A molecular genetic linkage map of mouse chromosome 2

GENOMICS

6,491-504

(1990)

A Molecular

Genetic Linkage Map of Mouse Chromosome

LINDA D. SIRACUSA,* COLLEEN M. SILAN,* MONICA J. JUSTICE,* JOHN A. MERCER,* YINON &r+NmAti,t DENIS DUBOULE,$ NICHOLAS D. HASTIE,~ NEAL G. COPELAND,* AND NANCY A. JENKINS*,’

2

ASNE R. BAustaN,t

*Mammalian Genetics Laboratory, BRI-Basic Research Program, NC/-Frederick Cancer Research Facility, P. 0. Box B, Frederick, Maryland 27 707; t The Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem 9 10 10, Israel; Sfuropean Molecular Biology Laboratory, Meyerhofstrasse 7, Postfach 10.22 09, D-6900 Heidelberg, Federal Republic of Germany; and §Medical Research Council, Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU Scotland Received

August

9, 1989;

revised

INTRODUCTION

A molecular genetic linkage map of the mouse genome can be used (1) to study genome organization and evolution, (2) to identify molecular loci at or near existing mutations, (3) to determine whether a newly identified gene or viral integration site is identical to a known gene or mutation, (4) to correlate cytogenetic alterations with changes at the molecular level, (5) to identify recessive oncogenes by deletion mapping or reduction to homozygosity of polymorphic alleles, (6) to identify regions of homology between the mouse and the human (or other) genomes, and ultimately (7) to identify mouse models for human diseases. Interspecific backcrosses (IBs) are a powerful tool for simultaneous multilocus mapping of the mouse genome (reviewed by Guenet, 1986; Avner et al., 1988). The crosses involve two mouse species whose evolucorrespondence

should

17, 1989

tionary distance has allowed for accumulation of differences at the DNA sequence level. DNA sequence differences, which result in restriction fragment length polymorphisms (RFLPs) between the parents of an IB, can be used to establish the map location of molecular markers. Mouse chromosome 2 contains many interesting loci, including several involved in developmental, morphological, and neurological abnormalities (reviewed by Green, 1981b). We previously used an IB involving the C57BL/6J inbred strain and MUS spretus mice to establish a molecular genetic linkage map of the distal portion of mouse chromosome 2 (Siracusa et aZ., 1989); our initial analysis has now been expanded by establishing a molecular genetic linkage map of the proximal portion of mouse chromosome 2 using the same IB. Several loci in this study had previously been regionally mapped on mouse chromosome 2. Somatic cell hybrid analysis showed that the Abl proto-oncogene locus was on chromosome 2 (Goff et al., 1982); in situ hybridization studies placed the Abl locus at band 2B (Threadgill and Womack, 1988). The homeobox gene5.1 (HOP5.1) was mapped by in situ hybridization to band 2D (Featherstone et al., 1988). However, the Abl and Hox-5.1 loci were not mapped with respect to other loci. The catalase-1 (Cu.+I) gene was mapped to chromosome 2 by standard intraspecific backcrosses (Dickerman et al., 1968; Hoffman and Grieshaber, 1974; Holmes and Duley, 1975; Colombatti et al., 1982). However, the precise localization of the &s-l locus remained in question due to variations in recombination distances noted between Gas-1 and flanking markers used in the different crosses. The structural locus for the fifth component of complement (C5) was mapped to the proximal portion of mouse chromosome 2 using somatic cell hybrids, recombinant inbred (RI) strains, standard inbred back-

Interspecific backcross mice were used to create a molecular genetic linkage map of chromosome 2. Genomic DNAs from Na progeny were subjected to Southern blot analysis using molecular probes that identified the Abl, Acra, Ass, C5, Gas-1, Fshb, Gcg, Hex-5.1, J&-l, Kras-3, Ltk, Pax-l, Pm-p, and Spna2 loci; these loci were added to the 11 loci previously mapped to the distal region of chromosome 2 in the same interspecific backcross to generate a composite multilocus linkage map. Several loci mapped near, and may be the same as, known mutations. Comparisons between the mouse and the human genomes indicate that mouse chromosome 2 contains regions homologous to at least six human chromosomes. Mouse models for human diseases are discussed. o lsso Academic PWS, 1110.

1 To whom

November

he addressed. 491

Copyright 0 1990 All rights of reproduction

osss-7543/90 $3.00 by Academic Press, Inc. in any form reserved.

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SIRACUSA

crosses (D’Eustachio et aZ., 1986), and an IB (Birkenmeier et al., 1988). Previous results indicated that the hemolytic complement activity (Hc) locus (reviewed by Michaelson, 1983; Colombatti et al., 1982) is the same as or very tightly linked to C5 (D’Eustachio et aZ., 1986). Somatic cell hybrids were used to map the mouse prion protein (Pm-p) locus to chromosome 2 (Sparkes et al., 1986); analysis of inbred strain backcrosses enabled placement of Pm-p between the interleukin-la (IZ-la) locus and the agouti (a) locus (Carlson et al., 1988). A mouse paired box-containing (Pax-l) gene was previously mapped to the distal region of chromosome 2 near the a locus using an IB (Dressier et al, 1988). RI strain analyses placed the Pax-l gene in the region of the undulated (un) mutation on chromosome 2; further studies showed that a point mutation in the Pax-l gene was present in mice carrying the un mutation (Balling et uZ., 1988). Somatic cell hybrid analysis was used to map the brain cY-spectrin (Spruz-2) locus (Barton et al., 1987), the argininosuccinate synthetase (Ass) locus (Nakamura et al, 1985), the P-subunit of follicle-stimulating hormone (F&b) locus (Glaser et uZ., 1986), and the glucagon (Gcg) locus (Lalley et cd., 1987) to mouse chromosome 2. The Spna-2 locus was previously localized to the centromeric region of chromosome 2 using the IB described in this paper (Birkenmeier et aZ., 1988). However, the regional localizations of the Ass, Fshb, and Gcg loci had not been established. Several previously unmapped loci were mapped to mouse chromosome 2 in our IB analysis. An anonymous mouse cDNA (Jgf-1) locus, a Kirsten ras-related (Kras3) locus, and the leukocyte tyrosine kinase (Ltk) locus (Ben-Neriah and Bauskin, 1988) have been added to chromosome 2. In addition, the muscle nicotinic acetylcholine receptor a-chain (Acru) gene was previously mapped to mouse chromosome 17 by analysis of an IB (Heidmann et al, 1986). However, this assignment was based on linkage to the cardiac actin (Actc-1) locus, which had previously been mapped to mouse chromosome 17 by somatic cell hybrid analysis (Czosnek et al., 1983). Recently, Actc-1 was mapped to mouse chromosome 2 using RI strains (Crosby et al., 1989), and Acra was mapped to mouse chromosome 2 using an IB (Elliott et al., 1989). The data presented here firmly establish the location of Acra in the central portion of mouse chromosome 2. MATERIALS

AND

METHODS

Mice The C57BL/6J inbred strain is maintained at the NCI-Frederick Cancer Research Facility. The M. spretus mice used for the IB were at the F7, Fg, FIO, or Flz generation of inbreeding and were a gift from

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AL.

E. M. Either (The Jackson Laboratory, Bar Harbor, ME). The [(C57BL/6J X M. spretus)F, X C57BL/6J] IB was performed at the NCI-Frederick Cancer Research Facility. A total of 205 N2 progeny were obtained; random subsets of these 205 mice were used to map certain loci. Probes The v-abl probe for the Abelson proto-oncogene (Abl) locus is a 1740-bp HindI fragment from the 5’ end of the v-abl gene of the Abelson murine leukemia virus (Abelson and Rabstein, 1970); the v-abl probe was purchased from Oncor (Gaithersburg, MD). The AChRa! 14-2 probe for the muscle nicotinic acetylcholine receptor a-chain (Acra) gene is a 1.8-kb mouse cDNA cloned in M13mp18 (Heidmann et al., 1986); the AChRa 14-2 probe was a gift from B. A. Mock (National Cancer Institute, Bethesda, MD) with permission from J. P. Merlie (Washington University School of Medicine, St. Louis, MO). The pAS 4/l/9 probe for the argininosuccinate synthetase (Ass) gene is a 1.5-kb human cDNA cloned in pBR322; the pAS 4/l/9 probe was derived from splicing together two overlapping cDNAs (pAS4 and pAS1) at a common Hind111 site (Daiger et uZ., 1984). The pAS 4/l/9 probe was purchased from the American Type Culture Collection (Rockville, MD). The pMC5.04 probe for the complement component (C5) gene is a 5.2-kb mouse liver cDNA cloned in pCD (Wetsel et cd., 1987); the pMC5.04 probe was a gift from B. F. Tack (Scripps Clinic and Research Foundation, La Jolla, CA). The CAT2-1 probe for the catalase-1 (Gas-1) gene is a l.lkb human liver cDNA cloned in Bluescribe (van Heyningen et al., 1985). The pFSHB-1.4 probe for the Psubunit of follicle-stimulating hormone (Fshb) is a 1.4kb human genomic sequence subcloned in pBR322 (Watkins et al., 1987); the pFSHB-1.4 probe was a gift from P. C. Watkins (Integrated Genetics, Framingham, MA). The 29-13A7 probe for the glucagon (Gcg) gene is a l.l-kb bovine cDNA cloned in pBR322 (Lopez et al., 1983); the 29-13A7 probe was a gift from B. A. Mock (National Cancer Institute) with permission from G. F. Saunders (M. D. Anderson Hospital and Tumor Institute, Houston, TX). The pGEM160 probe for the HOE5.1 gene contains 160 bp of 5’ coding sequences cloned in pGEM-1 (Featherstone et al., 1988). The probe for the Jgf-1 locus is an anonymous mouse cDNA clone; the probe was a gift from G. Radice, J. Lee, and F. Costantini (Columbia University, College of Physicians and Surgeons, New York, NY). The pSW 11-l probe for the Kras-3 locus is a full-length l.l-kb K-rm cDNA cloned in pUC13 (McCoy et al., 1984); the pSW 11-l probe was purchased from the American Type Culture Collection. The pRK14 probe for the leukocyte tyrosine kinase (L&z) gene is a 2.3-kb mouse cDNA

MOUSE

CHROMOSOME

2 LINKAGE

TABLE Loci Abbreviations,

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MAP

1

Loci Names, and RFLPs

Used for IB Mapping Fragment

Locus” Abl Acra ASS c5 cas-1 Fshb Gw Hox-5.1 J&l Kras-3 Ltk PaX-1 Pm-p Spna-2

RE”

Name Abelson proto-oncogene Muscle nicotinic acetylcholine Argininosuccinate synthetase Complement component 5 Catalase-1 Follicle-stimulating hormone Glucagon Homeobox gene-5.1 JGF-1 Kirsten ras-related locus Leukocyte tyrosine kinase Paired box-containing gene-l Prion protein Brain a-spectrin

receptor

a-chain

b-subunit

C57BL/6J

PstI PUUII B&I* TaqI’ XboI PstI TaqI Hind111 PstI HindIII’ TaqI EcoRI BamHI ToqI

Mus

6.9, 4.4, 1.7, 0.8, 0.7 4.5

2.2, 1.4 6.6 9.0 8.4, 2.5, 2.2, 1.9, 0.8, 0.5,0.3

Southern

Blot Analyses

High-molecular-weight genomic DNA was extracted from mouse tissues as described (Jenkins et al., 1982). Conditions for restriction endonuclease digestions, Southern blot analyses, and autoradiography were as described (Siracusa et al., 1989), with the exception that filters were usually washed at 62-65°C in 1X SSCP, 0.1% SDS, followed by two washes in 0.5X SSCP, 0.1% SDS.

Statistical

spretus

6.2,4.4,1.7,0.8,0.7 w u -11 7.9,1.1 -ll, 3.2, 2.4 f3.J 5.4 0.6 -@ u, 1.4, u 6.5, s.2 -21 3.l, 2.2, 1.9,0.8,0.5,0.3

--18, 1.1 6.7, 3.2, 2.4 4.6 7.2 2.6

a References for each of the probes used to identify each locus are listed under Materials and Methods. b “RE” is the restriction endonuclease used to detect each RFLP. c The fragment sizes are listed in kilobases. The restriction fragments followed in the IB are underlined. *Ass useudozenes were also detected (94): only the restriction fragment that mapped to mouse chromosome ’ More than 10 bands were visible in C57BL/6J and M. spretus. ’ Only the restriction fragment identifying the Kras-3 locus is listed.

cloned in pSP65 (Ben-Neriah and Bauskin, 1988). The probe for the Pax-l gene was synthesized by the polymerase chain reaction amplification (Saiki et al., 1985) of mouse genomic DNA using synthetic oligodeoxynucleotides corresponding to nucleotides 4-36 and the complement of nucleotides 228-193 of the Pax-l paired box (Deutsch et al., 1988). The ~1.40 probe for the mouse prion protein (PrP) gene (Pm-p) is an -2-kb hamster brain cDNA cloned in a pBR322 derivative (Oesch et al., 1985; Basler et al., 1986); the ~1.40 probe was a gift from G. A. Carlson (McLaughlin Research Institute, Great Falls, MT). The RBF2 probe for the brain a-spectrin (Spna-2) locus is a 2.5-kb EcoRI fragment from a rat a-fodrin cDNA cloned in pSP65 (Leto et al., 1988); the RBF2 probe was a gift from T. L. Leto (National Institute of Allergy and Infectious Diseases, Bethesda, MD). Probes for the B2m, B-la, Hck-1, Emv13, Psp, Emu-15, Src-1, Ada, Sup-l, and Pck-1 loci were previously described (Siracusa et al., 1989).

size(s) ’

2 is listed.

Analyses

The recombination frequencies for the IB progeny were calculated as described (Green, 1981a) using the computer program SPRETUS MADNESS developed by D. Dave (Data Management Services, Inc., Frederick, MD) and A. M. Buchberg (NCI-FCRF, BRIBRP, Frederick, MD). RESULTS Initial

Screen

RFLPs between the parents of the IB, C57BL/6J and A4. spretus, were detected by Southern blot analyses. The restriction endonucleases tested in the initial screen were BamHI, BglI, EcoRI, HindIII, KpnI, MspI, PstI, PvuII, Z’aqI, and/or XbaI. The loci used as anchors for mouse chromosome 2 were the µglobulin (B2m) locus and the agouti (a) locus. Agouti alleles were typed by observation of coat color. Our previous analysis of the [(C57BL/6J X M. spretus)F1 X C57BL/ 6J] IB allowed the mapping of 11 loci (a, Ada, B2m, Emu-13, Emu-15, Hck-1, 11-la, Pck-1, Psp, Src-1, and Sup-l) on the distal portion of mouse chromosome 2 (Siracusa et al., 1989). Our current analysis has added 14 loci (AU, Acra, Ass, C5, &s-l, Fshb, Gcg, Hox-5.1, Jgf-1, Kras-3, Ltk, Pax-l, Pm-p, Spna-2) to mouse chromosome 2 (Table l), most of which reside in the proximal portion of the chromosome.

494

SIRACUSA

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spna-2 q mmumum0m0m0mumumnmum0mumummmmm000 kd 0m0mmumumumumumumum0mum0m0mmmmmufl0 4p-l' q mum0mm0m0m0m0mum0mumum0m0mmmmm000 c5 q mumumummumnmumumumnmumomuummmmmou ~~~umc~mnm~m~mmomumomc~mum~momnuou~mmmn h-a q murn q m urn q mum n 0mumomo n umumuuuuuummm 0.d q mq m q m0m0m q mumm0mumn mum0 n umuu00mmm R&b q m q m q m cIm q m q m omuum0mo n um0 n IzImuuu0mmm ~tk q m0m0m q mumum 0mumummu n 0mnmumuuu0mmm ~2~ q m0mum q mumum 0m0mum0mmumu n umuuu0mmm prn-p q m0m0m0mnmum0mum0m0m0mm0mnmuum0mmm pax-~ q mum q momom q mumumumum umnmmomummmnun a q mq mom q murn q mq mumumum umumummmmmm0u~ 191120100033303301441001232112111111 FIG. 1. Pedigree analysis of 76 Nz progeny from the IB. The loci followed chromosome identified in the Nz progeny that was inherited from the (C57BL/6J M. spretusallele. The black squares represent the C57BL/6J allele. The number the bottom.

in the IB are listed on the left. Each column represents the X Mus spretus) F, parent. The open squares represent the of N2 progeny carrying each type of chromosome is listed at

The results of the initial screen showed that all of the probes detected RFLPs between the parents of the IB. Locus abbreviations, locus names, and the corresponding RFLPs used for mapping are shown in Table 1. The segregation of restriction fragments from M. spretus was followed in the Nr progeny. The loci were ordered by arranging the loci to obtain the least number of double crossovers. The order of 11 of the 14 loci

been typed for a, Emu-15, Hck-1, and Psp, and these mice have been included in our analysis. In addition to the N2 progeny shown in Fig. 1, additional Nz progeny were typed for various loci in order to more accurately determine recombination distances. The ratios of the total number of mice carrying recombinant chromosomes to the total number of mice analyzed for each pair of loci and the gene order are Spna2-7/146-Abl-5/146-Jgf-l-2/148-C5-11/84-Gcg-7/83Acra-lO/llO-Gas-I-l/130-Fshb-12/110-Ltk-1/113-

(Abl, Acra, CS, Cas-1, Fshb, Gcg, J&-l, Ltk, Pax-l, Prnp, and Spna-2) with respect to the B2m locus and the a locus is shown by analysis of 76 Nz progeny that were

B2m-5/150-Il-la-12/14O-Pax-l-lO/l58-Hck-l-l/ 172-Psp-3/199-a-1/205-Emv-15-1/150-Src-1-4/150[Ada, Sup-l]-11/150-Pck-I-2/75-Kras-3. The recom-

typed for all 11 loci as well as the 2 anchor loci (Fig. 1). Three loci (Ass, Hox-6.1, and Eras-3) were typed for a subset of Nz progeny in these analyses. No crossovers were detected between (1) the Abl and Ass loci in 54 N2 progeny, giving an upper 95% confidence limit of 5.4 CM between the loci; (2) the Acra and Hox-5.1 loci in 84 N2 progeny, giving an upper 95% confidence limit of 3.6 CM between the loci; and (3) the I&la and Pm-p loci in 142 Nr progeny, giving an upper 95% confidence limit of 2.1 CM between the loci. To most accurately determine the recombination distance of these three pairs of loci from the loci flanking them, the Abl, Acra, and 11-la loci were chosen for comparison with flanking loci, since the Abl, Acra, and 11-la loci were typed in more mice than the Ass, Hox-5.1, and Pm-p loci. The Spna-2 locus (previously mapped using an avian clone) and the C5 locus were previously mapped to the proximal region of mouse chromosome 2 in our IB (Birkenmeier et al., 1988); we have extended these analyses by using a rat probe to detect the Spna2 locus and by typing more mice for the C5 locus. Our previous analysis using this same IB established the order of 11 loci in the distal region of mouse chromosome 2 (Siracusa et al., 1989); more mice have since

bination distance f the standard error between each pair of loci is Spna-24.8 It 1.8 CM-[Abl (Ass) J-3.4 +- 1.5 CM-Jgf-l-1.4 f 1.0 CM-C5-13.1 k 3.7 CM-Gcg-8.4 + 3.1 CM-[Acru (Hox-5.1)]-9.1 f 2.7 CM-Gas-l-0.8 +- 0.8 CM-Fshb-10.9 + 3.0 CM-Ltk-0.9 + 0.9 CM-B2m3.3 f 1.5 CM-[I&la (Pm-p)]-8.6 + 2.4 CM-Pax-l-6.3 +- 1.9 CM-Hck-l-0.6 t_ 0.6 CM-[(Emu-13) Psp]-1.5 +- 0.9 CM-a-O.5 + 0.5 CM-Emu-15-0.7 f 0.7 CM-Srcl-2.7 +- 1.3 CM-[Adu, Svp-11-7.3 + 2.1 CM-Pck-l-2.7 & 1.9 CM-Kras-3. Figure 2C shows the order of the loci and the recombination distance between each pair of loci obtained from the IB analysis. The results show that Spna-2 is the most proximal locus mapped and Kras-3 is the most distal locus mapped. The IB map covers -87 CM of the estimated 110 CM of mouse chromosome 2 (Green et al., 1972; Roderick and Davisson, 1981).

IB Analysis

DISCUSSION The mapping results from one unambiguous orientation of 25 mosome 2 (Fig. 2C). The potential ing the number of loci mapped

IB have provided an loci on mouse chroremains for increasto this chromosome

MOUSE

CHROMOSOME

‘2 LINKAGE

495

MAP

D

----------------_

I i_-___------_ t/cm I fI 1 fI

s-d

t

II

-.

e-------J

::

--_--_----__:

16

&2&z@.

L?-ffxc)

--------. - L%-6: t%p,l

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anx

I

;

fii!m.Ly-25 ~J-r~-----z--zL

,

“n

!

_!

_

fax-f Hck-l

QGnv-JJ Psp -&g ---------_--_-_-a ;.!tkw-15 ,= Alab, svp-2 P&-f xras-3

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I-I

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u 72 76 61

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Aph-kfsj.

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FIG. 2. Comparison of genetic and cytological maps of mouse chromosome 2. (A and B) Chromosome atlas genetic and cytological maps prepared by M. F. Lyon (81); the maps are reproduced with changes by permission from M. F. Lyon. The T28H breakpoint is in band 2H4 (40) and the TlSn breakpoint is in band 2Hl (41). The T30H translocation has been added to the map (114). The proximal breakpoints of the In2H and InBRk inveraions on the chromosome atlas genetic map are taken from Roderick (108). (C) The loci mapped in the IB and the recombination distance between each pair of loci. (D) The composite mouse map prepared by M. T. Davisson, T. H. Roderick, A. L. Hillyard, and D. P. Doolittle (January 1989); the information and map were provided from GBASE, a computerized database maintained at The Jackson Laboratory. Loci that have been mapped in humans are underlined (see Fig. 3).

496

SIRACUSA

using the [(C57BL/6J X M. spretus)F1 X C57BL/6J] IB. More than 350 loci covering almost the entire mouse genome have been mapped in this single IB to date (Birkenmeier et aZ., 1988; Buchberg et al., 1988, 1989a,b; Ceci et aZ., 1989; Hill et aZ., 1989; Kingsley et al., 1989; Mock et al., 1989; Mucenski et al., 1988; Siracuss et al., 1989; A. M. Buchberg, J. D. Ceci, D. J. Gilbert, D. M. Kingsley, M. J. Justice, L. F. Lock, C. M. Silan, L. D. Siracusa, N. A. Jenkins, and N. G. Copeland, unpublished results). The data confirm that IBs are a powerful tool for establishing simultaneous multilocus linkage maps of the mouse genome (reviewed by Guenet, 1986; Avner et al., 1988). Comparison of Linkage Chromosome 2

Maps for Mouse

Figure 2 shows the molecular genetic linkage map of mouse chromosome 2 obtained from our IB analysis (Fig. 2C) compared to the composite mouse map prepared by M. T. Davisson, T. H. Roderick, A. L. Hillyard, and D. P. Doolittle (Fig. 2D) and the chromosome atlas genetic and cytological maps prepared by M. F. Lyon (Figs. 2A and 2B). The maps have been aligned at the a locus because the location of the a locus is known for each map and the a locus is an anchor locus for mouse chromosome 2; many crosses involving the a locus that confirm its location have been performed (summarized by Davisson and Roderick, 1981; Michaelson, 1983). The a locus most likely resides at band 2H1, as demonstrated by two cytogenetically visible translocations (Searle et al., 1979) and one cytogenetically visible inversion (Evans-and Phillips, 1978) that alter a locus phenotypes. The IB map has also been aligned with the cytological map based on results of in situ hybridization that placed the Abl locus at band 2B (Threadgill and Womack, 1988), the Hox-5.1 locus at band 2D (Featherstone et al., 1988), and the Emu-15 locus at band 2Hl (Lovett et d., 1987). The IB map appears consistent and colinear with the chromosome atlas cytological map (Figs. 2B and 2C). The IB map has been adjusted at the proximal and distal ends so as to keep it colinear with the cytological map and not altar the total predicted length (110 CM) of chromosome 2 (Green et aZ., 1972; Roderick and Davisson, 1981). However, we do not know the exact recombination distances in the most centromeric and most telomeric regions of the IB map. This view of chromosome 2 is somewhat different from either the chromosome atlas genetic map or the composite mouse map (Fig. 2C compared to Figs. 2A and 2D). Several implications exist for the linkage map of mouse chromosome 2 based on the results of the IB analysis. The IB map showed no statistically significant differences in the region between B2m and Sup-l when compared to results obtained using RI strains (Siracusa

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et al., 1989). The genetic distances between the B2m and a loci are in good agreement among the maps in Figs. 2A, 2C, and 2D; the distances are 18, 20, and 16 CM, respectively. The alignment of the IB map with the cytological map predicts that -23 CM of chromosome 2 lie distal to the a locus. This finding suggests that the placement of the most distal loci, a-protein1 (Aph-1) and a-protein-2 (Aph-2), and possibly placement of the natural killer antigen-2 (Nk-2) locus, is different from their placement on the composite mouse map and the chromosome atlas genetic map, since these three loci are placed 229 CM distal to the a locus. The finding of 53 recombinants between the Aph-1 and the a loci out of 137 mice analyzed (Harada et al., 1986) means that the 95% confidence limits for linkage are 30-47 CM; linkage of the Aph-1 locus to the a locus appears tenuous. The Aph-1 and Aph-2 loci may not reside proximal to the a locus, since significant linkage was not detected between the Aph-2 and Hc loci (Harada et al., 1988). Therefore, the Aph-1 and Aph-2 loci either do not reside on chromosome 2 or are the most distal loci mapped, with placement near the telomere resulting in recombination frequencies somewhat higher than those predicted from comparison with the chromosome atlas cytological map. Further crosses are necessary to distinguish among these possibilities. Since the Nk-2 locus was mapped only with respect to the a locus (Pollack and Emmons, 1982), the Nk-2 locus may reside proximal (instead of distal) to the a locus. The position of the Kras-3 locus near the telomeric end of chromosome 2 suggests that the Kras-3 locus may provide molecular access to the wasted (wst) and Ragged (Ra) region. The largest discrepancies among the IB map and the two composite maps appear to be in the central region of chromosome 2. The genetic distances between the &s-l and B2m loci are 5, 12, and -1 CM in Figs. 2A, 2C, and 2D, respectively. The precise localization of the Gas-1 locus has remained in question due to the variation in recombination distances observed in independent analyses involving the Cus-1 locus and flanking markers (Dickerman et aZ., 1968; Hoffman and Grieshaber, 1974; Holmes and Duley, 1975). However, our IB results are consistent with RI strain analyses that place the Gas-1 locus several centimorgans proximal to the B2m locus (Colombatti et al., 1982; A. Seawright, W. A. Bickmore, and N. D. Hastie, unpublished results). The genetic distances between the Acra and B2m loci are in good agreement between Figs. 2C and 2D; the distances are 22 and 21 CM, respectively. RI strain analysis suggested placement of the Actc-1 locus just proximal to the B2m locus (Crosby et al., 1989) and IB analysis placed the Acra locus 19 CM from the Actc-1 locus (Heidmann et al., 1986). Our results are in agreement with these findings and with the IB anal-

MOUSE

CHROMOSOME

ysis of Elliott et al. (1989) that placed the Acru locus -10 CM proximal to the Cus-1 locus. Distances between the centromere and the loci on chromosome 2 (Figs. 2A and 2D) are based on the distance between Danforth’s short tail (Sd) and the centromere determined from crosses involving Robertsonian translocations (Beechey and Searle, 1980). The possibility of crossover suppression in mice heterozygous for the Rb(2.18)6Rma Robertsonian translocation cannot be ruled out (Beechey and Searle, 1980). Therefore, the amount of chromosomal material between Sd and the centromere may be underestimated (Figs. 2A and 2D). The alignment of the IB map with the chromosome atlas cytological map predicts that -14 CM of chromosome 2 lies proximal to the Spna2 locus. Identification of Molecular Existing Mutations

Loci at or near

There are several examples of genes that may be candidates for existing mutations on the basis of their map location. Previous studies showed that the Pax-l gene most likely identifies the un mutation (Balling et al., 1988). Homeobox-containing genes are believed to play a role in development relating to the establishment of positional information (reviewed by Holland and Hogan, 1988). It has recently been proposed that the Hex-5.1 gene may be involved in the rachiterata (rh) mutation, based on its map location from in situ hybridization and the pattern of expression of the Hox5.1 gene (Featherstone et al., 1988). Analysis of developing mouse embryos has shown that the Hox-5.1 gene is expressed in the spinal cord and prevertebrae (Featherstone et al., 1988). Compared to normal mice, homozygous rh mice have abnormal vertebral development that results in the absence of one cervical vertebra and malformations of the thoraco-lumbar region (summarized by Green, 1981b). Abnormalities in rh/ rh mice have been detected as early as Day 11 of development, consistent with the earliest observed expression of the Hox-5.1 gene. In addition, several homeobox-containing genes that compose the Hoxd gene complex have recently been identified and shown to be tightly linked to the Hox-5.1 gene (Duboule and Dolle, 1989). Therefore, genes of the Hox-5 complex are potential candidates for the rh mutation. The map positions of both Hox-5.1 and Acra genes indicate that these genes also map in the region of the muscular dystrophy with myositis (m&n) mutation (Lane, 1985). The mdm mutation is a recessive lethal mutation that arose spontaneously; homozygous mutant mice show deformed curvature of the spinal column and become stiff and immobile, usually dying by 2 months of age (Lane, 1985); histological analysis revealed severe degeneration and inflammation of mus-

2 LINKAGE

MAP

497

cles. The acetylcholine receptor (AChR) expressed in vertebrate skeletal muscle is a transmembrane protein that serves as a neurotransmitter receptor; AChR is composed of four subunits arranged as an a&y6 pentamer (reviewed by Changeux et al., 1984). The Acra gene encodes the a-subunit of the AChR receptor. Comparisons of the mammalian muscle acetylcholine receptor a-subunit precursors to those of the electric eel have identified regions that are potentially involved with acetylcholine binding and the ion channel (Noda et al., 1983). Therefore, Acra is a potential candidate gene for the mdm mutation. The tight skin (Tslz) mutation is a spontaneous mutation that is homozygous lethal in utero. Heterozygotes have tight skins, a dermis that is thicker than normal, hyperplasia of connective tissue, and increased growth of cartilage and bone (summarized by Green, 1981b). Both 11-la and 11-lb map in the same region as the Tsk mutation (D’Eustachio et al., 1987; Siracusa et al., 1989). In addition to the numerous effects of 11-l on the immune system, 11-l is involved in inflammation and wound healing (reviewed by Oppenheim et al., 1986; Dinarello, 1988). 11-l has been implicated in bone remodeling and repair; 11-l can induce differentiation of osteoblasts as well as stimulate proliferation of bone cells and bone resorption. Therefore, 11-la and 11-lb are potential candidate genes for the Tsk mutation. If the genes listed above are not involved in mutant phenotypes, they may be useful for gaining molecular access to the mutations of interest. Additional crosses can be performed to determine precisely the distance of the molecular probes from the mutations of interest; any recombinant mice obtained would be useful for determining the direction of chromosome walking from the molecular starting point to the mutation of interest. The close proximity of the Psp and Emu-15 loci to the agouti locus has already been presented (Lovett et al., 1987; Siracusa et al., 1987a,b, 1989). These loci are not responsible for agouti phenotypes but map within chromosomal walking distance and thus provide molecular access to the agouti region. Identification of Recessive Oncogenes by Deletion Mapping Interstitial deletions of mouse chromosome 2 have been correlated with the appearance of radiation-induced myeloid leukemias (Hayata et al., 1983; Resnitzky et al., 1985). The deletions are hemizygous; one copy of chromosome 2 remains intact. The high incidence of deletions and the detection of deletions in the preleukemic phase (Trakhtenbrot et al., 1988) strongly suggest that deletion of chromosome 2 plays an important role in the development of myeloid leukemia. These hemizygous deletions are compatible with several mechanisms of oncogenesis, including (1) a dosage

498

SIRACUSA

effect, (2) oncogene activation, and (3) reduction to homozygosity leading to expression of a mutant allele on the intact chromosome. Two groups have performed extensive cytological analysis of numerous radiation-induced myeloid leukemias; the results showed that two regions were commonly deleted: region 2C-D (Hayata et al., 1983) and region 2D-G (Resnitzky et al., 1985). It seems most likely that if the myeloid leukemias observed by both groups have a single cause, then the gene(s) involved must reside in band 2D. To limit the region involved, molecular probes identifying loci known to reside on chromosome 2 (Abl, B2m, Src-1, and Hox-4.1) were used to screen the leukemias (Blatt and Sachs, 1988; Silver et al., 1988). The Hox-4.1 locus was the only locus found to be deleted in four leukemias analyzed (Blatt and Sachs, 1988). The Hox-4.1 locus (Lonai et al., 1987) is probably a member of the Hoxd gene complex (Duboule and Dolle, 1989); its absence is consistent with the in situ localization of Hon-5.1 to band 2D (Featherstone et aZ., 1988). It is conceivable that a homeoboxcontaining gene may be causally associated with radiation-induced myeloid leukemia (Blatt and Sachs, 1988) or, alternatively, that the gene(s) involved is closely linked to the Hox-5 gene complex. Our IB map of chromosome 2 (Fig. 2C) suggests additional molecular probes (such as those identifying the Acra, Gcg, Gas-1, Fshb, and Ltk loci) to be used in analysis of radiation-induced myeloid leukemias; the results will further refine the extent of the deleted region and may lead to the gene(s) responsible for leukemogenesis. It is likely that a recessive oncogene involved in the human WAGR syndrome maps near Cm-1 and Fshb on mouse chromosome 2 (see below). In addition, the TALL translocation breakpoint cluster region found in human T-cell leukemias maps close to, but distinct from, the WAGR locus (Boehm et al., 1988). It will be interesting to determine whether these loci are involved in radiation-induced myeloid leukemogenesis as well. Mouse-Human Homologies Figure 3 shows the positions of linkage homologies in mouse and human. The map is based on our IB analysis, with additional markers added from comparisons made between the IB map (Fig. 2C) and the chromosome atlas genetic map and the composite mouse map (Figs. 2A and 2D). We tried to present the simplest interpretation of the map, based on minimizing interruptions of conserved linkage groups between mice and humans. Ultimately, the order of the loci not mapped in our IB will have to be confirmed. The placement of Blur just distal to Fshb is based on its published map location (von Deimling et al., 1984; Hilgers and PoortKeesom, 1986; Peters et al., 1989) and the fact that another locus that maps to human chromosome 11~13

ET

AL.

resides -3 CM proximal to &s-l on mouse chromosome 2 (N. A. Jenkins, N. G. Copeland, A. Seawright, W. A. Bickmore, N. D. Hastie, unpublished results). The order of the loci mapping to human chromosome 15q is our best estimate based on comparisons of our data for Ltk with previously published reports for Actc1 (Crosby et al., 1989) and Sdh-1 (Andrews and Peters, 1983). Mouse chromosome 2 has loci that are homologous to at least six human chromosomes. References describing the mapping of homologous loci in the human genome are listed in the legend to Fig. 3. Mouse chromosome 2 shows five regions of conserved synteny with human chromosomes: (1) a 9.6-cM region with human chromosome 9q, (2) an 8.4-CM region with human chromosome 2q, (3) an 0.8-CM region with human chromosome llp, (4) an -~-CM region with human chromosome 15q, and (5) an -21-CM region with human chromosome 20. Mouse chromosome 2 also exhibits 2 regions of homology with human chromosomes: (1) Blur maps to human chromosome 7p14-ten, and (2) 11-la and 11-lb map to human chromosome 2q13 and 2q13-q21, respectively. From comparisons of mouse and human linkage maps, we can predict the locations of certain loci in the human genome. It is interesting to note that the murine homologs of genes mapped to human chromosome 20 have been mapped only to mouse chromosome 2 to date (summarized by Nadeau, 1989). This observation suggeststhat loci mapped to mouse chromosome 2 between the Pm-p and the Ada loci, such as the Pax-l locus and the ugouti locus (Siracusa et al., 1989), have potential homologs on human chromosome 20. Mouse Models of Human Diseases Deletion of human chromosome 11~13 has been implicated in the genesis of the WAGR (Wilms tumor, aniridia, gonadoblastoma, mental retardation) syndrome (summarized by McKusick, 1988). Translocation and deletion mapping of molecular probes has provided evidence for closely linked but separate loci involved in Wilms tumor (WT) and aniridia (AN2); the two loci are known to lie between the CAT and the FSHB loci in the order centromere-CAT- WT-AN2FSHB (Glaser et al., 1986; Davis et al., 1988; Seawright et al., 1988). We have mapped Co-s-1proximal to Fshb on mouse chromosome 2 and defined this region of conserved synteny with human chromosome 11~13. The map location places Gas-1 and Fshb in the region of small eye (Sey) (Fig. 2), a hereditary semidominant spontaneous mutation that results in lens thickening, an absent orbit that results in an asymmetric skull and brain, and other tissue adhesiveness (summarized by Green, 1981b). We predict that the Sey locus resides

MOUSE

Mouse Chromosome

4.8

CHROMOSOME

2

2 LINKAGE

499

MAP

Location in Human Genome

Human Gene Name

' Spna-2

9q33-q34

SpTANl

- Ah/Ass

9q34.1, 9q34

Ai%, ASS

' c5

9q32-q34

c-25

- Gcg

2q36-q37

GCG

1 Acra, Hex-51

2q24-932.

Cas-l / %Y -Fshb BZvr Sdh-1 Adc-f j 55%

llp13 1 lp13 llp13 7p14-ten

L//-fa, fl-fb ..,Pm-p PP

2q13, 2q13-q21 ZOpter-p12 20pter-ten

t Hck-1 Src-1 Ada

ZOqll-q12

HCX

2Oql2-ql3 2oq13.1-q13.2

SRCI

4.8

a.4

9.1

0.8

10.9

0.9 3.3

2q3 1 -q37

CHRNA, Cf3

15pter-q21 15qi 1-qter

tg21-q22

FIG. 3. Comparative map of mouse-human homologies. The map of mouse chromosome 2 is based on the IB map (Fig. 2C); the recombination distances listed are from the 13 analysis. The loci with dotted lines intersecting chromosome 2 were added to the IB map from comparisons with the chromosome atlas genetic map (Fig. 2A) and the composite mouse map (Fig. 2D). The map locations and gene names in humans are listed to the right of the mouse chromosome 2 map. The black areas show conserved regions between mice and humans. The chromosomal locations of homologous loci in humans are from the following sources: SPTANl (5, 76); ABL (6, 30, 59, 69); ASS (20, 21, 85); C5 (67, 130); GCG (113, 125); ACRA (10); Cl3 (18); CAT (45,47, 70,95, 104, 115,126); AN2 (46), FSHE (45,47,104,115, 128); BLVR (86,99); SORD (36), ACE (54); TYKl (8, J. Kroleweki, R. Eddy, T. B. Shows, and R. Dalla-Favera, personal communication); J32M (43, 49,116); ZLlA (72,89); ILIB (129); ITPA (65,84,90); PRNP (77,107, 121); HCK (105); SRCl (75, 112); and ADA (68,91,101,102,123).

between Gas-I and Fshb in the mouse and is the mouse homolog of human aniridia. Recent studies have shown that molecular probes from the human 11~13 region

segregate with the Sey mutation in the mouse; in addition, a subset of these probes is deleted in an allele of Sey, the Dickie small eye (By) mutation (Glaser

SIRACUSA

500

and Housman, 1989). Thus, the Sey mutation and its alleles now provide a mouse model for the study of human aniridia (Glaser and Housman, 1989). The mouse mdx mutation has proven to be a valuable model system for Duchenne muscular dystrophy in humans (Ryder-Cook et al, 1988). In addition to Xlinked muscular dystrophy in humans, an autosomal recessive form of muscular dystrophy (muscular dystrophy II) that is similar to Duchenne muscular dystrophy has been observed (summarized by McKusick, 1988). The age of onset is before 5 years, with death usually occurring prior to 20 years. Although this form of muscular dystrophy has not yet been mapped, the parallels to the mouse mdm mutation in age of onset, morphology, and mode of inheritance (seeabove) leave open the possibility that mdm mice may serve as a model system for muscular dystrophy II in humans. The potential involvement and/or close linkage of Acra and the Hox-5 gene complex to the mdm mutation in the mouse (see above) suggests that these molecular probes can serve as a starting point for linkage analyses aimed at identifying molecular probes for muscular dystrophy II in humans. These analyses will ultimately lead to identification of the map location of muscular dystrophy II in humans and to the genes responsible for the disease.

ET AL.

5.

6.

7.

8.

9. 10.

11.

12. ACKNOWLEDGMENTS We thank P. C. Watkins, B. F. Tack, G. F. Saunders, G. Radice, J. P. Merlie, B. A. Mock, T. L. Leto, J. Lee, E. M. Either, F. Costantini, and G. A. Carlson for generously sharing their resources with us. We thank M. F. Lyon and D. P. Doolittle for valuable scientific discussions and for granting us permission to publish their maps of mouse chromosome 2. We thank A. S. Perkins, I. J. Jackson, A. M. Buchberg, and W. A. Bickmore for critically reviewing the manuscript. We thank A. M. Buchberg for help in constructing the figures. We thank S. Yang, D. A. Swing, A. Seawright, B. Eagleson, J. Diem, W. Chan, and M. Bodamer for excellent technical assistance. The research was supported in part by the National Cancer Institute, DHHS, under Contract NOl-CO-74101 with BRI. NCI-FCRF is fully accredited by the American Association for Accreditation of Laboratory Animal Care. L.D.S. is the recipient of a National Research Service Award, Postdoctoral Fellowship GM12721-01. J.A.M. is a Leukemia Society of America Fellow.

13. 14.

15.

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