization and evolutionary change. Nucleic Acids Res 14: 5295-5307, 1986. Nishioka, Y.: Y chromosomal DNA polymorphism in mouse inbred strains. Genet Res 50: 69-72, 1987. Nishioka, Y.: Genome comparison in the genus Mus: a study with B1, MIF (mouse interspersed fragment), centromeric and Y chromosomal repetitive sequences. Cytogenet Cell Genet 50: 195-200, 1989. Nishioka, Y. and Lamothe, E.: Isolation and characterization of a mouse Y chromosomal repetitive sequence. Genetics 113: 417--432, 1986. Page, D.C., Mosher, R., Simpson, E.M., Fisher, E.M., Mardon, G., Pollack, J., McGillivray, B., de la Chapelle, A., and Brown, L.: The sex determining region of the human Y chromosome encodes a finger protein. Cell 51: 1091-1094, 1987. Roberts, C., Weith, A., Passage, E., Michot, J.L., Mattei, M.G., and Bishop, C.E.: Molecular and cytogenetic evidence for the location of Tdy and Hya on the mouse Y chromosome short arm. Proc Natl Acad Sci USA 85: 6446--6449, 1988. Schafer, R., All, S., and Epplen, J.T.: The organization of the evolutionarily conserved GATA/GACA repeats in the mouse genome. Chromosoma 93(6): 502-510, 1986. Simpson, E., Chandler, P., Hunt, R., Hogg, H., Tomonari, K., and McLaren, A.: H-Y status of X/XXSxr' male mice: in vivo tests. Immunology 57: 345-348, 1986. Simpson, E., McLaren, A., Chandler, P., and Tomonari, K.: Expression of H-Y antigen by female mice carrying Sxr. Transplantation 37: 17-21, 1984. Simpson, E.M. and Page, D.C.: An interstitial deletion in mouse Y chromosomal DNA created a transcribed Zfy fusion gene. Genomics 11: 601-608, 1991. Singh, L. and Jones, K.W.: Sex reversal in the mouse is caused by a recurrent non-reciprochal crossover involving the X and an aberrant Y chromosome. Cell 47: 49%504, 1982. Soriano, P., Keitges, E.A., Schorderet, D.F., Harbers, K., Gartler, S.M., and Jaenish, R.: High rate of recombination and double crossovers in the mouse pseudoautosomal region during male meiosis. Proc Natl Acad Sci USA 84: 7218-7220, 1987. Styrna, J., Klag, J., and Moriwaki, K.: Influence of partial deletion of the Y chromosome on mouse sperm phenotype. J Reprod Fertil 92: 187-195, 1991. Sutcliffe, M.J. and Burgoyne, P.S.: Analysis of the testes of H-Y negative XOSxr ~ mice suggests that the spermatogenesis gene (Spy) acts during the differentiation of the A spermatogonia. Development 107: 373-380, 1989. Tucker, P.K., Lee, B.K., and Eicher, E.M.: Y chromosome evolution in the subgenus Mus (genus Mus). Genetics 122: 16% 179, 1989. Yamazaki, K., Beauchamp, G.K., Bard, J., and Boyse, E.A.: Chemosensory identity and the Y chromosome. Behav Genet 20: 157-165, 1990.
eHollle 9 Springer-VerlagNew York Inc. 1992
Mouse Y Chromosome Colin E. Bishop Department of Obstetrics and Gynecology, University of Tennessee, Division of Reproductive Genetics, 711 Jefferson Avenue, Memphis, Tennessee 38105, U S A Received February 17, 1992
Introduction
Molecular characteristics
The Y Chromosome (Chr) is the most specialized of mouse chromosomes, being involved almost exclusively in controlling primary sex determination, spermatogenesis, and fertility. Unlike autosomes, which can pair and recombine along their entire length during meiosis, X-Y recombination is restricted to the tiny pairing/exchange or pseudoautosomal region located at the Yq telomere. This makes normal meiotic mapping impossible outside this region. The localization of genes/functions/DNA probes (with the exception of pseudoautosomally located Sts and movl5) is due to a combination of direct in situ hybridization to metaphase spreads and/or the use of rearranged Y Chrs--in particular the sex-reversed mouse mutanl Sxr (see below). This first Y Chr committee report will concentrate on a description of functional genes mapped to the Y, establishment of a preliminary deletion map, and the placement of these genes on it. A description of the many anonymous DNA fragments and viral integration sites can be found in the appropriate references, and a full list can be found in the mouse database or Eppig (1991). It is hoped that probes will all be assigned DY numbers and map posilions by the next report.
At the molecular level the majority of the Y Chr consists of highly repeated DNA sequences of no obvious function. These include Murvy (murine repeated virus-Y linked; Eicher and Washburn 1986; Eicher et al. 1989) and a large number of random repeated DNA probes isolated by several laboratories (Lamar and Palmer 1984; Bishop et al. 1985; Baron et al. 1986; Nallaseth and Dewey 1986; Nishioka and Lamoth 1986; Harbers et al. 1986; Bishop et al. 1987; Avner et al. 1987; Garchon et al. 1989; Nishioka 1989; Tucker et al. 1989). The pericentric region of the Y is characterized by a high concentration of simple repeat sequences ([GATA]n/[GACA]n) originally isolated from the banded krait minor satellite DNA fraction (Bkm; Jones and Singh 1981; Singh and Jones 1982; Schafer et at. 1986; Epplen et at. 1988). To date no random DNA probes have been directly isolated from the pseudoautosomal region. Isolation of DNA flanking an experimentally induced fortuitous integration of Mov15 (Moloney leukemia virus-15) in this region has produced only highly repeated sequences (Harbers et al. 1986). Several other loci can be defined on the Y by sites of viral integration: endogenous xenotropic murine leukemia viruses, Xmv-7,40,11 (Frankel et al. 1989a) and X m m v - Y (Blattet at. 1983); polytropic mu-
Table
1. Locus Li*tfor mouse Chr Y.
New Locus
Ge~e name Yqinked zinc finger protein- 1 Y-linked zinc finger protein-2 Y-linked Hi~ompatibility antigen Sdma Yoliakedserologically defined male antigen Spy Y-linked Spermatogenesis U~ly Y-linked Ubiquitin activating enzyme El homolog (fo~,nerlyShy o~A ls9Y- 1) sty Y-lir,ked S~x d~enninmg r~ Y-linked primary testis determining Ss~y Y-linltedspermiogenesis specific transcript (fo~erly pYMT2/B) Stsy Y-linked Steroid sulfatase Zfy-I Zfy-2 Hya
* *
*
Map position S:~r/Yp Sxr/Yp Sxr/Yp Sxr/Yp Sxr/Yp Sxr/Yp
Deletion interval 3/2 (or 1/2)junction 1/2 (or 3t2) junction
T D,B D,B
Method I,D,P I,D,P
2 2
B B
D D
ZFy ZFy HYA gDMA (?)
2 2
B D
D D,P
NONE NONE
S~r/Yp Sxr/Yp Yq
3 1 or 3 4,5,6
D,V,B D,P
Yq (Psendoautosomal)7
It. symbol
H. location Ypll.2-pter Ypll.2-pter Yq Yq(?)
Reference 55,42 55,42 44,56 23 9 47,33
B
D
gRY TDy
D
D
NONE
YpI 1.2-pter 24,3~ Ypl 1.2-pter 24,36 5
B
L
STs-Y
Yq
34,35A9
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C.E. Bishop: Mouse Y Chr
fine virus, Pmv-34 (Frankel et al. 1989b); mammary tumor virus Mtv-31 and Moloney leukemia virus Mov24 (Soriano et al. 1987). The precise localization of most of these loci is not known except that they all lie on the Y outside the pseudoautosomal region.
Genes mapped to the Y Chr
At present almost all the genetic functions of the Y (listed in Table 1) have been mapped to its minute short arm (Fig. 1) by use of the sex-reversed mouse. These include Hya, the structural or controlling gene for expression of the male specific minor histocompatibility antigen H-Y as defined by killer or proliferative T helper cells (Roberts et al. 1988; McLaren et al. 1988); Sdma, a gene controlling the expression of the serologically defined male antigen SDMA (which may or may not be identical to H-Y; Goldberg et al. 1991); Spy, a gene controlling spermatogonial proliferation and/or survival (Burgoyne et al. 1986); Zfy-I and Zfy2, genes encoding DNA-binding proteins/transcription factors of the zinc finger type (Page et al. 1987; Mardon et al. 1989); Ubely, a Y-linked homolog of the X-linked, ubiquitin-activating enzyme E1 (Mitchell et al. 1991; Kay et al. 1991), which has been proposed as a good candidate for Spy; and Sry, which is almost certainly identical to Tdy (Gubbay et al. 1990; Koopman et al. 1991). It has been shown that a 14-kb DNA fragment containing Sry can induce male development in XX + Sry transgenic mice (Koopman et al. 1991). It thus seems proven that Sry is the long-sought-after, primary testis-determining gene Tdy. Zfy-1/2 have a closely related X-linked homolog Zfx in the mouse and a pseudogene Zfa on Chr 10 (Mitchell et al. 1989; Mardon et al. 1989). A single X and Y homolog exists in the human (ZFX and ZFY). Using repeated probe pY353, Bishop and Hatat (1987) detected a testis-specific transcript. The corresponding cDNA (pYMT2) was sequenced and shown to contain an open reading frame of 696 bp, which is expressed only in round spermatids and from multiple loci (Burgoyne, personal communication; Bishop, un-
YP i ~
r!
Yq
A B c
D E Fig. 1. The mouse Y is the smallest mouse chromosome (approximately 50-60 Mb), representing some 2% of the haploid genome. It is composed of a minute short arm (Yp), a centromeric region, a long arm (Yq), and a small X-Y homologous pairing/recombination or pseudoautosomal region, located at the Yq telomere. The Y can be distinguished from other mouse chromosomes by its characteristic G banding pattern, which produces five resolvable bands on Yq (A-E) and by the presence of the short arm visible only in good preparations.
published results). Although no function can as yet be attributed to this transcript, it has been given a preliminary gene symbol Ssty (Spermiogenesis specific transcript from the Y). The only gene to be definitively mapped to the pseudoautosomal region is steroid sulfatase (Sts), which carries active copies on the X and Y Chrs (Keitges et al. 1985). The observed Sts recombination frequency with respect to sex (Tdy) is 50%, and thus it must map very close to the Yq telomere. Using Sxr to mark the telomere, Nagamine and colleagues (1987a) obtained a recombination frequency of 1%, wheras Keitges and co-workers (1987) reported a 9.8% recombination frequency in a nearly identical cross. Further, a double recombinant between Tdy, Sts, and Sxr was reported. Sts is located distally to the Mov-15 integration site in the pseudoautosomal region, and double recombinants between Tdy, Mov-15, and Sts have been described (Soriano et al. 1987). This contrasts with the situation in the human, where double crossover events have not been found in the pseudoautosomal region.
Y Chr rearrangements
Sex reversed The most useful rearrangement for mapping is the sexreversed mutation Sxr, first described by Cattanach and colleagues (1971). Sxr, or [Tp(Y)ICt] as it is more properly termed, is a small fragment of the Y Chr short arm, transposed distal to the pairing/recombination region of the Y in XYSxr mutant mice (Singh and Jones 1982; Roberts et al. 1988; McLaren et al. 1988). As Sxr is distal to the X-Y recombination region in these carrier males, four types of sperm are produced in equal proportions during male meiosis: X and YSxr sperm derived from the unrecombined chromatids, and XSxr and Y sperm derived from the recombinant chromarids. Thus four types of offspring are produced, mimicking an autosomal inheritance pattern: XX fertile females, XXSxr sterile males, XY fertile males, and XYSxr fertile carrier males. Viable XSxrO male mice can be produced by mating XO females with XYSxr carrier males. These XSxrO males have Sxr attached distally to their single paternal X chromosome. By comparing XSxrO males with normal XY males, one can determine which Y-linked functions are provided by Sxr and which are not. As both XXSxr and XSxrO mice are male and express the minor transplantation antigen H-Y (McLaren et al. 1984; Simpson et al. 1984), the Sxr region must carry the primary testisdetermining gene Tdy and the structural/controlling gene for H-Y antigen expression, Hya. It has been shown that XO germ cells in XO/XY mosaics never progress beyond meiotic prophase owing to the lack of a Y Chr-located spermatogenesis gene termed Spy (Levy and Burgoyne 1986). Since XSxrO germ cells are not subject to this block (Cattanach et al. 1971), the Sxr region must also encode Spy.
C.E. Bishop: Mouse Y Chr
In 1984 McLaren and co-workers described a deletion variant of Sxr termed Sxr' (now referred to as Sxr b and the original Sxr as Sxra). Sex-reversed mice carrying Sxr b were male but were found to be H-Y negative (McLaren et al. 1984; Simpson et al. 1986), and an analysis of the germ cells in XSxrbO testis showed them to be blocked prior to the first meiotic metaphase (Burgoyne et al. 1986; Sutcliffe and Burgoyne 1989). This further localized Hya and Spy to the Sxr a DNA deleted in Sxr b. It has recently been shown that Sxr a mice are SDMA positive and Sxr b mice SDMA negative, thus placing Sdma in the deletion (Goldberg et al. 1991). Recent evidence has shown that the S x r b deletion breakpoints lie within the Zfy-1/Zfy-2 genes (Simpson and Page 1991). Thus in Sxr ~ a fusion gene comprising the promoter region of Zfy-2 linked in frame to the coding region of Zfy-1 has been produced with the deletion of the intervening DNA. This now allows the gene order Zfy-2, [Hya, Sdma, Spy], Ubety, Zfy-1 to be determined, although orientation with respect to the centromere is unknown. It can be shown from physical mapping that the deletion is greater than 900 kb and Ubely is located 30 kb 5' of Zfy- ! (Mitchell and Bishop 1992; Bishop et al. unpublished). With a synthetic oligonucleotide telomere probe, restriction fragment length polymorphisms (RFLPs) identifing the telomeric region of Yp and Yq have been reported (Elliott and Yen 1991). Unusual pairing and recombination have been reported involving the YSxr ~ Chr (Chandley and Speed 1987; Roberts et al. 1988; McLaren et al. 1988). A low frequency of back-pairing and recombination can occur between Yp and Sxr ~, resulting in the transfer of Yp material to Sxr ~. When Sxr a is carried on the X Chr, X-Y pairing and exchange can occur between Sxr ~ and Yp in addition to normal pseudoautosomal exchange (Cattanach 1991). It should be noted that XSxr"O males are sterile, producing abnormal germ cells, especially with regard to sperm head morphology. Eicher and Washburn (1986) have, therefore, suggested that there is a sperm morphogenesis gene located outside the Sxr a region on the long arm of the Y. In this respect the testis-specific transcript detected by repeated Y probe pY353 is a good candidate for this proposed gene (P.S. Burgoyne, personal communication). Y* Chr
This is a complex Y Chr rearrangement first reported by Eicher and co-workers (1986). Recombination between Y* and the X produces two recombinant products: X Y* and a Y*• X Y* consists of almost the entire Y attached to the X Chr, wheras y . X consists of most of the pseudoautosomal region attached to a non-Y centromere and lacks any Y-specific DNA (Eicher et al. 1991; Hale et al. 1991). Two large, visible interstitial deletions of Yq
These have been described, one derived from the B10.BR strain (Styrna et al. 1991), the other from RIII,
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which has now been transferred to the B10 background B10SmY (small Y; P.S. Burgoyne, personal communication). Both strains show an increased frequency of abnormal sperm heads, supporting the view that gene(s) necessary for the proper development of the sperm head are located there. About half of the repeated sequences defined by pY353 are deleted in the StaY Chr.
Deletion map of the mouse Y Chr
A preliminary deletion map comprising seven intervals can now be constructed for the mouse Y Chr with these rearranged Y Chrs and is shown in Fig. 2.
Other traits assigned to the Y
It has been shown that the Y carries gene(s) influencing a variety of sperm head abnormalities (KryzaYpTel
Zfy-2
YpTel---I~
Sdma Hya Spy Ubely Zfy-1
Sx rb - 4 ~ Sxrb
>900kb [30kb
Sty [Tdy]
B10SmY---~'-
i=iliSperm head
B10SmY--ID,-
ov-15
[ ~ 1
Sts
u
Fig. 2. Interval 1, containing the Yp telomere, can be defined by the telomeric RFLP described by Elliot and co-workers (1991); interval 2 is comprised of the Sxr ~ DNA deleted from Sxr b, the breakpoints lying within the Zfy genes, as described by Simpson and colleagues (1991). Interval 3 would comprise the rest of the nondeleted Sxr ~ Yp DNA. On Yq, interval 5 is defined by the Y DNA deleted from the Stay Chr, and interval 4 as the DNA lying between it and the Sxr ~ break. Interval 6 is the region lying between the distal break in interval 5. The pseudoautosomal region is interval 7 and contains Mov-15, Sts and the Yq telomere RFLPs. Tdy (Sry) can be placed in interval 1 or 3, and the orientation of interval 2 is not known. Boundaries between the intervals are indicated by arrows. Physical distances are based on cosmid/phage and YAC contigs (Mitchell and Bishop 1992; C.E. Bishop et al., unpublished observations).
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nowska 1969, 1976, 1986; Eicher et al. 1982): testis weight (Hayward and Shire 1974; Herrick and Wolfe 1977); a gene(s) (provisionally termed Yaa) involved in the acceleration of a lupus-like autoimmune syndrome in recombinant inbred BXSB mice and their Fl hybrids with NZB or NZW strains (Hudgins et al. I985; Izui et al. 1988); Y-controlled chemosensory cues similar to those mapped to the major histocompatibility complex (MHC) playing a role in individual recognition, mate selection, and aggressive interactions (Yamazaki et al. 1990; Maxon 1990); gene(s) influencing pubertal (but not adult) testosterone levels (Jutley and Stewart 1986); and glucose intolerance (Leiter 1988). M.m. domesticus/musculus polymorphisms
With RFLPs it has been shown that the Y Chr in the majority of inbred laboratory strains is of M.m. musculus origin, not M.m. domesticus, as indicated by mitochondrial and protein polymorphisms (Bishop et al. 1985). Data are consistent when repeated or singlecopy probes are used (Nishioka 1987; Mardon et al. 1989). It is most probable that the Y has been introduced by interbreeding with the very closely related Asiatic subspecies M . m . molossinus (Bonhomme 1986; Boursot et al. 1989). Common strains carrying a domesticus type Y include: AKR/J, BFM/2, BUB/ BnJ, FUB/N, IS/CamEl, Ma/MyJ, NCS, PL/J, RF/J, SJL/J, St/bJ, SWR/J, and SWV; those carrying a musculus type Y include: 129/J, A/J, AEJ/GnLe, BALB/c, BDP/J, CBA/FaCam, CE/J, C3H/HeJ, C3H/An, C57BL/6J, DA/HuSn, DBA/I, DBA/2J, I/LnJ, NZB/ Scr, NZB/BINJ, NZW/LacJ,P/J, RIIIS/J, SB/Le, SEA/GnJ, SECflReJ, SF/CamEi, SM/J, WB/ReJ, and YBR/Ei. The introduction of certain domesticus type Y Chrs into the C57BL/6 genome can lead to sex reversal, generating XY females and hermaphrodites (Eicher et al. 1982; Eicher and Washburn 1986; Nagamine et al. 1987b). Y-linked RFLP's have been found Within M.m. domesticus strains, which may correlate with the degree of sex reversal they induce (Bishop et al. 1987; Biddle et al. 1991).
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