A Comprehensive Genetic Map of Murine Chromosome 11 Reveals Extensive Linkage Conservation Between Mouse and Human

Home , Chromosome 11, Chromosome 17, Chromosome 18

Arthur M. Buchberg,* Elise Brownell: Shigukazu Nagata? Nancy A. Jenkins* and Neal G. Copeland* *Mammalian Genetics Laboratory, BRI-Basic Research Program, NCI-Frederick Cancer Research Facility, Frederick, Maryland 21 701,+Molecular Therapeutics Inc., West Haven, Connecticut 06516, and *Osaka Bioscience Institute, Suita, Osaka 565, Japan Manuscript received November 8, 1988 Accepted for publication January9, 1989

ABSTRACT Interspecific backcross animals froma cross between C57BL/6J andMus spretus mice were used to generate a comprehensive linkage map of mouse chromosome11. The relative map positions of genes previously assigned to mouse chromosome I1 by somatic cell hybrid or genetic backcross analysis were determined (Erbb, Rel, 11-3, Csjp, Trp53-1, Evi-2,Erba, Erbb-2, Csjg, Myhs, Cola-1, Myla, Hox-2 and Pkca). We also analyzed genesthat we suspected would mapto chromosome 11 by virtue of their location in humanchromosomes and the known linkage homologies thatexist between murine chromosome 11 and human chromosomes (Mpo, Ngfr, Pdgfr and Fms). Two of the latter genes,Mpo and Ngfr, mapped to mouse chromosome 11. Both genes also mapped to human chromosome 17, extending the degree of linkage conservation observed between human chromosome 17 and mouse chromosome 11. Pdgfr and Fms, which are closely linked to 11-3 and Csfp in humans on chromosome 5, mapped to mouse chromosome18 rather than mouse chromosome11, thereby definingyet another conserved linkage group between human and mouse chromosomes. The mousechromosome 11 linkage map generated in these studies substantially extendsthe framework for identifying homologous genes in the mouse that are involved in human disease, for elucidating the genes responsible for several mouse mutations, and for gaining insights into chromosome evolution and genome organization.

STABLISHMENT of comprehensive multilocus Thus, identification and mapping of a mutation on E linkage maps for mouse chromosomes will pro- the X chromosome of one mammalian species would vide important tools for studying genome organiza- enable the identification of homologous loci on theX tion and linkage conservation betweenspecies. Exten- chromosome of another mammalian species. sive linkage maps will also aid in the identification of The ability to perform a multilocus linkage cross animal models of genes important in human devel- with the mouse has beenhindered because most opment and disease, as well as in the accurate place- inbred mouse strainsare closely related (FERRIS,SAGE ment of genes alongthe total length of a chromosome. and WILSON1982). The relatedness between inbred A recent example of the identification of an animal strains makes identificationof restriction fragment model for human disease via chromosome mapping is length polymorphisms (RFLPs) or protein polymor- the congenital goiter, cog, mutation in the mouse phisms for multiple loci difficult. However, a powerful (TAYLORand ROWE1987). Hereditary hypothyroid- genetictechnique for establishing genetic linkage ism in humans has been associated with defects in the maps has been recently described(ROBERT et al. 1985; thyroglobulin, TG, locus (VAN HERLE,VASSART and reviewed in AVNERet al. 1988). This technique,analy- DUMONT1979). Thisknowledge enabledTAYLOR and sis of the segregation of polymorphic alleles in inter- ROWE (1987) to demonstrate that thecog mutation in specific backcross progeny, enables the simultaneous mice is closely linked to the Tg locus and may be a mapping of numerous loci in a single cross. The mutation in the Tg structural locus. Another example strength of the technique resides in the evolutionary of the value of cross-species mapping has been dem- distancebetween the twoparental species used in onstrated for the mammalian X chromosome. This these crosses, Mus domesticus (represented by C57BL/ chromosome has been highly conserved throughout 6J in thesestudies) and Mus spretus (BRITTONand evolution (OHNO1969); mapping comparisons have THALER1978). This evolutionary distance, 3-5 mil- demonstrated that the human X chromosome can be lion years (BONHOMMEet al. 1984), has allowed for made colinear with the murine X chromosome by a the accumulation of DNA sequence differences be- minimum of five inversion events (AVNERet al. 1988). tween the two species; these sequence differences are

Crenetics 122: 153-161 (May, 1989) 154 A. M. Buchberg et al. revealed in the form of RFLPs. Numerous examples ase digestion,agarose gel electrophoresis, Southern blot of linkage maps generated from interspecific mouse transfer, hybridization and washes were performed as described (JENKINS et al. 1982; BUCHBERGet al. 1988). backcrosses have been reported (AMAR et al. 1985; Probes: The probes used and their corresponding loci AVNERet al. 1987; BUCANet al. 1986; BUCHBERCet are listed in Tables 1 and 2. al. 1988; DAUTICNYet al. 1986; ROBERTet al. 1985; Statistical analysis: Statistical analysis of the recombina- SELDINet al. 1987; WEYDERTet al. 1985). With the tion frequencies from theresults of interspecificbackcrosses exception of the proximal region of chromosome 17 was performed by calculating the maximum likelihood esti- mates of linkage parameters as described by GREEN (1 98 l), (M. HAMMER andL. M. SILVER,personal communi- using the computer program “SPRETUS MADNESS” (de- cation), no large chromosome alterations have been veloped by D. DAVE [Data ManagementServices, Inc., Fred- found to exist between M. spretus and M. domesticus. erick,Maryland] and A. M. BUCHBERG).Gene order was Thus, the maps generated by interspecific backcross confirmed by the maximum likelihood analysis (BISHOP analyses are colinear with linkage maps generated 1985). Statistical analysis of the number of double recombinants was performed by W. G. ALVORD (Data Manage- using standard laboratory mice (reviewed in AVNERet ment Services, Inc., Frederick, Maryland); the statistic test al. 1988). used was a large sample normal approximation to thebino- We have been interested in developing an extensive mial distribution. linkage map of mouse chromosome 1 I because of the largenumber of proto-oncogenes,growth factors, RESULTS growth factor receptorsand common viral integration sites that are known to map to mouse chromosome Identification of RFLPs and mapping of loci on 11. Our previously reported linkage analysis of mouse chromosome 22: Genomic DNA from C57BL/6J and chromosome I I, which included the genes Erbb, Rel, M. spretus animals was digested with several restriction 11-3,Csfgm, Trp53-I, Evi-2, Erba, Erbb-2 and Csfg endonucleases and analyzed by Southern blot hybrid- (BUCHBERCet al. 1988), has now been extended by ization using probes for the loci listed in Table 1 to examining the linkage of these and several additional identify RFLPs useful for gene mapping.The strength loci in 144 N2 interspecific backcross progeny. The of interspecific backcross analysis was realized in these additional loci examined include: 1) loci defined by studies in thatat least one informativeRFLP was the viral integration sites Pad-I, Mov-9 and Int-4 (A. identified for each probe (Table 1). SONNENBERC,personal communication; RIJSEWIJKet The segregation of M. spretus alleles in 144 al. 1987; CHUMAKOVet al. 1982; H. ROELINKand R. [(C57BL/6J X M. spretus) X C57BL/6J] backcross NUSSE, personal communication; NUSSE 1988); 2) progeny was then followed by Southern blot analysis structural genes Myhs, Cola-I, Mpo and Myla (WEY- using each of the probes listed in Table 1. The results DERT et al. 1983; HARBERSet al. 1984; MORISHITAet of the segregation analysis are summarized in Figure al. 1987; BARTONet al. 1988); 3) growth factor recep- 1. Mice were either heterozygous for the C57BL/6J tors and protein kinase genes Ngfr, Pdgfr,Fms and and M. spretus alleles or homozygous for the C57BL/ Pkca (JOHNSON et al. 1986; PARKERet al. 1986; YAR- 6J allele at each locus. No novel genotypes were DEN et al. 1986; GISSELBRECHTet al. 1987); and 4) a observed. The frequency of C57BL/6J and M. spretus gene potentially important in development, Hox-2 alleles for all of the loci examined in the N2 progeny (HAUSERet al. 1985; JOYNER et al. 1985; HARTet al. didnot differ significantly fromthe expected 1:l 1988). The results of the mapping analysis have re- ratio. Gene order was determined by minimizing the vealed further extensive linkage homology between number of doublerecombinants between loci and mouse chromosome 1I and human chromosome I7 confirmed by the maximum likelihood analysis as well as several other human chromosomes. These (BISHOP 1985). Erbb, the most proximal marker in the results also aid in identifying genes in the mouse that cross, was used as the anchor locus, and the other loci are homologous to genes involved in human disease. were placed distal to Erbb as shown in Figure 2. The distance between loci wascalculated as follows: Erbb- 3.5 1.5 cM-ReE--12.5 2.5 cM-Pad-1-6.3 k MATERIALSAND METHODS f fz 2.0 cM-[I1-3, Csfgml-6.3 f 2.0 cM-Myhs-4.9 * Mice: The C57BL/6J inbred strain is maintained at the 1.8 cM-Trp53-1-2.0 f 1.2 cM-Mov-9-0.7 k 0.7 NCI-Frederick Cancer Research Facility. The Mus spretus cM-Evi-2-11.2 f 2.6 cM-[Cola-I, Hox-21-0.7 * mice were at the F7,F9, Flo or Fl2 generation of inbreeding 0.7 cM-[Erba, Erbb-2, Csfgl-4.2 1.7 cM-[lnt-4, and were a gift from E. M. EICHER[The Jackson Laboratory f (Bar Harbor, Maine)]. The interspecific backcross [(C57BL/ Myla]-3.5 f 1.5 cM-Pkca. 6J X Mus spretus) X C57BL/6J] was performed at the NCI- There were several groups of lociin which no Frederick Cancer Research Facility as described previously recombinants were observed, indicating a maximum (BUCHBERGet al. 1988); a total of 144 N2 progeny were map distance of 1.4 cM (upper 95% confidence limit) analyzed for this report. between the loci in each cluster. These clusters were DNA isolation and Southern blotanalyses: High molecular weight genomic DNAs were preparedfrom frozen 1) 11-3 and Csfgm; 2); Cola-I and Hox-2; 3) Erba, Erbb- mouse tissues (JENKINS et al. 1982). Restriction endonucle- 2 and Csfg; and 4) Myla and Int-4. Linkage Map of Mouse Chromosome 11 155

TABLE 1 Listing of loci initially mapped in the interspecific backcross animals

C57BL/6J frag- M. sgrehrs frag- Locus Gene name Probe Enzyme ment sizes (kb) ment sizes (kb)" Reference

Cola-I cul-Collagen PI TaqI 4.6, 3.3, 2.5, -4.8, 3.3, 2.5, HARBERSet al. (1984) 2.1, 1.5, 1.0 2.1, 1.5, 1.0 csfg Granulocyte colony-stim- pBRG-4 TaqI 3.9 -2.5 TSUCHIYAet al. (1986) ulating factor csf- Granulocyte-macrophage pEl-11 PstI 2.8 -6.4 MIYATAKEet al. (1985) colony-stimulating factor 11-3 Interleukin-3 fpGV-IL 12 Msp 1 2.1 2.4, 1.4 FUNGet al. (1984), BUCH- " BERG et al. (1988) Erba Avian erythroblastosis vi- v-ErbA Tag I 4.4, 4.1, 1.5 -2.3, 1.5 BUCHBERCet al. (1988) rus A oncogene Erbb Avian erythroblastosis vi- v-ErbB BamHI 9.3 -11.0 BUCHBERGet al. (1988) rus B oncogene Erbb-2 Neu proto-oncogene neuc(t)/sp64OO PstI 4.0 -4.4 BARGMANN,HUNG and WEINBERC(1 986) Evi-2 Ectropic viral integra- p597.1 Taql 2.1 -1.7 BUCHBERGet al. (1988) tion site-2 HOX-2 Homeobox locus-2 pMu 1 Mspl 2.4 1.9, 0.5 JOYNERet al. (1985) " Int-4 MMTV integration site-4 pBG 14 Tag1 4.4 -6.8 H. ROELINKand R. NUSSE(personal communication) MOV-9 Moloney virus integra- pM0v9- 1-2 MspI 3.5 -1.9 CHUMAKOVet al. (1982) tion site-9 Myhs Myosin heavy chain P32 Taql 18.5, 12.2, 11.0, 18.5, 12,2, 11.0, WEYDERTet al. (1983) 6.0, 4.9, 4.5, -9.0, 3.3, 2.5 3.3, 2.5 Myla Myosin light chain PMYIa Taql 6.5, 2.3, 1.5, 1.0 -4.8, 2.3, 1.5, 1.0 BARTONet al. (1 988) Pad-1 MMTV LTR integration pPad- 1 TaqI 6.0 -2.4 A. SONNENBERC(personal site communication) Pkca Protein kinase C a-chain pbPKC-a2 1 Hind111 13 -9.3 PARKERet al. (1 986) Re1 Reticuloendotheliosis vi- v-re1 Tag1 10.0 -4.7 BROWNELLet al. (1985) rus oncogene Trp53-I Transforming protein 53 p53-~19 BglI 18.0 -5.8 BENCHIMOLet al. (1 984)

a Underlined restriction fragment size indicates the segregating allele(s) that was typed in the analysis.

and Fms are linked to 11-3 and Csfgn on human chromosome 5 (YARDENet al. 1986). We were interested in determining if the linkage of Pdgfr and/or Fms to 11-3 and Csfgm was conserved between mouse and man. RFLPs were identified for Pdgfr and Fms (Table 2) and the segregation of M. spretus alleles was followed in the N2 backcross animals. There was no FIGURE1 ."Summary of the results of the interspecific backcross analysis. Genes mapped in the analysis are listed on the left. Each evidence of linkage of Pdgfr and Fms to any locus on column represents the chromosome identified in the N2 progeny chromosome 11 (data not shown). However, the re- that was inherited from the [C57BL/6J X M.spretus] FI parent. sults demonstrated that Pdgfr and Fms were closely The black boxes represent the presence of a C57BL/6J allele and linked (no recombinants in 86 N2 animals scored), the open boxes represent the presence of a M. spretus allele. The number of each type of chromosome dbserved in the interspecific and map to mouse chromosome 18 (HOGGANet al. backcross analysisis listed at the bottom. 1988). Close linkage of Fms and Pdgfr in the mouse is consistent with their close linkage in humans (ROB- Linkageconservation between human chromo- ERTS et al. 1988). some 5 and mouse chromosome 22: 11-? and Csfgm, Linkageconservation between human chromo- which map to mouse chromosome 11, have been some 27 and mouse chromosome 22: Comparative localized to human chromosome 5 (IHLE,SILVER and mapping results demonstrated that mouse chromo- KOZAK1987; HUEBNERet al. 1985). The genes Pdgfr some 11 contains an extensive region of homology to 156 A. M. Buchberg et al. ing the extent of this linkage conservation between mouse chromosome 11 and human chromosome 17. Ngfr and Mpo have been localized to human chromosome 17 near Hox-2 and Erba at band q21 (HUEBNER et al. 1986; VAN TUINENet al. 1987a; CHANCet al. 1987). Ngfr and Mpo have not been previously localized in the mouse. RFLPs were determined for Ngfr and Mpo (Table 2). The segregation of M. spretus alleles was determined in the interspecific backcross progeny. The results of the segregation analysis revealed that Ngfr and Mpo are localized to mouse chromosome 11 and allowed for a placement of these genes on chromosome 11 (Figures 1 and 2). The mapping results place oe. eo. Cfep Mpo 5.6 f 1.9 cM distal to Evi-2 and 5.6 f 1.9 cM Acrb. Myhs * proximal to Cola-1. Ngfr mapped to the gene cluster Hhs) BdafRe) defined by Cola-1 and Hox-2, with no recombinants &?&? Re. Bsk, Rnufe-f. &t among any of these three genes. ShmfRe) /I/Re)

A/ DISCUSSION Bbv rs We have generateda multilocus linkage map of 11. 70% J7W-ps X2 Mlv-3 f&-3), My/a * mouse chromosome This mapcovers over of ~~*"Es-5cod {Es-3) the chromosome [55.8 cM mapped out of a total ii 1s length of 78 cM for mouse chromosome 11 (T. H. Mmv-ff RODERICK,M. T. DAVISSON,A. L., HILLYARDand D. Mmv-13 Mmv-6 P. DOOLITTLE,personal communication)]. The den- 17p Rpo2-f 17q21-q22 Tk-f sity of markers in this cross was 0.34 loci/cM (19 loci 17 Tse-f Umpb-2 mapped over a 55.8 cM distance, with the largest xmv-4 Xmv-5 distance between two adjacentmarkers being 12.5 cM). Thus, we are quite confident of detecting most, FIGURE2.-Linkage map of mouse chromosome 11. The chromosome on the right shows the 1988 linkage map of mouse chro- if not all, double recombinants. A total of 69 single mosome I1 compiled by T. H. RODERICK,M. T. DAVISSON,A. L. crossover events were detected among 144 informa- HILLYARDand D. P. DOOLIITLE (personal communication). The tive interspecific backcross animals. Six double recom- loci with asterisks (*) indicate differences in map position as deter- binants were observed (Figure l), which is not signif- mined from this study (see DISCUSSION).The chromosome on the icantly different 0.05) from the expected number left is the linkage map of mouse chromosome I1 generated from (P> our interspecific backcross analysis. The loci mapped in this study of 11 double recombinants. and their distance in cM from each neighboring locus are shown Comparison to previouslypublished mapping on the left chromosome. Located between the two chromosomes data: Several loci mapped in our analysis have previ- are thelocations of the underlinedloci on the human chromosome ously been positioned on mouse chromosome 11. Hox- linkage map. 2 has been localized 1 cM proximal to Rex (Re)by the analysis of recombinant inbredand intraspecific back- humanchromosome 17 (reviewed in NADEAUand cross animals (HARTet al. 1988). Our results using REINER1989). We have been interested in determin- multilocus interspecific backcross analysis place Hox-2

TABLE 2 Listing of loci mapped in the interspecific backcross animals based on human-mouse homologies

M. sprefus C57BL/6J frag- fragmentsizes Locus name Gene sizes Probe ment Enzyme (kb) (kb)" Reference Fms Feline sarcoma virus oncogeneI-ppl 34 Mspl 3.2 -3.5 SOLAet 01. (1 986) (Csfm receptor) Mpo Myeloperoxidase Mpo pCM706 BamHI 2.4 -4.0 MORISHITAet ai. (1 987) NgfrNerve growth factor receptor P5b Taq I 6.8, 3.4, 1.8 6.9, 3.4, 1.8 B~~~etal.(1989) PdgfrPlatelet-derived growth factor pGR 102 TaqI 7.1, 4.8, 1.5 5.6, 3.4, 1.5 YARD EN^^^^. (1986) - receptor Underlined restriction fragment size indicates the segregating allele(s) thatwas typed in the analysis. Linkage Map of Mouse Chromosome 11 157 in the same location (1 cM proximal to Re) using as frequency (Xu et al. 1987), indicating that they are the sole anchor locus, Erbb, which is 47 cM proximal closely linked in humans. to Hox-2. The results of the Hox-2 mapping provide Linkageconservation between human chromo- support for the utility and fidelity of using interspe- some 5 and mouse chromosome 21: A small con- cific backcross analysis for linkage studies. served linkage group, defined by Csfp and 11-3, has Myhs was previously placed on mouse chromosome been identified between human chromosome 5q and I I, 33 cM distal to Hba, by interspecific backcross mouse chromosome I I (BARLOWet al. 1987; BUCH- analysis (ROBERTet al. 1985; WEYDERTet al. 1985); BERG et al. 1988). Another locus, sparc (osteonectin), these results would place Myhs 1 cM distal to cocked has also been mapped to both human chromosome5q (co) and openeyelids (oe) (Figure 2). However, our and mouse chromosome I I, showing linkage with results place Myhs approximately 10 cM proximal to Csfgm and 11-3 in both mouse and human (MASONet co and oe (Figure 2). The original mapping studies of al. 1986; SWAROOP,HOGAN and FRANCKE 1988). This Myhs used hemoglobin a-chain (Hba)and esterase-3 (Es- findingdefines a thirdmember of the conserved 3) as flanking markers; these two genes are 61 cM linkage group. However, it is evident that other loci, apart on chromosome 11. The large distance separat- such as Pdgfr, Csfi and Fms, which also map to human ing these markers would preclude a precise localiza- chromosome 5q, are not located on mouse chromo- tion of Myhs on chromosome 11. Our multilocus link- some 11. Two of these genes, Pdgfr and Fms, map to age analysis, with a marker density of 0.34 loci/cM, mouse chromosome 18, defining yet another con- allows for a more precise placement of Myhs on chro- served linkage group between mouse and human (HOGGANet al. 1988; this study). The chromosomal mosome 11. Similarly, we find a different map loca- location of Csfm is presently unknown; however, in- tion for Myla from that previously published. Myla terspecific backcross analysis indicated that it does not was originally placed 6.8 zk 3.3 cM proximal to Es-3 map to mouse chromosome I I or mouse chromosome using interspecific backcross analysis (ROBERTet al. 18 (BUCHBERGet al. 1988; this study). The long arm 1985) andis placed 3 cM proximal to Es-3 on themost of human chromosome 5 is often deleted in human recent mouse chromosome map(T. H. RODERICK,M. myeloid disease, macrocytic anemia and acute non- T. DAVISSON,A. L. HILLYARDand D. P. DOOLITTLE, lymphocytic leukemia (5q- syndrome) (reviewed in personalcommunication). Although we didnot in- BUNN1986). The genes Zl-3, Csfgm, Fms and Csfi clude Es-3 in our cross, our results would place Myla are almost always deleted in this syndrome (LEBEAU approximately 13 cM proximal to its previous loca- et al. 1986).However, todate no deletion or re- tion. arrangement of mouse chromosome I I has been as- Clusters of genes on chromosome 22: The inter- sociated with murine myeloid disease. The absence of specific backcross analysis reportedhere identified a comparable 5q- syndrome in mice may reflect the four clusters of closely linked genes (there were no dispersion of the gene(s) involved in the 5q- syndrome recombinants out of 144 progeny analyzed, indicating in mice. There are several other genes that map to a maximum map distance of 1.4 cM, 95% confidence human chromosome 5q, including the monocyte cell interval). These clusters were: 1) 11-3 and Csfp; 2) surface antigen, CD14, &adrenergic receptor (ADRBR) Cola-1, Ngfr and Hox-2; 3) Erba, Erbb-2 and Csfg; and and acidic fibroblast growth factor (endothelial growth 4) Myla and Int-4. The presence of gene clusters factor, FGFA) (GOYERTet al. 1988; KOBILKA et al. implies either close linkage or may result from small 1987; MODI, JAYE and O’BRIEN 1987). It will be of inversions in M. spretus chromosomes relative to interest to determine the chromosomallocalization of C57BL/6J chromosomes, causing a suppression of these genes in mouse to determine the extent of the recombination in these regions. The latter explana- linkage conservation with mouse chromosome I I and tion seems unlikely for several reasons. First, the map 18. position of Hox-2 was accurately determined in the Linkageconservation between human chromo- interspecific cross using an anchor locus, Erbb, that some 27 and mouse chromosome 12: A much larger mapped 47 cM proximal to Hox-2. Second, Csfpand conserved region is observed when the distal portion 11-3 are known to be closely linked molecularly in of mouse chromosome I I is compared to human mouse; both loci are presenton the same 230-kb chromosome 17. To date, every locus on human chro- restrictionendonuclease fragment (BARLOW et al. mosome I7 that has been mapped in the mouse has 1987). Thus, the close genetic linkage of 11-3 and been localized to mouse chromosome 11, distal to Csfpwas not unexpected. Similarly, Erbb-2 and Erba Myhs. The map distance between Myhs and galactoki- are frequently coamplified in human tumors (VANDE nase (Glk), the most proximal and distal marker on VIJUERet al. 1987)and gene transfer experiments mouse chromosome 1 I showing synteny with human involving human chromosome I7 have demonstrated chromosome 17,is 36 cM (Figure 2). This conserved that Ngfr, Cola-I and Hox-2 are cotransferred at a high region represents one of the largest conserved seg- 158 A. M. But Ehberg et al.

1977; LARSONet al. 1984). Two gene clusters, defined P53 by 1) Ngfr, Hox-2 and Cola-I and 2) Erba, Erbb-2 and Csfg (regions I1 and 111, respectively, in Figure 3), KYHS Mybs which map 0.7 & 0.7 cM apart onmouse chromosome 6RBB-2 Trp53- f I I, have been mapped to the long arm of human ERBA APL Breakpoint dfl MPO chromosome 17. The two clusters map to either side MPO of the APL breakpoint (Xu et al. 1987). The location COLA -I Co/a - f. Ngfc HOX-2 NCFR Erbb-2, Erba, Csfg of MPO is distal to the APL breakpoint but proximal /ox-2 to both these closely linked clusters on mouse chro- PKCA pkC8 mosome 11, indicating the presence of at least one rearrangement in this interval between the two chro- Human Chromosome f7 Mouse Chromosome ff mosomes. Pkca which maps distal on mouse chromosome I1 (region IV) (YANG-FENG,ULLRICH and FIGURE3.-Comparison of mouse chromosome I I and human chromosome 17. Mousechromosome I I (right)represents the FRANCKE 1987),also maps distal to the APL break- region of mouse chromosome I! that is homologous to human pointon human chromosome 17 (COUSSENSet al. chromosome 17 (left). Mouse chromosome I I shows the relative 1986). These observations suggest that human chro- position of loci that have beenlocalized on human chromosome17. mosome I7 can be generated from mouse chromo- The regional location of those loci are depicted on human chro- some I1 by a rearrangement in regionI andthe mosome 17. The regions of synteny are shown in different shadings and labeled with Roman numerals(I-IV). The location of the acute insertion of region I11 between region I and region I1 promyelocytic breakpoint(APL) is shown. (Figure 3). Identification of murine homologs of genes in- ments yet identified between mouse and human (NA- volved in human disease: It has been recently re- DEAU and TAYLOR1984; reviewed in NADEAUand ported that rearrangements in MPO are detected in REINER 1989). two of four cases examined of APL translocation Figure 3 shows a comparison of gene locations on chromosomes, suggesting thatMPO might be causally mouse chromosome I I with respect to their locations associated with APL (WEILet al. 1988). However, a on human chromosome 17. The loci Myhs and Trp53- causal association between these MPO rearrangements I are located 5 cM apart on mouse chromosome I I and APL has not yet been firmly established. The andare both located onthe short arm of human mapping results presented here suggest that the mu- chromosome 17 (MYHS and TP53, respectively; re- rinehomolog of thehuman chromosome 17 APL gion I in Figure 3). One would predict that the gene breakpoint region might be located between the two encoding the large subunit of RNA polymerase 11, closely linked gene clusters definedby COLA-I-NGFR- RPII (Rpo2-I, locus designation in mice), which has HOX-2 and ERBB-2-ERBA-CSFG, if this region is con- been mapped to the short armof human chromosome served between mouse and man. These clusters are I7 (CANNIZZAROet al. 1986) and to mouse chromo- 0.7 +- 0.7 cM apart, which roughly correlates to about some I I by somatic cell hybrid analysis (PRAVTCHEVA 0.8 to 1.6 million base pairs (Mbp) [assuming the total et al. 1986), would be located in the region defined length of the mouse genome is 1600 cM (RODERICK by Myhs and Trp53-I in the mouse. The next more and DAVISSON198 1) and there is 3 X 10' Mbp in the distal gene on mouse chromosome 1 I whose location mouse genome]. Alternatively, the observation that is known in humans is MPO (region I1 in Figure 3). the linear order of genes is not conserved between MPO is located on the long arm of human chromo- mouse chromosome I1 and human chromosome 17 some 17 at band q21-24 (VANTUINEN et al. 1987a; makes it difficult to predict the exact location of the CHANGet al. 1987). Since TP53-1 is located at the murine homolog of the human chromosome 17 APL telomere of the short arm of human chromosome I7 breakpoint region. In this regard, preliminary in situ and MYHS is located toward the centromere of the hybridization results using a human homolog of Evi- shortarm of humanchromosome 17 (ISOBE et al. 2, a common viral integration site in murine myeloid 1986; MCBRIDE,MERRY and GIVOL 1986;LEINWAND tumors, maps Evi-2 to human chromosome 17ql I- et al. 1983), it is evident that at least one inversion q12, in the region near the APL breakpoint (M. M. occurred to account for the inverted order of Myhs, LEBEAU, personalcommunication). This localization Trp53-1 and Mpo between mouse and human, assum- makes Evi-2 another potential candidate for involve- ing gene order is reliable in both species. ment in the translocation breakpoint. Evi-2 maps ap- A convenient physical marker for the long arm of proximately 11 cM proximal to Cola-I-Ngjr-Hox-2 on humanchromosome 17 is the translocation break- murine chromosome I I (Figure 2). If Evi-2 is the point at band 17q12 that is seen in all patients with mouse counterpart of the humanchromosome 17 acute promyelocytic leukemia (APL) (KANEKOand region causally associated with humanAPL, this SAKURAI1977; ROWLEY, GOLOMB and DOUCHERTY would suggest the presence of yet another chromo- Linkage MapLinkage of Mouse Chromosome 11 159 some rearrangement separating mouse chromosome BARTON,P., B. ROBERT,A. COHEN,1. GARNER,D. SASSOON,A. 11 andhuman chromosome 17. We arecurrently WEYDERTand M. BUCKINGHAM,1988 Structure and se- quenceof the myosin alkali lightchain expressed in adult pursuing the precise localization of Evi-2 with respect cardiacatria and fetal striated muscle. J. Biol. Chem. 263: to the translocation breakpoint to determine if it is 12669-12676. the gene that is causally associated with human APL. BENCHIMOL,S., J. R. JENKINS, L. V. CRAWFORD,K. LEPPARD,P. The gene defect involved in von Recklinghausen LAMB,N. M. WILLIAMSON,D. C. PIM and E. HARLOW, neurofibromatosis (vRNF) has also been localized to 1984 Molecularanalysis of thegene for the p53 cellular the long arm of human chromosome 17, at or near tumor antigen, pp 383-392 in CancerCells 2/0ncogenes and Viral Genes, edited by A. J. LEVINE,G. F. VANDE WOUDE, W. bands qll-12 (BARKERet al. 1987; SEIZINGERet al. C. TOPPand J. D. WATSON.Cold Spring Harbor Laboratory, 1987; VANTUINEN et al. 1987b). The localization of Cold Spring Harbor, N.Y. vRNF makes it likely that the humanhomolog of Evi- BISHOP, D. T. 1985The informationcontent of phase-known 2 would be closely linked and might serve as a useful matings for ordering genetic loci. Genet. Epidemiol. 2: 349- molecular marker to gain access to the vRNF locus. 361. BONHOMME, F.,J. CATALAN,J. BRITTON-DAVIDIAN, V.M. CHAP- We thank TERRYROBBINS (Abbott Laboratories, Chicago, llli- MAN, K. MORIWAKI,E. NEVO and L. THALER,1984 Bio- nois),ALAN BERNSTEIN(Mt. Sinai Research Institute, Toronto, chemical diversity and evolution in the genus Mus. Biochem. Canada), MARIANO BARBACID (NCI-Frederick Cancer ResearchFa- Genet. 22: 275-303. cility, BRI-Basic Research Program, Frederick, Maryland), MOSES BRITTON,J., and L. THALER, 1978 Evidence for the presence of CHAO (Cornell University Medical College,New York, New York), two sympatric species of mice (genusMusin southernL.) France RUDOLFJAENISCH (Whitehead Institute for Biomedical Research, based on biochemical genetics. Biochem. Genet. 16 21 3-225. Cambridge, Massachusetts), MARGARETBUCKINCHAM (Pasteur In- BROWNELL,E., S. J. O'BRIEN,W. G. NASH andN. RICE, stitute,Paris, France), ALEXANDRA JOYNER (Mt.Sinai Hospital, 1985 Genetic characterization of human c-re1 sequences. Mol. Toronto, Canada), JAIME ESCOBEDO(Howard Hughes Medical In- Cell. Biol. 5: 2826-2831. stitute, University of California, San Francisco, California), ROEL BUCAN,M., T. YANG-FENG, A. M. COLBERG-POLEY, D.WOLCE- J. NUSSE(The Netherlands Cancer Institute, Amsterdam, The Neth- MUTH, J. L. GUENET, U.FRANCKE and H. LEHRACH, erlands), ARNOULD SONNENBERG(The Netherlands Cancer Insti- 1986 Genetic and cytogenetic localization of the homeo box tute, Amsterdam, The Netherlands), JAMES IHLE (St. Jude Chil- containing genes on mouse chromosome 6 and human chro- dren'sResearch Hospital, Memphis, Tennessee), PIERRE TAM- mosome 7. EMBO J. 5 2899-2905. BOURIN (INSERM, Paris, France), and AXEL ULLRICH (Genetech BUCHBERG, A. M.,H. G. BEDIGIAN,B. A. TAYLOR,E. 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