Review article Mouse homologues of human · Creutzfeldt-Jakob, predisposing Crigler-Najjar, type I...

I Med Genet 1994;31:1-19

Review article

Mouse homologues of human hereditary disease

A G Searle, J H Edwards, J G Hall

AbstractDetails are given of 214 loci known to beassociated with human hereditary dis-ease, which have been mapped on bothhuman and mouse chromosomes. Fortytwo of these have pathological variants inboth species; in general the mouse vari-ants are similar in their effects to thecorresponding human ones, but excep-tions include the Dmd/DMD and Hprt/HPRT mutations which cause little, ifany, harm in mice. Possible reasons forphenotypic differences are discussed. Inmost pathological variants the gene pro-duct seems to be absent or greatlyreduced in both species. The extensivedata on conserved segments betweenhuman and mouse chromosomes areused to predict locations in the mouse ofover 50 loci of medical interest which aremapped so far only on human chromo-somes. In about 80% of these a fairlyconfident prediction can be made. Somelikely homologies between mappedmouse loci and unmapped human onesare also given. Sixty six human andmouse proto-oncogene and growth factorgene homologies are also listed; those ofconfirmed location are all in known con-served segments. A survey of 18 mappedhuman disease loci and chromosome re-gions in which the manifestation orseverity of pathological effects is thoughtto be the result of genomic imprintingshows that most of the homologous re-gions in the mouse are also associatedwith imprinting, especially those withhomologues on human chromosomes lIpand 15q. Useful methods of acceleratingthe production of mouse models ofhuman hereditary disease include (1) useof a supermutagen, such as ethylnitro-sourea (ENU), (2) targeted mutagenesisinvolving ES cells, and (3) use of genetransfer techniques, with production of'knockout mutations'.

(J Med Genet 1994;31:1-19)

The need to develop good animal models ofhuman hereditary disease has been recognisedever since the subject was first reviewed' 2 but,until recently, progress in this field has beenslow. It is clear that the most relevant modelsare likely to emerge when the comparable.human and animal conditions are known to

involve homologous loci. In this respect ourgenetic knowledge of the laboratory mouseoutstrips that for all other non-human mam-mals. The 829 loci recently assigned to bothhuman and mouse chromosomes3 has nowrisen to 900, well above comparable figures forother laboratory or farm animals. In a previouspublication,4 102 loci were listed which wereassociated with specific human disease, hadmouse homologues, and had been located inboth species. The number has now more thandoubled (table 1A). Of particular interest arethose which have pathological variants in boththe mouse and humans: these are listed in table2. Many other pathological mutations havebeen detected and located in the mouse; abouthalf these appear to lie in conserved chromo-somal segments. Thus the likely position oftheir human homologues can be predictedwith some confidence.

Homologous lociTable IA lists 187 autosomal and 27 sex linkedloci associated with pathological effects, whichhave been located on both human and mousechromosomes.3 They are ordered in terms ofthe associated human disease(s), sometimeswith two entries for particular loci. For ease ofreference, table 1B has a tabulation of the sameset in alphabetical order of human gene sym-bols.5 The MIM number, location, etc comefrom McKusick's catalogue6 and other work,7which also gives details of the disorders.Schinzel et a18 also list human clinical dis-orders with chromosomal localisations of thegenes concerned. Information on correspond-ing mouse genes is given in several publica-tions,3910 while the latest locus map of themouse"' has been used to show mouse genelocations as distances in centimorgans from thecentromere (figures after the full stop). Whenthere is a double zero after the full stop thegene concerned has not yet been localised onthe linkage map. Positions ofmouse loci on theG banded map are derived from the MouseChromosome Atlas.'2 References given in table1 are for recently reported disease homologies;for earlier ones please consult Human GeneMapping 1J1.3With reference to polycystic kidney disease5'

it should be noted that the mouse Pkd-1 locushas not been identified but two flanking DNAmarkers to the human PKD1 locus were usedto show that the region concerned mapped tomouse chromosome 17. Some unconfirmed

MRC RadiobiologyUnit, Chilton, Didcot,Oxon OXll ORD, UKA G Searle

Genetics Laboratory,University of Oxford,Oxford OX1 3QU, UKJ H Edwards

Department ofPediatrics,University of BritishColumbia, BCChildren's Hospital,Vancouver, CanadaV6H 3V4J G Hall

Correspondence toDr Searle

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Searle, Edwards, Hall

Table IA Mapping and other data on loci for human hereditary diseases which have been assigned to human and mouse chromosomes. In Diseasename, a dash signifies deficiency and + an excess. A variant which may not be harmful is indicated by (v) after the name. Some loci associatedwith more than one disease are entered twice. For further information see text

Disease name

AcatalasaemiaAcid phosphatase -Adenomatosis, colorectalAdrenal hyperplasia IIIAdrenal hyperplasia IVAdrenal hyperplasia VAdrenocorticotrophin (ACTH) -Albinism, oculocutaneous type IIAlbinism, partialAlbinism, tyrosinase negativeAlphafetoprotein persistence (v)Alzheimer, type IAmelogenesis imperfectaAmyloid in fam Med feverAmyloid neuropathyAmyloidosis IV, Iowa typeAmyloidosis V, Finnish typeAmyloidosis, B2M depositionAmyloidosis, cerebral, Dutch typeAmyloidosis, secondary, susceptibility toAmyotrophic lateral sclerosis-1Anaemia, haemolytic (AKI-)Anaemia, haemolytic (G6PD-)Anaemia, haemolytic (GPI-)Anaemia, haemolytic (GSR-)Anaemia, haemolytic (HK1-)Anaemia, haemolytic (PFKL-)Anaemia, haemolytic (PGK-)Anaemia, haemolytic (TPI-)Anaemia, macrocytic (TCN2-)Anaemia, megaloblastic (DHFR-)AnalbuminaemiaAniridia-2Antitrypsin, alpha 1 -Apolipoprotein AI and CIII -Apolipoprotein AII -Apolipoprotein H -

ArgininosuccinicaciduriaAtransferrinaemiaCancer, colorectalCancer, mammary, one formCardiomyopathy, hypertrophicCardiomyopathy, one formCataract, Coppock-likeCerebrotendinous xanthomatosisCharcot-Marie-Tooth neuropathy 1Chondrodysplasia punctata, XCitrullinaemiaColourblindness, deutan/protan (v)Complement 3 -

Complement 4 -

Cortisol resistanceCreutzfeldt-Jakob, predisposingCrigler-Najjar, type ICystic fibrosisDebrisoquine sensitivityDiabetes insipidus, neurohypophysealDiabetes mellitus, MODY type IIDiabetes mellitus, rare form, MODYDiabetes mellitus, type IIDopamine-beta-hydroxylase -

Duchenne muscular dystrophyDwarfism (pygmy)Dwarfism, LaronDysfibrinogenaemia, gamma chainEctodermal dysplasia, anhidroticEhlers-Danlos, type IVEhlers-Danlos, type XElliptocytosis- 1Elliptocytosis-2, spherocytosis 3Elliptocytosis-3, spherocytosis 1Enolase deficiencyEpidermolysis bullosa simplexEpidermolysis bullosa simplex, generalisedFabryFactor V -

Fetal hydantoin syndromeFletcher factor -FucosidosisGalactokinase -GalactosaemiaGangliosidosis, generalised GM1GaucherGerstmann-Straussler, predisposingGlomerulonephritis (HF1-)Glycogen storage II (Pompe)Glycogen storage VI (Hers)Glycogen storage VIIIaGlyoxylase -Gonadal dysgenesis, XY typeGranulomatous, chronic X linkedGranulomatous, chronic autosomalGreig's cephalopolysyndactylyGrowth hormone -, Illig typeGynaecomastia (aromatase +)Haemoglobinuria, paroxysmalHaemophilia AHaemophilia B, Christmas diseaseHistidinaemiaHomocystinuria, B6 responsive and

non-responsiveHypercholesterolaemia, familial

MIM No Human sym

115500 CAT171650 ACP2190070 KRAS2201910 CYP21202010 CYPIlBI202110 CYP17176830 POMC203200 OCA2172800 KIT203100 TYR104140 AFP104760 APP301200 AMELX104750 SAA1176300 TTR105100 APOAI105120 GSN109700 B2M104760 APP104770 APCS105400 ALSI103000 AKI305900 G6PD172400 GPI138300 GSR142600 HK1171860 PFKL311800 PGK1190450 TPI 1275350 TCN2126060 DHFR103600 ALB106210 PAX6107400 PI107680 APOAI107670 APOA2138700 APOH207900 ASL190000 TF159350 MCC176705 PHB192600 MYH6125660 DES123660 CRYGI213700 CYP27118220 CMT1A302960 CDPX2215700 ASS303900 RCP120700 C3120810 C4A,C4B231570 GRL176640 PRNP197140 UGTIA1219700 CFTR236850 CYP2D192340 ARVP138079 GCK176730 INS147940 IAPP223360 DBH310200 DMD147440 IGF1262500 GHR134850 FGG305100 EDA120180 COL3A1135600 FN1130500 EL1182860 SPTA1182870 SPTB172430 ENOI131900 KRT14131900 KRT1301500 GLA227400 F5132810 EPHX229000 KLK3230000 FUCAl230200 GALKI230400 GALT230500 GLB1230800 GBA137440 PRNP134370 HF1232300 GAA232700 PYGL311870 PHKA1138750 GLO1480000 TDF306400 CYBB233710 NCF2175700 GCPS139250 GH1107910 CYP19107271 CD59306700 F8C306900 F9235800 HAL236200 CBS

143890 LDLR

nbol Human location Mouse symbol Mouse locationt Mouse G band Ref

lipl3llpll12pl2.16p21.38q2 110q24-q252p2315ql 1.2-ql24q121 lql4-q214ql 1-ql321 q21.2Xp22.3-22. 1lp15.118q1 1.2-ql2.11 1q23-q249q331 5q2 1-q2221q21 .2lq21-q2321q22. 1-q22.29q34.1Xq2819ql3.18p2l.110q2221q22.3Xql312pl322ql 1.2-qter5ql 1.2-q13.24ql 1-ql31lpl314q32.111q23-q24lq21-q2317q23-qter7cen-ql 1.23q215q2 117q2114ql 1.2-ql32q352q33-q352q33-qter17pl2-pl 1.2Xq27-q289q34.1Xq2819pl3.3-p13.26p2l.35q31-q3220pter-p 1 22q377q3122ql3.1-ql3.220pter-pl 2.27pl5-pl3I lpl5.512pl2.3-pl 1.29q34Xp2l.212q235p 14-pl 24q28Xql32q312q34-q36lp36.2-p341q2114q24. 1-q24.2lp3617ql 1-q2212ql 1-ql3Xq22lq23Ip 1 -qter4q34-q35lp3417q21-q229pl33p23-p221q2120pter-p 1 21q3217q2314q1 1.2-q24.3Xql3.16p21.3-p21.1Ypl 1.3Xp2l.11q257pl317q22-q2415q2111 p14-p 13Xq28Xq27. 1-27.212q22-q2321q22.3

Cas-I *

Acp-2Kras-2Cyp21-psCyp llbCypl 7Pomc-1P*Kit*Tyr (c) *AfpAppAmelSaaTtrApoa-iGsnB2mAppSapSod- IAk-iG6pdGpi-iGr-IHk-iPfklPgk-iTpi-iTcn-2DhfrAlb-iSey (Pax-6) *AatApoa-iApoa-2ApohAslTrfMccPhbMhyc-aDesCrygCyp27Tr*Bpa*Ass-iRsvpC3C4Grl-lPrn-pUgtlalCftr*Cyp2dArvpGkIns-2IappDbhmdx(Dmd) *Igf- IGhrFggTa*Col3a-iFn-IElp-iSpna- *Spnb- I*Eno-iKrt- .i14Krt-2AgsCf-5Eph-iKal3FucaGlkGaltBglGba*Prn-pCfhGaaPyglPhkaGlo-iTdyCybbNcf-2Xt* (Gli3OGhCypi 9Ly-6Cf-8Cf-9Hal*Cbs

Ldlr

2.402.006.7017.1915.2419.3712.017.275.377.415.46

16.49X.737.2418.049.252.262.4616.491.72

16.512.24X.357.128.1010.3010.51X.486.6111.0113.525.462.4912.499.251.71

11.585.009.5218.2411.0014.191.001.311.00

11.35X.332.21X.3717.2817.1918.212.551.376.0715.342.7111.037.726.602.20X.3710.5415.023.59X.411.241.334.581.73

12.314.7311.0015.45X.581.681.768.004.5811.774.199.623.602.551.56

11.7412.28X.4517.17Y.00X.011.52

13.1811.689.2715.20X.38X.2610.5917.18

9.04

C1-D

G1-G3B-CC-D2Dl -D2Cen-FlB3-CD-E1D3E2-FB5-C4F2-terB3-CCen-B2Cen-A4C1-DE3-E4B5-C4H5-terB5-C4B-DB-CA3-B1A1-A4Cen-B4B3-ClD-F1F-G3Cen-A2C1-D2E2-FE3-E4E-F1Cen-A4H5-terD-E1

E3-terCen-B2DDI-ElC3C2-C4

B1-B5B-CBB-CD-E1B-CCen-B2Fl-GC3-C4Cen-B 1D3-EHi -H4Cen-A2F1-F4F-G3C1-DB-CCl-DIA2-BID-F3C-DA4-BC2-C4D2H5-terCen-FlD3-terDE-F1FlH3-H5H5-terB2-B3D2E1-E2Al-A5E3-terD-F3Fl-GC4-H3El-E2Cen-FlDA3-BA1Al-A2C4-H3A2-A3El-E2A4-EC-D2B-CA6-A7Cl-DIA3-B

14

15

16

17

18,19

20

1621,22

23,24

25,26

2728

29

30

31,3233

34,35

36

Cen-A4

2

l9pl13.3



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Table 1A-contd

Disease name MIM No Human symbol Human location Mouse symbol Mouse locationt Mouse G band Ref

Hyperlipoproteinaemia 238600 LPL 8p22 Lpl 8.26 C1-C3Hyperlipoproteinaemia, type III 107741 APOE l9q13.2 Apoe 7.06 Cen-A3Hyperproglucagonaemia 138030 GCG 2q36-q37 Gcg 2.34 Ci-DHypertension, essential, susceptibility 106150 AGT lq42-q43 Agt 8.48 C3-E1 37Hypobetalipoproteinaemia 107730 APOB 2p24-p23 Apob* 12.03 Cen-FlHypoceruloplasminaemia 117700 CP 3q23-q25 Cp 9.00 DHypogonadism, hypogonadotrophic 227200 LHRH 8p2l-pl 1.2 Gnrh(hpg)* 14.29 D3-E3 38Hypoparathyroidism, familial 168450 PTH 11p15.2-pl5.1 Pth 7.48 E1-E3Hypophosphataemia 307800 HYP Xp22 Hyp* X.69 F2-terHypophosphataemia II, with deafness 307810 GY Xp22 Gy* X.70 F2-terHypophosphatasia, infantile 146300 ALPL lp36. 1-p34 Akp-2 4.60 D2-D3Hypopituitarism 173110 PITI 3q Pit I(dw)* 16.39 A-B5Hypoprothrombinaemia 176930 F2 llpll1-ql2 Cf-2 2.46 E3-E4Hypothyroidism, goitrous 188450 TG 8q24 Tgn* 15.17 CHypothyroidism, non-goitrous, TSH - 188540 TSHB lpl3 Tshb 3.67 F3-HIIchthyosis, sex linked 308100 STS Xp22.32 Sts X.88 F3-terImmunodeficiency due to CD3Z 186780 CD3Z lq22-q25 Cd3z 1.68 H1-H5 39Immunodeficiency due to NP - 164050 NP 14q11.2 Np-i1 14.16 B-ClImmunodeficiency, severe combined 102700 ADA 20ql2-ql3.1 1 Ada 2.74 H3-H4Immunodeficiency, severe combined 147680 1L2 4q26-q27 I1-2 3.39 C-DImmunoglobulin heavy chain - 146900 IGH 14q32.33 Igh 12.65 E-FlInfections, recurrent 217050 C6 5pl3 C6 15.01 A2-B1Infections, recurrent 217070 C7 5p13 C7 15.01 A2-BIInfections, recurrent 120960 C8B lp32 C8b 4.44 C7Infections, recurrent pyogenic 120650 CR2 1q32 Cr-2 1.83 H5-terInfections, recurrent (candidiasis) 254600 MPO 17q2l .3-q23 Mpo 11.49 DInfertility, male, one form 136530 FSHB llpl3 Fshb 2.42 C1-D3Infertility, male, one form 102480 ACR 22q1I3-qter Acr 15.33 D3-EInterferon, alpha - 147660 IFNA 9p22 Ifa 4.39 C3-C6Interferon, gamma - 147570 IFNG 12q24.1 Ifg 10.69 Ci-DIKrabbe 245200 GALC 14q2l-q3l twi* 12.29 Cen-FlLactoferrin- neutrophils 245480 LTF 3q2l-q23 Lrtf 9.00Leprechaunism 147670 INSR l9p1I3.3-p13.2 Insr 8.01 Al-A4Lesch-Nyhan 308000 HPRT Xq26 Hprt X.30 A6-BLeucocyte adhesion - 116920 ITGB2 21q22.3 Itgb2 10.51 B3-C1 40Leucodystrophy, metachromatic 250100 ARSA 22ql3.31-qter As-2 15.00 ELipoid adrenal hyperplasia 201710 CYPI IA 15q23-q24 Cypila 9.27 Cen-A4Li-Fraumeni (familial cancer) 191170 TP53 l7pl3.1 TrpS3 11.42 B4-B5Lupus C2-, predisposing 217000 C2 6p21.3 C2 17.19 B-CLupus C5-, prediaposing 120900 CS 9q34.1 Hc* 2.18 C1-DLymphoma, Burkitt's 190080 MYC 8q24 Myc 15.15 A2-CMalignant hyperthermia, one form 145600 RYRI l9q13.1 Ryr 7.08 Cen-A3McArdle 232600 PYGM 1lql2-ql3.2 Pygm 19.03 BMenkes 309400 MNK Xql3.2-ql3.3 MO* X.45 DMental retardation, X linked, one for 309550 FRAXA Xq27.3 Fmr-I X.38 B-CMethaemoglobinaemia, enzymopathic 250800 DIAl 22q13.31-qter Dia-) 15.00 EMethylmalonicaciduria, mutase - 251000 MUT 6p2l Mut 17.23 DMiller-Dieker (lissencephaly) 247200 MDCR 17p13.3 DilBayl 11.00Mucopolysaccharidosis I 252800 IDUA 4p16.3 Idua 5.33 B-ElMucopolysaccharidosis II 309900 IDS Xq27.3-q28 Ids X.30 A6-BMucopolysaccharidosis VI 253200 ARSB 5pll-ql3 As-Is 13.65 Cl-D2Mucopolysaccharidosis VII 253220 GUSB 7q22 Gus* 5.63 F-G3Mullerian, persistent duct 261550 AMH l9p13.3 Amh 10.49 B3-Cl 41Myoadenylate deaminase - 102770 AMPDI 1p13 Ampd-i 3.67 F3-HIMyoglobinuria, exertional (LDHA -) 150000 LDHA 1llpl5.l-pl4 Ldh-i 7.23 B3-CMyopathy, lipid storage 201470 ACADS 12q22-qter Bcd-i 5.49 E2-FMyotonia congenita 118425 CLCNI 7q35 Clc-i 6.20 Bl-B3 42Nance-Horan 302350 NHS Xp22.3-p2l1. Xcat* X.64 Fl-F2Niemann-Pick 257200 SMPDI llpl5.4-pl5.1 spm* 18.12 Cen-B2Norunm 245900 LCAT 16q22.1 Lcat 8.42 C3-E1Ornithinaemia, gyrate retinal atrophy 258870 OAT 10q26 Oat 7.64 Fl-F4Ornithine transcarbamylase - 311250 OTC Xp21.1 Otc(spf)* X.02 Al-A2Osteodystrophy, Albright 139320 GNASI 20q13.2 Gnas 2.86 H3-H4Osteogenesis imperfecta, one type 120160 COL1A2 7q2l .3-q22. 1 Cola-2* 6.04 Cen-BIOsteogenesis imperfecta, one type 120150 COLIAI 17q2l.3-q22 Cola-i 11.54 DOsteoporosis due to renal acidosis 259730 CA2 8q22 Car-2 3.04 Cen-A2Otopalatodigital syndrome 311300 OPDI Xq28 ptd* X.30 A6-B 43,44Paralysis, hyperkalaemic periodic 170500 SCN4A 17q23.1-q25.3 Scn4a 11.52 D 45,46,Paramyotoniacongenita ~~~170500 SCN4A 17q23. I-q25.3 Scn4a 11.52 D 45,4

Pelizaeus-Mersbacher 312080 PLP Xq2l.3-q22 PIP(jp)*X.56 FlIPhenylketonuria due to QDPR -261630 QDPR 4lpl5.3 Qdpr 5.28 B-ElPhenylketonuria, common form 261600 PAH 12q22-q24.2 Pah* 10.53 Cl 47Piebaldism 172800 KIT 4q12 Kit* 5.37 D-E1 48,49Placental lactogen - 150200 CSHI 17q22-q24 P1-i 13.00Plasminogen Tochigi 173350 PLG 6q26-q27 pig 17.08 A2-A3Plasminogen activator - 173370 PLAT 8pl12 Plat 8.07 Al-A4Platelet alpha/delta storage pool -173610 GRMP 1q2l-q24 Grmp 1.68 H3-H5Polycystic kidney disease, adult 173900 PKDI 16p13.3 Pkd-i 17.00 50,51Polyposis coli, adenomatous 175100 APC 5q2l-q22 Min* 18.15 Cen-B2 52,53Porphyria, acute hepatic 125270 ALAD 9q32-q34 Lv 4.30 AS-C2Porphyria, acute intermittent 176000 PBGD 1 lq23.2-qter UPS 9.24 Cen-A4Porphyria, hepatoerythropoietic 176100 UROD lp34 Urod 4.49 C7-D1 54Prolidase-170100 PEPD 19q12-ql3.2 Pep-4 7.15 A3-BlProperdin-312060 PFD Xp2l-pllI Pfc X.03 A3Protoporphyria, erythroid 177000 FECH 18q21.3 Fech* 18.40 C-D 55Pseudohermaphroditism, LH derived 152780 LHB l9q13.32 Lhb 7.22 CPseudohermaphroditism, SRDSA1 derived 264600 SRD5A1 5plS Srd5a-i 13.51 C1-D2 56Pseudohermaphroditism type Is 103580 GNASI 20q13.2 Gnas 2.86 H3-H4Pyridoxine dependency with seizures 266100 GADI 2q31 Gad-I 2.38 Cl-DPyruvate dehydrogenase - 312170 PDHAI Xp22.1 Pdha-i X.00 F3-F4Retinal degeneration, slow 179605 RDS 6p12 rds* 17.24 D-EI 57,58Ketinitis pigmentosa 4, rhodopsin 180380 RHO 3q21-q24 Rho 6.49 FRetinoblastoma 180200 RB1 13qI4.2 Rb-l* 14.27 D3-E2Retinol binding protein-l - 180260 RBP1 3q21-q22 Crpb 9.46 E3-terRetinol binding protein-3 - 180290 RBP3 10ql 1.2 Rbp-3 14.14 BRetinol binding protein-4 - 180250 RBP4 10q23-q24 Rbp-4 19.19 D1-D2Sandhoff 268800 HEXB 5q13 Hexb 13.53 C1-D2Sialidosis I and II 162050 NEU 6p21.3 Neu-i 17.19 B-CSly 253220 GUSB 7q22 Gus 5.63 F-G3Spherocytosis-2 182900 ANKI 8p21.1-pl1.2 Ank-I* 8.07 A1-A4Spherocytosis, Japanese type 177070 EPB42 15qI5 pa* 2.53 Fl-F3 59Stickler 108300 COL2A1 12qI3.11-13.2 Col2a-i 15.33 D3-E 60Tay-Sachs (GM2-gangliosidosis I) 272800 HEXA 15q22 Hexa 9.29 A4-ETesticular feminisation 313700 AR Xql2 Tfm(Ar)* X.40 B-D

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Table 1A-contd

Disease name MIM No Human symbol Human location Mouse symbol Mouse locationt Mouse G band Ref

Thalassaemia, alpha 141800 HBA1 16p13.3 Hba* 11.14 Al-BIThalassaemia, beta 141900 HBB 11pI5.5 Hbb* 7.49 E3Thrombophilia 107300 AT3 lq23-q25 At-3 1.66 H3-H5Thyroid hormone defect 274500 TPO 2pl3 Tpo 12.09 Cen-FlThyroid hormone unresponsiveness 190120 THRAI 17ql 1.2-q12 Erba 11.56 D-E1Thyrotropin unresponsiveness 275200 TSHR 14q24-q31 Tshr 12.48 E-F1Trypsinogen - 276000 TRYI 7q32-qter Try-i 6.20 B1-B3Tyrosinaemia I 276700 FAH 15q23-q25 Fah 7.41 D3 61Tyrosinaemia II 276600 TAT 16q22.1 Tat 8.46 C3-E1Urolithiasis, 2,8-dihydroxyadenine 102600 APRT 16q24 Aprt 8.63 El-terWaardenburg, PAX3 related 193500 PAX3 2q35 Sp(Pax-3)* 1.36 C3 62Wilms's tumour 194070 WT1 lIpl3 Wt-i 2.41 C1-DWolf-Hirschhorn 142983 HOX7 4pl6.1 Hox-7 5.14 B-ElWolman 278000 LIPA 10q24-q25 Lip-i 19.00Xeroderma pigmentosum IX 278700 XPA 9q32-q34.1 Xpa 4.00 C2Xeroderma pigmentosum, group D 126340 ERCC2 19q13.2-q13.3 Ercc-2 7.06 Cen-A3 63

* Mouse gene with pathological allele.t Given as chromosome number, followed after full stop by estimated distance of locus from centromere in cM. A double zero indicates that regional location isunknown.

Table lB Data from table lA shown in alphabetical order of human locus symbols with associated diseases

Symbol Name of disease

ACADS Myopathy, lipid storageACP2 Acid phosphatase -ACR Infertility, male, one formADA Immunodeficiency, severe combinedAFP Alphafetoprotein persistence (v)AGT Hypertension, essential, susceptibilityAKI Anaemia, haemolytic (AKI-)ALAD Porphyria, acute hepaticALB AnalbuminaemiaALPL Hypophosphatasia, infantileALSI Amyotrophic lateral sclerosis-IAMELX Amelogenesis imperfectaAMH Mullerian, persistent ductAMPD1 Myoadenylate deaminase -

ANKI Spherocytosis-2APC Polyposis coli, adenomatousAPCS Amyloidosis, secondary, susceptibility toAPOAl Apolipoprotein Al and CIII -APOAI Amyloidosis IV, Iowa typeAPOA2 Apolipoprotein AII -APOB HypobetalipoproteinaemiaAPOE Hyperlipoproteinaemia, type IIIAPOH Apolipoprotein H -

APP Amyloidosis, cerebral, Dutch typeAPP Alzheimer, type IAPRT Urolithiasis, 2,8-dihydroxyadenineAR Testicular feminisationARSA Leucodystrophy, metachromaticARSB Mucopolysaccharidosis VIARVP Diabetes insipidus, neurohypophysealASL ArgininosuccinicaciduriaASS CitrullinaemiaAT3 ThrombophiliaB2M Amyloidosis, B2M depositionC2 Lupus C2-, predisposingC3 Complement 3 -C4A,C4B Complement 4 -

C5 Lupus C5-, predisposingC6 Infections, recurrentC7 Infections, recurrentC8B Infections, recurrentCA2 Osteoporosis due to renal acidosisCAT AcatalasaemiaCBS Homocystinuria, B6 responsive and

non-responsiveCD3Z Immunodeficiency due to CD3ZCD59 Haemoglobinuria, paroxysmalCDPX2 Chondrodysplasia punctata, XCFTR Cystic fibrosisCLCN1 Myotonia congenitaCMT1A Charcot-Marie-Tooth neuropathy 1COLlAl Osteogenesis imperfecta, one typeCOLlA2 Osteogenesis imperfecta, one typeCOL2A1 SticklerCOL3A1 Ehlers-Danlos, type IVCP HypoceruloplasminaemiaCR2 Infections, recurrent pyogenicCRYGI Cataract, Coppock-likeCSHI Placental lactogen -

CYBB Granulomatous, chronic X linkedCYPlIA Lipoid adrenal hyperplasiaCYPIlBl Adrenal hyperplasia IVCYP17 Adrenal hyperplasia VCYP19 Gynaecomastia (aromatase +)CYP21 Adrenal hyperplasia IIICYP27 Cerebrotendinous xanthomatosisCYP2D Debrisoquine sensitivityDBH Dopamine-beta-hydroxylase -

DES Cardiomyopathy, one formDHFR Anaemia, megaloblastic (DHFR-)DIAl Methaemoglobinaemia, enzymopathicDMD Duchenne muscular dystrophyEDA Ectodermal dysplasia, anhidroticELl Elliptocytosis-lENO1 Enolase deficiency


EPB42 Spherocytosis, Japanese typeEPHX Fetal hydantoin syndromeERCC2 Xeroderma pigmentosum, group DF2 HypoprothrombinaemiaF5 Factor V -

F8C Haemophilia AF9 Haemophilia B, Christmas diseaseFAH Tyrosinaemia IFECH Protoporphyria, erythroidFGG Dysfibrinogenaemia, gamma chainFN1 Ehlers-Danlos, type XFRAXA Mental retardation, X linked, one

formFSHB Infertility, male, one formFUCAl FucosidosisG6PD Anaemia, haemolytic (G6PD-)GAA Glycogen storage II (Pompe)GAD1 Pyridoxine dependency with seizuresGALC KrabbeGALK1 Galactokinase -

GALT GalactosaemiaGBA GaucherGCG HyperproglucagonaemiaGCK Diabetes mellitus, MODY type IIGCPS Greig's cephalopolysyndactylyGH1 Growth hormone -, Illig typeGHR Dwarfism, LaronGLA FabryGLB1 Gangliosidosis, generalised GMIGLOI Glyoxylase -

GNAS1 Osteodystrophy, AlbrightGNAS1 Pseudohypoparathyroidism type IaGPI Anaemia, haemolytic (GPI-)GRL Cortisol resistanceGRMP Platelet alpha/delta storage pool -

GSN Amyloidosis V, Finnish typeGSR Anaemia, haemolytic (GSR-)GUSB Mucopolysaccharidosis VIIGUSB SlyGY Hypophosphataemia II, with deafnessHAL HistidinaemiaHBAI Thalassaemia, alphaHBB Thalassaemia, betaHEXA Tay-Sachs (GM2-gangliosidosis I)HEXB SandhoffHFI Glomerulonephritis (HF1-)HKI Anaemia, haemolytic (HKI-)HOX7 Wolf-HirschhornHPRT Lesch-NyhanHYP HypophosphataemiaIAPP Diabetes mellitus, type IIIDS Mucopolysaccharidosis IIIDUA Mucopolysaccharidosis IIFNA Interferon, alpha -

IFNG Interferon, gamma -

IGFI Dwarfism (pygmy)IGH Immunoglobulin heavy chain -

IL2 Immunodeficiency, severe combinedINS Diabetes mellitus, rare form, MODYINSR LeprechaunismITGB2 Leucocyte adhesion -

KIT Albinism, partialKIT PiebaldismKLK3 Fletcher factor -

KRAS2 Adenomatosis, colorectalKRTI Epidermolysis bullosa simplex,

generalisedKRT14 Epidermolysis bullosa simplexLCAT NorumLDHA Myoglobinuria, exertional (LDHA-)LDLR Hypercholesterolaemia, familialLHB Pseudohermaphroditism, LH derivedLHRH Hypogonadism, hypogonadotrophicLIPA WolmanLPL Hyperlipoproteinaemia


LTF Lactoferrin- neutrophilsMCC Cancer, colorectalMDCR Miller-Dieker (lissencephaly)MNK MenkesMPO Infections, recurrent (candidiasis)MUT Methylmalonicaciduria, mutase -

MYC Lymphoma, Burkitt'sMYH6 Cardiomyopathy, hypertrophicNCF2 Granulomatous, chronic autosomalNEU Sialidosis I and IINHS Nance-HoranNP Immunodeficiency due to NP -

OAT Ornithinaemia, gyrate retinal atrophyOCA2 Albinism, oculocutaneous type IIOPDI Otopalatodigital syndromeOTC Ornithine transcarbamylase -

PAH Phenylketonuria, common formPAX3 Waardenburg, PAX3 relatedPAX6 Aniridia-2PBGD Porphyria, acute intermittentPDHA1 Pyruvate dehydrogenase -

PEPD Prolidase -

PFD Properdin -

PFKL Anaemia, haemolytic (PFKL-)PGK1 Anaemia, haemolytic (PGK-)PHB Cancer, mammary, one formPHKA1 Glycogen storage VIIIaPI Antitrypsin, alpha 1 -

PIT1 HypopituitarismPKD1 Polycystic kidney disease, adultPLAT Plasminogen activator -

PLG Plasminogen TochigiPLP Pelizaeus-MersbacherPOMC Adrenocorticotrophin (ACTH) -PRNP Creutzfeldt-Jakob, predisposingPRNP Gerstmann-Straussler, predisposingPTH Hypoparathyroidism, familialPYGL Glycogen storage VI (Hers)PYGM McArdleQDPR Phenylketonuria due to QDPR -

RB1 RetinoblastomaRBPI Retinol binding protein-1 -

RBP3 Retinol binding protein-3 -

RBP4 Retinol binding protein-4 -

RCP Colourblindness, deutan/protan (v)RDS Retinal degeneration, slowRHO Retinitis pigmentosa 4, rhodopsinRYR1 Malignant hyperthermia, one formSAAI Amyloid in fam Med feverSCN4A Paralysis, hyperkalaemic periodicSCN4A Paramyotonia congenitaSMPD1 Niemann-PickSPTA1 Elliptocytosis-2, spherocytosis 3SPTB Elliptocytosis-3, spherocytosis 1SRD5A1 Pseudohermaphroditism, SRD5A1

derivedSTS Ichthyosis, sex linkedTAT Tyrosinaemia IITCN2 Anaemia, macrocytic (TCN2-)TDF Gonadal dysgenesis, XY typeTF AtransferrinaemiaTG Hypothyroidism, goitrousTHRAI Thyroid hormone unresponsivenessTP53 Li-Fraumeni (familial cancer)TPIl Anaemia, haemolytic (TPI-)TPO Thyroid hormone defectTRYI Trypsinogen -

TSHB Hypothyroidism, non-goitrous, TSH-TSHR Thyrotropin unresponsivenessTTR Amyloid neuropathyTYR Albinism, tyrosinase negativeUGTlAI Crigler-Najjar, type IUROD Porphyria, hepatoerythropoieticWTI Wilms's tumourXPA Xeroderma pigmentosum IX

4 Searle, Edwards, Hall



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Table 2 Listing of pathological variants in presumptive mouse homologues of human disease loci.6910 See also table IA and B. McKusick'sclassification of human phenotypes as dominant (D), recessive (R), or sex linked (X) is given in parentheses after locus symbol

Locus symbol Name of disease/mutant Phenotypic effects in mice

Human Mouse Human Mouse

Aniridia-2Spherocytosis-2Polyposis coli, adenomatousHypobetalipoproteinaemia

Testicular feminisation

Lupus C5, predisposingAcatalasaemiaChondrodysplasia punctata, dominantCystic fibrosisCharcot-Marie-Tooth neuropathyOsteogenesis imperfectaDuchenne muscular dystrophy

EDA(X) Ta Ectodermal dysplasia, anhidroticEPB42(D) pa Spherocytosis

FECH(D)* Fech Protoporphyria, erythropoieticGALC(R)* twi Krabbe

GBA(R)* Gba

GCPS(D)=GLI3 XtGUSB(R)* gusGY(X) Gy

HAL(R) hisHBA1(D)* HbaHBB(D) HbbHYP(X) Hyp

KIT(D) W

LHRH(D)* hpg=GNRHMNK(X) Mo

NHS(X) XcaOCA2(R) p

OPDI(X) ptd

OTC(X)* spf

PAH(R) PahPIT1(D)* dwPLP(X)* jpRB1(D) Rb-I

RDS(D) rdsSMPDI(R)* spm=NPDSPTA1(D)* sphSPTB(D)* ja+TG(D)* cog+TYR(R)* cWS1, WS3(D) Sp(i= PAX3

Gaucher

Greig cephalopolysyndactylyMucopolysaccharidosis VIIHypophosphataemia with deafness

HistidinaemiaThalassaemia, alphaThalassaemia, betaHypophosphataemia

PiebaldismHypogonadism, hypogonadotrophic

Menkes kinky hair disease

Small eyeNormoblastic anaemiaMultiple intestinal neoplasiaApob deficient

Testicular feminisation

Haemolytic complement nullAcatalasaemiaBare patchesCftr deficientTremblerOsteogenesis imperfectaMuscular dystrophy

TabbyPallid

Ferrochelatase deficientTwitcher

Gba deficient

Extra toesMucopolysaccharidosis VIIGyro, phosphate transport defect

HistidinaemiaThalassaemia, alphaThalassaemia, beta, polycythaemiaHypophosphataemia, phosphate

transport defectDominant spottingHypogonadal

Mottled, copper transport defect

Nance-Horan cataract-dental syndrome X linked cataractAlbinism, oculocutaneous type 2 Pink eyed dilution

Otopalatodigital Palate-tail-digits anomaly

Ornithine transcarbamylase deficiency Sparse fur

PhenylketonuriaHypopituitarismPelizaeus-Merzbacher

I Retinoblastoma

Pax-3)

Retinal degeneration, slowNiemann-Pick disease

Elliptocytosis-2, spherocytosis-3Elliptocytosis-3, spherocytosis-IHypothyroidism, goitrousAlbinism, tyrosinase negativeWaardenburg I and III

HyperphenylalaninemiaDwarfJimpyRb-i deficient

Retinal degeneration, slowSphingomyelinosis

SpherocytosisJaundicedCongenital goitreAlbinismSplotch

Small eyes, colobomata, homozygous lethalJaundiced young, splenomegaly etc, gallstonesAdenomata along intestinal tractDecreased concentrations of lipoproteins,

cholesterol. Some with hydro- andexencephalus

Hemizygous males look female with minutetestes, androgen insensitivity

Lowered resistance to infectionIncreased susceptibility to liver tumoursSkin and skeletal lesions, hemizygous lethalIntestinal obstruction, homozygous lethalTremor, convulsions, defective myelinationMultiple fractures, bone thinning, etcTremors, incoordination in old mice, muscle

fibre degenerationDefective teeth, skin, hairsProlonged bleeding time, depigmentation,

inner ear defectsAnaemia, photosensitivity, liver diseaseTremor, wasting, early death, psychosine

accumulationHomozygous lethality, lysosomal storage of

glucocerebrosidePolydactyly etc, homozygous lethalitySmall, male sterile, lack of adipose tissueRickets, inner ear anomalies, hemizygous

sterilityBalance defectThalassaemia, homozygous lethalThalassaemia, polycythaemiaSkeletal changes like rickets

White spotting, macrocytic anaemia, sterilityUnderdeveloped reproductive tracts

Defective collagen, keratin, pigmentation, andbehaviour; some alleles male lethal

Total lens opacity in hemi/homozygoteHomozygotes with much reduced

pigmentation, ocular albinism in pFrequent hemizygous lethality with cleft

palate; survivors with crooked tail,polydactyly, etc

Small, wrinkled skin, lack of hair, bladderstones

Homozygotes with hyperphenylalaninemiaHomozygotes small, sterileLethal, convulsions, myelin deficiency, etcHeterozygotes associated with pituitary

tumours. Homozygotes lethal in uteroEarly onset retinal degenerationTremor, ataxia, death. Foam cells invade

liver, spleen. Purkinje cell depletionLethal spherocytic anaemia, no alpha spectrinSevere microcytic anaemia, no beta spectrinSmall, enlarged thyroidAbsence of melanin, defective visionDepigmentation, homozygous lethal with

neural tube defects* Gene product absent or greatly reduced in pathological variants of both species.t Homology based on absence of dystrophin in both DMD and mdx variants.6970$ja is thought to be a mutant at the Spnb-i locus, homologous with SPTB, but this has yet to be confirmed. The same situation applies to cog and the Tgn locus,homologous with human TG.

homologies, based mainly on phenotypicresemblances, have been omitted from theselistings, for example, those between humanWAS (Wiskott-Aldrich syndrome) and mousesf,64 also IP (incontinentia pigmenti) andmouse Td (tattered).65 However, the findingsof Laval and Boyd66 have made these homo-logies more likely. Homology between the Xlinked agammaglobulinaemia locus (AGMX1)and X linked immune deficiency (xid) alsoneeds clarification, as there are several humanX linked immunodeficiencies. However, the Xlinked loci for human otopalatodigital syn-

drome (OPD 1) and mouse palate-tail-digitsanomaly (ptd) have been included in the tablesbecause of their unique and similar pheno-types and equivalent position on the map.4344

Chromosome maps of diseasehomologiesFig 1 is a synthesis of the data on chromosomallocations of disease genes (given in table 1) andof their mouse homologues, arranged in orderof human chromosomes. Chromosomal loca-tions of mouse homologues are shown underthe human map, so as to indicate conservedsegments. These can be used to predict thelikely position in one species of a disease genelocated to a conserved segment in the other.Since the mouse locus positions of fig 1 arearranged in order of increasing distance fromthe centromere, the slope of the result (ifdiscernible) indicates whether orientationswith respect to the centromere are the same inboth species (as in human chromosome Ip and

AN2(D)* = PAX6 SeyANK1(D)* nbAPC(D) MinAPOB(D) Apob

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Mouse chromosomes

Figure 2 Oxford grid"7 which shows numbers of loci associated with hereditary diseasewhich have been assigned to different pairs of human and mouse autosomes. Smalltriangles refer to individual loci, large triangles to groups offive. Where triangles pointdownwards loci are in the short arm (pJ, where upwards they are in q. Small circlesrepresent a single locus unassigned to p or q.

mouse 4) or opposite (as in human q andmouse 1). However, this point of evolutionaryimportance can be analysed with greater preci-sion by use of the whole database (now com-prising more than 900 pairs of assignments)rather than just the disease homologies, so isnot considered further here.

Oxford gridThe Oxford grid67 is designed to show thedistribution of homologous loci and conservedsegments among human and mouse autosomalarms. In the grid for all the assigned loci46there is a general tendency for conserved re-gions to be found in chromosomes of similarrelative size in the two species. This sametendency is found in the present grid (fig 2) forloci associated with hereditary diseases, sinceentries around the top-left to bottom-rightdiagonal are much more numerous thanaround the opposite diagonal. Homologousdisease loci have been assigned on all humanand mouse chromosomes, but human 13 isonly represented once and human 18 twice.The X chromosome has more homologousdisease loci than any others (12% of the total)with human chromosomes 1 (10%) and 11(9%) next. However, when all known human-mouse assignments are considered, humanchromosome 1 has 68% more homologous locithan chromosome 1 1.

Nature of variation in mousehomologuesWe list 214 loci associated with humanhereditary disease which have homologues

located in the mouse. These should provideuseful and valid mouse models for such dis-eases, once suitable mutants have beenobtained.For 32 of the mouse loci (15%) no variants

have been reported. There are 143 loci (67%)associated with restriction fragment length

68muhuevariants, much used in mapping, but patho-logical variants have been reported so far fromonly 42 (20%). These are marked with anasterisk in table 1A and their characteristicsare summarised in table 2. They include ex-amples of the successful production of patho-logical variants by targeted mutagenesis, suchas the mouse models for cystic fibrosis(CFTR),7'72 for Gaucher disease (GBA),73 andfor retinoblastoma (RB 1).74 75 Non-patholo-gical variants other than RFLVs are knownfrom 49 loci (23%).Homologies given in table 2 are based

mainly on molecular and other biochemicalcriteria, apart from certain X linked loci (forexample, human CDPX2, EDA, NHS) wherethey are based on phenotypic resemblance andexpected location. Mouse symbols are as givenin the standard listing'" but some alternatives,based on recent research throwing light onhomology, are also given in parentheses. Atseveral mouse loci multiple pathological allelesare known; only the most relevant one (or twoin the case of Hbb) are given in table 2. McKu-sick6 tabulates human phenotypes under auto-somal dominant, autosomal recessive, and Xlinked; these are indicated in table 2. For themouse dominants, heterozygous effects areindicated in the table although homozygousones (often lethality) may also be shown. Formouse recessives, homozygous effects areshown and both hemi- and heterozygous onesas a rule with the X linked variants. From acomparative point of view the most usefulhomologies are those in which the pathologicaleffects seem to result from lack of the samegene product, for example, inactivation of thesame enzyme in both species. The basis forhomology has been marked with an asterisk intable 2 where this appears to be the case. Itshould be noted, however, that if the enzymedeficiency is the result of a chromosome dele-tion involving the gene concerned (as mayfrequently happen with radiation induced mu-tations), adjacent loci will often be affectedalso.Among the 49 loci for which only non-

pathological variants other than RFLVs havebeen described in the mouse are those associ-ated with Fabry disease (GLA), gangliosidosis(GLB 1), haemolytic anaemia resulting fromG6PD deficiency (G6PD), Lesch-Nyhan dis-ease (HPRT), Creutzfeldt-Jakob disease(PRNP), and X linked ichthyosis (STS). Ingeneral, these variants determine differentforms of the enzyme concerned (often found indifferent mouse strains, races, or species)rather than enzyme deficiencies. An exceptionis the HPRT homology. A mouse mutant cellwith loss of HPRT activity was selected incultured embryonic stem (ES) cells and thenincorporated into embryos to give mousechimeras, from which mutant mice having the

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same genetic defect as Lesch-Nyhan patientswere generated.7677 These were viable andapparently normal at birth and still appearednormal on later examination although they hadabnormal dopamine levels, as expected withHPRT deficiency. It has now been reported78that if Hprt deficient mice are given an APRTinhibitor they develop a Lesch-Nyhan type ofself-injurious behaviour. Thus, mice seemmore reliant on APRT than HPRT for theirpurine salvage, in contrast to humans.Thus HPRT deficiency cannot be included

among the pathological variants of the mouse,despite its severe effects in human hemi-zygotes. Another locus with contrasting effectsin human and mouse deficiencies is that forDuchenne muscular dystrophy (DMD). Thishas been included among the mouse patholo-gical variants (table 2) because affected micedevelop tremors and mild incoordination when'old',79 but effects in human victims of thisdisease are much more severe and do notinvolve incoordination beyond that secondaryto weakness.The most appropriate comparisons of

pathological effects at human and mousehomologous loci are those between those hav-ing the same mutant gene dosage, whetherhomozygotes, hemizygotes, or heterozygotes.A problem arises with some recessive patholo-gical variants in the mouse since the nature of amutant homozygote may be unknown at thehomologous human locus. One probable ex-ample is myelin basic protein (MBP) defi-ciency, which leads to the shiverer (shi) con-dition in mice, with a much shortened lifespan,violent shivering, and locomotor difficulties.9Heterozygotes have normal behaviour but onlyhalf the normal amount of MBP. Effects ofhuman homozygosity for MBP deficiencyseem to be unknown.6 Another exampleinvolves colony stimulating factor 1 (CSFI).This protein gene is absent in the macrophagedeficient osteopetrotic (op/op) mouse,80 but thephenotype of human homozygotes for CSF1deficiency is unknown.6

In general, scrutiny of table 2 together withinformation on the relevant human homo-logues6 suggests that effects of pathologicalmutants are similar in both species. Of coursethis would be expected for those loci for whichhomologies have been postulated mainly onthe basis of phenotypic effects (as well asappropriate chromosomal location), but it alsoseems to be true for those in which the homo-logy is based on knowledge of proteins orDNA sequences involved.

Positional predictions for loci withoutknown homologiesMany human or mouse pathological loci havebeen mapped in the one species but areunknown in the other. However, our know-ledge of conserved regions in the two species isnow so extensive that it is often possible topredict the likely map position of the undis-covered human or mouse locus from its knownposition in the other species, thus facilitatingany search for the locus concerned.

A list of mouse loci, in alphabetical order ofgene symbols, was scanned for pathologicalmutants. Data from the first 50 which had beenregionally mapped but had as yet no humanhomologues (from asebia ab to grey lethal gl)were analysed in relation to any neighbouringloci which had regionally assigned humanhomologues. It was found that for 26 of theloci (that is, over 50%) the position of a humanhomologue could be confidently predictedbecause the mouse locus concerned lay withinor very close to a known conserved region.Even higher rates of prediction were

obtained when a series of mapped humandisease loci without known mouse homologueswas analysed. Table 3 shows that for about80% of these it was possible to predict regionallocations of a mouse homologue with a fairdegree of confidence. Only future mappingstudies will show whether this confidence isjustified.Table 4 deals with the opposite situation, in

which loci with pathological effects in themouse have been located accurately but theirpossible human homologues have not. Thereare, of course, many other similar syndromesin the two species8"82 for which genetic in-formation is more limited.

Proto-oncogenesAnother group of genes of considerable med-ical interest, besides those directly responsiblefor human hereditary disease, are the proto-oncogenes. An increasing number are nowknown to control various aspects of cell growthand differentiation when in their normal form.If, however, their essential functions are dis-rupted through mutation, structural change orother mechanisms, they may become onco-genic. Table 5 lists those proto-oncogene lociwhich have been mapped on both human andmouse chromosomes, as well as growth factorloci, many known to have oncogenic effects.These and other neoplasia related loci, includ-ing those for endogenous mouse mammarytumour and leukaemia viruses as well as genescontrolling viral replication, viral and tumourspecific antigens, etc, are listed by Kozak83 andby Roderick et al.84 The recently discoveredfamily of Wnt genes is included as membersare clearly oncogenic and seem to have animportant role in intercellular signalling andother aspects of developmental regulation.85Of the 69 loci listed here, 67 are in conserved

segments of human-mouse homology, often ofconsiderable length. The two apparent excep-tions are REL and RET, but the human loca-tions of both are regarded as provisional.6 Thethree oncogene loci JUNB, JUND, and MEL,together with the lymphoblastic leukaemialocus LYL1 and the insulin resistance geneINSR, form a medically interesting conserved(but disrupted) segment between human l9pand mouse 8, with no other known members.86The oncogene/growth factor group of lociseem to be fairly evenly spread over humanand mouse chromosomes, with highestnumbers on human 1 (7) and mouse 7 (9).

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Table 3 Probable location on mouse autosomes of homologues for mapped human disease loci

Name of disorder Symbol Human location

Acetyl-CoA carboxylase deficiencyAcoustic neuromaAdrenal hyperplasia IIAlagille syndromeAlcohol intolerance, acuteAlpha-l-antichymotrypsin deficiencyAngiodemaAtaxia telangiectasiaBasal cell naevus syndromeBeckwith-Wiedemann syndromeCardiomyopathy, hypertrophicCerebrotendinous xanthomatosisDeafness, low toneDentinogenesis imperfecta IDiabetes mellitus, MODY type IDiastrophic dysplasiaDiGeorge syndromeEpidermolysis bullosaEpilepsy, juvenile myoclonalFanconi anaemia 1Friedreich ataxiaHaemochromatosisHuntington's diseaseLanger-Giedion syndromeLong QT syndromeMarfan syndromeMaroteaux-Lamy syndromeMultiple endocrine neoplasia IMuscular dystrophy, facioscapulohumeralMuscular dystrophy, limb-girdleMyotonic dystrophyNail-patella syndromeNemaline myopathyNeurofibromatosis, von RecklinghausenOroticaciduriaParagangliomaPlasmin inhibitor deficiencyPolycystic ovarian diseasePrader-Willi syndromeRubinstein-Taybi syndromeSanfilippo syndromeSmith-Magenis syndromeSpinal muscular atrophySpinocerebellar ataxia 1Split hand/foot deformity type 1Torsion dystoniaTreacher-Collins mandibulofacial dysostosisTrichorhinophalangeal syndromeTuberous sclerosis 1Usher syndrome, type 1van der Woude syndromevon Hippel-Lindau syndromevon Willebrand diseaseWerner syndromeWilson diseaseXeroderma pigmentosum, group BZellweger syndrome 1

ACACNF2HSDB3AGSALDH2AACTC1NHATABCNSBWSMYH7CYP27LFHL1DGI1MODYIDTDDGCRCOL7A1EJM1FAFRDAHFEHDLGCRLQTFBN1ARSBMENIFMDLGMD1DMNPS1NEMINFIUMPSPGLPLIEDH17B1PWCRRSTSGNSSMCRSMASCAISHFD1DYTITCOF1TRPS1TSC1USHIVWSVHLVWFWRNWNDERCC3ZWS1

17q2122q1 1.21-q13.1lpl3.120pll.212q24.214q32. 11 Iql 1-q13.11 1q22-q239q311 lpter-pl5.414q122q33-qter5q31-q334ql3-q2120q135q3 1-q3422ql 13p2l6p21l.320q9ql3-q21.16p2l.34pl6.38q24.11-q24.131 lpl5.515q21.15ql 1-ql31lql34q34-qter5q31.3-q33.519qI3.2-q13.39q34lq21-q2317ql 1.23q131 Iq22-q2317pter-p1217q 1-ql215qll16pl3.312ql417p 11.25ql2.2-ql3.36p21.3-p21 .27q21.2-q21.39q32-q345q31.3-q33.38q24.129q33-q3414q1q323p24-p2512pter-p128p12-pl 113ql4-q212q217ql 1.23

Predicted mouse location

ChromosomeNo

1115 or 163210121992 or 4712111421116917219?1751572 or 913198?11721119?9111171610111317521815212 or 1416 or 14681425 or 6

Map units (cM)from centromere

49-6225-27 or 12-1863-6755-6556-7049-terCen-1614-2510-30 or 25-3523-2620-3125-3223-3036-5074-ter23-3012-1854-7017-23

17-2313-3115-2823-5051-56 or 26-2752-65Cen-16- 30?23-30Cen-2214-2671-7344-5045-5214-2537-4344-5026-33Cen-1271-7337-4352-6617-2553-6914-2617-3515-2814-26

47-5635-45 or cen-1050-715-1028-ter27-56

Table 4 Genetically unassigned human syndromes suspected of homology with mouse genes of known regionallocation, thus allowing tentative predictions of likely human gene location

Name of human syndrome MIM No Mouse mutant(s) Locations

Mouse Human (predicted)

Acromesomelic dysplasia 201250 Ulnaless (Ul) 2.35 2q31-q37Cenani-Lenz (syndactylism) 212780 Limb deformity (Id) 2.53 15q15Chediak-Higashi (lysosomal) 214500 Beige (bg) 13.17 lq43/7pEpilepsy, temporal lobe - Epilepsy (El-I) 9.51 3q21Fraser (cryptophthalmos) 219000 Blebs (my) or 3.39 or 4q26-q27 or

Blebbed (bl) 5.44 4q11-q13Fryns 229850 Short ear (se) 9.38 6pl2/15qHermansky-Pudlak 203300 Cocoa (coa) or 3.07 or 8q or 5q

pearl (pe) 13.62Pituitary dwarfism III 262600 Miniature (mn) 15.26 22ql2/8q24Osteopetrosis (Albers-Schonberg) 259700 Grey lethal (gl) 10.25 6q21Restrictive dermopathy 275210 Pupoid fetus (pI) 4.61 or lp36 or

or tight skin (Tsk) 2.56 2q/15q/20pSitus inversus viscerum 270100 Situs inversus viscerum (iv) 12.63 14q32Spondylocostal dysplasia 277300 Rachiterata (rh) 2.35 2q31-q37

Their regional location shows no marked signs as those of any mutation which it carries.of a proximal or distal bias. Normally, of course, an autosomal gene is

inherited from both parents but a deletion ofGenomic imprinting the locus concerned, or such phenomena asIn recent years it has been realised that the non-disjunction or meiotic segregation inroute of inheritance of a gene, that is, the translocation heterozygotes, can lead to trans-parent of origin, can influence its phenotypic mission from one parent only, that is, toeffects and expression in various tissues as well uniparental disomy or monosomy. For certain

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Table 5 Proto-oncogene (0) and growth factor (GF) homologies in human and mouse chromosomes

Locus symbol Name Human location Mouse location

Man Mouse Chr G band Chr cM* G band

ABL1 AblABL2 AbllAKTI AktARAFI ArafEGF EgfEGFR ErbbERBB2 Erbb-2ETS1 Ets-1ETS2 Ets-2FES FesFGFI Fgf-1FGF2 Fgf-2FGF3 Fgf-3FGF4 Fgf-4FGF5 Fgf-5FGF6 Fgf-6FGFR1 FgfrlFGR FgrFOS FosFYN FynGLI GliGLI3 Gli-3GROl MgsaHRAS Hras-1HSl His-1IGFI Igf-IIGF1R Igfl rIGF2 Igf-2IGF2R Igf2rINT4 Int-4JUN J7unJUNB JunbJUND J7undKIT KitKRAS2 Kras-2LYN LynMASI MasMEL MelMET MetMGF SiMOS MosMYB MybMYC MycMYCL1 Lmyc-IMYCN Nmyc-lNGFB NgfbNGFG NgfgNGFR NgfrNRAS NrasPDGFA PdgfaPDGFB PdgfbPDGFRA PdgfraPDGFRB PdgfrbPIM Pim-1PVT1 Pvt-lRAFI Raf-lREL RelRET RetRRAS RrasSEA SeaSKI SkiSRC SrcTGFB1 Tgfb-iTGFB2 Tgfb-2TGFB3 Tgfb-3THRAI ErbaWNT1 Wnt-1WNT2 Wnt-2WNT3 Wnt-3

Abelson leukaemia 0ABL-like 0Murine thymoma viral 0Raf related 0Epidermal GFEpidermal GF receptorErythroblastosis B2 0E26 avian leukaemia 1 0E26 avian leukaemia 2 0Feline sarcoma 0Fibroblast GF 1, acidicFibroblast GF 2, basicFibroblast GF 3 (INT2 0)Fibroblast GF 4 (HSTF1 0)Fibroblast GF 5Fibroblast GF 6Fibroblast GF receptor 1Gardner-Rasheed feline sarcoma 0FBJ osteosarcoma 0FYN oncogeneGlioblastoma 0Glioblastoma 0 3GRO1 0, melanoma growth stim activityHarvey rat sarcoma 0His-I 0Insulin-like GF 1Insulin-like GF 1 receptorInsulin-like GF 2Insulin-like GF 2 receptorMammary tumour virus integration site 4 0Avian sarcoma virus 0Avian sarcoma virus B 0Avian sarcoma virus D 0Kit (Hardy-Zuckerman) 0Kirsten rat sarcoma 2 0Yamaguchi sarcoma, viral related 0Mas 0NK14 derived transforming 0Met 0Mast cell GFMoloney sarcoma 0Avian myeloblastosis 0Myelocytomatosis 0Lung carcinoma, myc related 0Neuroblastoma, myc related 0Nerve beta GFNerve gamma GFNerve growth factor receptorNeuroblastoma transforming 0Platelet derived GF alphaPlatelet derived GF betaPlatelet derived GF receptor alphaPlatelet derived GF receptor betaProviral integration, MCF, 0Plasmacytoma variant translocation 0Murine leukaemia viral 0Reticuloendotheliosis 0Ret 0Related ras viral 0S13 avian erythroblastosis 0Sloane-Kettering avian viral 0Rous sarcoma 0Transforming beta 1 GFTransforming beta 2 GFTransforming beta 3 GFThyroid hormone receptor 0Wingless related integration site 1 0Wingless related MMTV integration site 2Wingless related MMTV integration site 3

9 q341 q24-q25

14 q32.3X pll.4-pll.234 q257 pl3-pl217 ql 1.2-q1211 q23.321 q22.315 q25-qter5 q31.3-q33.24 q26-q27

11 q1311 q134 q2112 p138 pl2-pl 1.21 p36.2-p36.1

14 q24.3-q316 q2112 q13.3-14.17 p134 q21

11 p15.52 ql4-q21

1 2 q231 5 q25-qter1 1 p15.56 q25-q2717 q21-q221 p32

19 p13.219 p13.24 ql I-qI212 p12.18 ql3-qter6 q24-q2719 p13.2-cen7 q31

12 ql4.3-qter8 qll6 q22-q238 q4.11 p322 p24.11 p13

19 -17 q21-q22

1 p137 p22

22 ql2.3-ql3.14 ql I-ql35 q33-q356 p218 q243 p252 pl3-pl210 qll.219 ql3.3-qter11 q13

1 q22-q2420 ql2-ql3.1119 qI3.11 q41

14 q2417 ql 1.2-ql212 q137 q31

17 q21-q22

2 21 B1 62 C5-H3

12 65 F1-F2X 7 A2-A33 78 F3-H111 8 A1-A211 56 D-E19 14 A1-A416 57 C3-C47 37 D1-D318 19 C-D3 18 A2-B7 74 FI-ter7 74 FI-ter5 50 F6 54 F3-G18 10 A1-A44 62 D312 35 Cen-Fl10 24 Cen-B410 72 D13 18 A25 45 E2-F7 31 C-D32 32 C10 54 Ci-Di7 31 C-D37 72 F1-ter17 11 A2-A311 62 E1-E24 40 C5-C78 29 C8 22 C5 37 D-E26 70 F3-G34 6 A1-A217 8 A2-A38 30 C6 6 Cen-BI10 65 Dl4 6 A1-A210 16 Cen-B415 15 D2-D34 50 C7-D112 4 Cen-Fi3 67 F3-H17 22 C

11 54 D3 63 D-H15 69 G

15 25 E5 37 D-E2

18 31 D17 17 A3-B15 16 D2-D36 45 C3

11 12 Al-BI6 46 C3-F37 22 C19 5 B4 69 D3-ter2 71 HI7 7 Cen-A31 79 H5-ter

12 36 Cen-Fl11 56 D-E115 41 F1-F36 6 Cen-BI

11 62 E1-E2

* Distance from centromere in centimorgans.

loci or chromosome regions uniparental in- associated with its paternal origin.92This dele-heritance has a detrimental effect, the nature tion is in a short region of conserved syntenyand extent of which may depend on whether between parts of human 15q and mouse 7.93the inheritance is maternal or paternal.87 In The latter chromosome has one imprintingaddition, distortion of segregation ratios, with region proximal to G band 7C and anotherhuman examples in cystic fibrosis, diabetes, distal to 7E1.9 The deleted region in AS/PWSneural tube defects, and allergy pedigrees,88 seems homologous to a more central region ofmay reflect a parent of origin effect.89 mouse 7, but recent evidence shows that thisTwo of the most convincing examples of region too is implicated in the imprinting

imprinting among human conditions concern phenomenon.95 These two human syndromesthe Angelman (AS) and Prader-Willi syn- also arise in the absence of deletions but associ-dromes (PWS) with different clinical pheno- ated with either iso- or heterodisomy of thetypes but both often involving deletions in maternal chromosome 15 (in PWS)96 or the15q11-q13. However, the Angelman syn- paternal one (in AS)97 as would be expected ifdrome is associated with maternal origin of the genomic imprinting is occurring in this region.deletion909' while the Prader-Willi syndrome is It now seems likely that there are separate

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Table 6 Mapped human disease loci and chromosomal regions possibly involved in genomic imprinting879 "4 with homologous regions in themouse.34 M,P= maternal or paternal inheritance when human anomaly is expressed. Where evidence for imprinting is described as 'slight' in lastcolumn, differential rates of recovery of maternal and paternal disomies have been reported"Chromosome Human Mouse

Disease/malformation Locus symbol Origin Homologous region in chr(s) Evidence for imprinting in these

4p16.3 Huntington's (severe early onset form) HD P 5B-F Slight6p21.3-21.2 Spinocerebellar ataxia SCAI P 17 Yes7 Pre- and postnatal growth retardation - Uniparental 2,5,6,11,13 Yes on 2,6,11

disomy M9q34-qter Chronic myeloid leukaemia - P 2,4 Yes on 2, none on 422cen-ql 1 M 10 None1lpl5.5 Embryonal rhabdomyosarcoma RMS Isodisomy P 7B5-E3 Yes1IpI5.5 Beckwith-Wiedemann BWS Duplication P* 7B5-E3 Yes1lpl3 Wilms's tumour WT1 Deletion M 2E4-F3 Yes (more distal)1 lq23-qter Paraganglioma PGL P 9A4-B None13ql4.1-ql4.2 Retinoblastoma 1 RB1 P 14D2-E1 Slight14 Dysmorphism, mental defect - Disomy P 12,14 Unknown on 12, slight on 1414 Short stature - Disomy M 12,14 Unknown on 12, slight on 1415qll-ql3 Angelman ANCR Deletion M 7B5-D3 Yes

Disomy P15qll-ql3 Prader-Willi PWCR Deletion P 7B5-D3 Yes

Disomy M16 Intrauterine growth retardation, abortion - Isodisomy Mt 7,8,11,16,17 Yes on 7,11,1717q11.2 Neurofibromatosis 1 NFI M 11B5-El Yes (more proximal)

(severe form)19q13.3 Myotonic dystrophy+ DM M 7cen-A3 Yes

(severe form)20qI3.11 Albright's osteodystrophy AHO M 2H Yes22ql1.21- Neurofibromatosis 2 NF2 M 10,11,15,16 Yes for 11qI3.1 (severe form)* Expression also with maternal inheritance; probably two genes involved.t Maternal disomy for chromosome 22 has also been reported but is apparently harmless,'"2113 as is maternal disomy for chromosome 4, paternal isodisomy forchromosome 6, and paternal heterodisomy for the X and Y chromosomes.8+ Associated with unstable DNA sequence (trinucleotide repeats)."4 As with the fragile X syndrome (FRAXA) there seems to be expansion of the repeats through anovary but not through a testis.

unique critical regions or even single genesresponsible for the Angelman and Prader-Willi syndromes.98Genomic imprinting has been suspected as

the mechanism behind a number of otherinstances of differential parental transmissionof human hereditary diseases.879>101 Those ofknown human location are listed in table 6,together with information on presumptivehomologous regions in the mouse. Only two ofthe 18 entries show a clear cut discrepancybetween findings in the two species. It shouldbe remembered, however, that little is knownabout the actual size of imprinted regions inthe mouse since those shown as such on themap"5 have been identified mainly by theaberrant behaviour of marked chromosomesegments which are proximal or distal to trans-location breakpoints, when heterozygotes forsuch translocations are intercrossed. Recentdata on this point for mouse 7 concern theclosely linked genes Igf2 and Hi 9, both map-ping to a distal region which is known to showimprinting effects with both maternal andpaternal duplication.94 Both genes areimprinted, with only the paternal gene activein Igf2l"6"17 and the maternal one in H19.118This suggests that imprinting signals areunlikely to act over large chromosomal re-gions. Indeed, single genes or small criticalregions may be responsible for these parent oforigin effects. Confirmatory evidence comesfrom Igf2r, which codes for the Igf2 receptorgene on mouse 17. This is expressed only fromthe maternally inherited chromosome (that is,not from paternal disomy/maternal nullosomy)but some very closely linked genes are notsubject to imprinting."19

In general, imprinting phenomena involvemajor effects on growth and behaviour, includ-ing overgrowth, hyperactivity, and tumours.

Mouse Igf2 imprinting effects involve growth,so it is interesting to note that both this geneand Hl9 have homologues in the short arm ofhuman chromosome 11, at llpl5.5.'20 Thisregion seems to contain a locus for the fetalovergrowth anomaly which leads to Beckwith-Wiedemann syndrome (BWS) and at least twogenes which predispose to Wilms's tumour,rhabdomyosarcoma, hepatoblastoma, etc. It isnow clear that parent of origin effects, includ-ing paternal duplication of this region, can befound in BWS and in associated tumours aswell as in Igf2 related growth anomalies.'2'-123The amount of human imprinting informa-

tion derived from the detection of uniparentalde novo disomies is increasing rapidly, as table6 shows. In its nature it closely resembles thatprovided by heterozygotes for Robertsoniantranslocations in the mouse when intercrossedand is particularly useful in its scanning of awhole chromosome for effects of imprinting.Prenatal lethality because of isodisomy may bedifficult to pick up in humans. Nevertheless, itmay play an important role in predicting theoutcome after chorionic villus sampling wheremosaicism is restricted to the placenta. It hasparticular importance for translocation car-riers. The outcome for these and the transmis-sion of single genes which manifest imprintingwill have important ramifications for geneticcounselling.88 It seems clear that explanationsbased on genomic imprinting will play animportant part in our future understanding ofthe origins of human hereditary disease.

DiscussionWe list 214 mapped human loci with knownpathological variants in which the position ofthe corresponding mouse locus has also beenmapped. Forty two of these mouse loci (20%)

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also have pathological variants, many of whichresemble the human condition and are thusactually or potentially useful mouse models ofhuman disease. These can throw light on thecauses of the disease but can also help indeveloping therapies for various conditionsnot only at the genetic level but also in study-ing effects of diet changes, medication, etc.82Gene therapy trials in humans are alreadybeing approved.'24 In general, the guidelinesfor these suggest that animal models are de-veloped for trials before human use. Manymodels are currently in use,21 126 but at presentonly a small proportion of human hereditarydisease loci have mouse models. The situationwill not improve if we wait for relevantspontaneous mutations to turn up. Amongalternative strategies are the following.

(1) Mutation induction with a supermuta-gen, such as ethylnitrosourea (ENU).127 Thishas already been used successfully in mice toinduce a mutant deficient in phenylalaninehydroxylase at the Pah locus,47 a dominantmutant at the Min (multiple intestinal neo-plasia) locus which develops numerous aden-omata and seems to be a homologue of the genefor familial adenomatous polyposis coli(APC),53 and a ferrochelatase deficiency at theFech locus which leads to anaemia, photo-sensitivity, and liver dysfunction when homo-zygous .5

(2) Targeted mutagenesis, in which a mut-ant cloned DNA sequence from the locusconcerned is introduced into mouse pluripo-tent embryonal stem (ES) cells by the processof homologous recombination. The altered EScells are then injected into mouse eight cellembryos or blastocysts, in the hope that someof these progeny will become part of the germcell lineage and thus make the mutation herit-able.'28 129 As described earlier, this method hasbeen used to generate a mutation at the Hprtlocus in mice, while further gene targeting hasled to the correction of an HPRT deficiency inan embryonic stem cell line'30 and generationof growth deficient Igf2 mice.98 An extensionof the targeting technique has allowed thecreation of a large deletion at the Tcrb (T cellreceptor P subunit) locus on mouse chromo-some 6.'3' The successful production of mousemodels of cystic fibrosis7' 72 and Gaucher dis-ease73 are other examples.

(3) Use of gene transfer techniques, withthe introduction of foreign DNA, either bymicroinjection into the pronuclei of fertilisedeggs or by retroviral infection of a specificorgan. This technique has been used to removethe pathological effects of a mutant gene, forexample, in shiverer (shi) mice, the locus beinghomologous with human MBP. The injectionof normal DNA at this locus led to the produc-tion of mice with normal behaviour. 132Meisler'33 has listed 13 insertional mutations atestablished mouse loci generated by the integ-ration of foreign DNA within a functionalgene, as well as pathological mutations at 16previously unknown loci. Undoubtedly someof these will become mouse models of humandisease. A steady flow of such models can beexpected from the random insertion of micro-

injected transgenes and resultant 'accidentalknockouts' of genes at medically importantloci.At least 670 disease loci have now been

mapped on human chromosomes,67 as com-pared with 214 on both human and mouse.Since many other loci have been mapped in themouse it seems likely that a large number ofhuman/mouse homologies for mapped loci re-main to be discovered. Because so much is nowknown about conserved segments in the twospecies, the 'positional cloning' approach'34 togene identification is likely to become increas-ingly useful in unmasking these hidden homo-logies. With the development of new in situtechniques, localising the human or mousehomologue on its chromosome should becomerelatively simple. Once the location of thehuman disease gene has been mapped by pedi-gree analysis, then perusal of both human andmouse chromosome maps may be useful inshowing 'candidate genes' if the locus lieswithin a conserved segment. Thus Waarden-burg syndrome type I (WS 1) was mapped to aregion of human chromosome 2 which shares along conserved segment with proximal mouse1. The similar mouse gene splotch (Sp) waslocated here at the appropriate spot and wassubsequently shown to be one of the pairedbox genes Pax-3. Affected WS1 families havebeen found to contain mutations in the humanhomologue of this gene, PAX3. These havenow been found associated with Waardenburgsyndrome type 3 (WS3) also.62 Similarly,human aniridia (AN2) and mouse small eye(Sey) are located in homologous regions onchromosomes 11 and 2 respectively and bothare the result of mutations in Pax-6. In addi-tion, Pax-1 is mutated in the chromosome 2mouse mutant undulated (un), with vertebraland other skeletal anomalies. Thus, this set ofpaired box containing genes clearly comprise avital component of the molecular mechanismsof mammalian development.'35Another recent example of a candidate gene

for a human hereditary disease is PMP22(peripheral myelin protein 22), for theCharcot-Marie-Tooth neuropathy type 1A(CMT1A). This maps to 17plI.2, with amouse model trembler (Tr) in a conservedsegment on chromosome 11. Tr and anotherallele have now been found to be mutant forPmp22, which maps very close to this locus.'36CMT1A is associated with a DNA duplicationand it has now been shown that PMP22 mapswithin this duplication.'37138 A similar con-dition results from partial trisomy ofhuman 17including the 17p segment concerned.

It is not really surprising that mouse mut-ants at homologous loci to those responsiblefor human disease sometimes fail to resemblethe human phenotype at all closely, since somany factors can lead to differences. Of courseit is most important to be sure that the genesare truly homologous. As Darling and Abbott82have pointed out, even if both mutate to givethe same enzyme deficiency, this may affect thestructural gene in one species but a regulatorygene in the other, switching off gene transcrip-tion. Introduction of a wild type structural

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gene into the latter would not correct the genedefect. Thus evidence at the DNA level is verydesirable. This may well show mutations ineach lineage since the common ancestral form.In view of our substantial knowledge of con-served segments, accurate location of a sus-pected homologue is also of great value, es-pecially where several 'mimic genes' are rivalcandidates.Even where homology is not in doubt the

actual nature of the mutation may be verydifferent in the two species, with divergenteffects on development as a result. Thus in thePMP22 homology described above, the Char-cot-Marie-Tooth neuropathy is the result ofduplication of part of the gene while thetrembler alleles in the mouse stem from basepair mutation. As mentioned earlier, even ifboth mutant phenotypes are deficiencies whichinactivate the gene, one or both may not beentirely intragenic, so that neighbouring locimay be affected also, complicating the analysis.It should also be remembered that manymouse loci have a whole series of multiplealleles, which may have surprisingly differentpleiotropic effects. Thus, at the microphthal-mia (ml) locus on chromosome 6 the 11 mutantalleles have a mixture of effects which involvepigmentation, size of eye, and capacity forsecondary bone absorption. Pigmentation isabnormal in all, in a variety of ways, but eachof the other traits is only found with some ofthe alleles, the most extreme of which (mi) islethal.9 The degree of dominance also variesgreatly. Where homology detection is based onmutants with partial gene inactivation, there-fore, comparison with a single allele may notbe sufficient. Thus, one mi allele (miit1) hasbeen thought a possible homologue of humanvitiligo because of its effects on pigmenta-tion.'39 However, other effects of mi alleles mayneed consideration before the true homologycan be established.The genetic backgrounds to homologous

genes cannot be the same for human andmouse chromosomes and this fact alone maylead to different phenotypic effects in the twospecies. It is known in the mouse that modify-ing genes can have a marked effect on geneexpression, so placing the mouse model on adifferent genetic background (for example, anunrelated inbred strain) may be useful.Presumably human ethnic differences mayhave a similar effect. Sometimes a completelydifferent species than the mouse may provide amore suitable model. Thus, the very slightdeleterious effect of X linked muscular dys-trophy in the mouse contrasts with the homo-logous canine condition (DMD) which is a

progressive degenerative myopathy "clinicallyand pathologically similar to Duchenne mus-

cular dystrophy in man"."4 This seems to be abetter animal model, possibly because dogslive longer than mice.These marked interspecific differences may

arise because of evolutionary changes in meta-bolic pathways which may, for instance, allowa toxic product to accumulate in one speciesbut to be efficiently removed in another. Timerelated effects should also be considered, es-

pecially when comparing species with lifespans as divergent as the human 70+ yearsand the mouse 2 + years, with phenotypicclassification of the latter often taking placesoon after weaning age (20 to 50 weeks and 3 to4 weeks respectively). Thus, homologues ofsome human hereditary diseases of late onsetmay not show up well in the mouse, even ifthey are kept until old. However, the lociconcerned may still be discovered by posi-tional cloning and other methods, as withAlzheimer disease (APP) (table 1).Summing up, the philosophy encapsulated

by Bateson's injunction: "Treasure your ex-ceptions!" is now bearing fruit, as more andmore of the mouse variants which were kept,bred, studied, and placed on the linkage andthen the chromosome map are proving to behomologues of human disease loci. Thus, theycan be used as models of human hereditaryconditions, as appropriate subjects for genetherapy tests, and as aids to the demarcation ofconserved segments and therefore to the local-isation of human genes. In this respect humanand mouse genetic advances can truly be calledsymbiotic.We are greatly indebted to Michelle Kirby for much assistancewith computer treatment of the data, to Colin Beechey for theOxford grid (fig 2), and Theresa Kent for her patience and skillin preparing many successive drafts of this review. We are alsograteful to Dr Mary Lyon for helpful comments on an earlierdraft.

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