! J\ 10" International Mouse Genome Conference October 740,1996

10""' Conference Internationale sur le Genome de la Souris 7-10 octobre 1996

Iristitut Pasteur - Paris, France DISCLAIMER

This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, make any warranty, exprrss or implied, or assumes any legal liabili- ty or responsibility for the accuracy, completeness, or usefulness of any information, appa- ratus, product, process disdosed, represents that its use would not infringe privately . or or owned rights. Reference herein to any specific commercial product, process, or senice by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States Government or any agency thereof. The views and opinions of authors expressed herein do not necessar- ily state or reflect those of the United States Government or any agency thereof. DISCLAIMER

Portions of this document may be illegible in electronic image products. Images are produced from the best available original document. Without the help and funds from &e hstimt patem we would not be able to organize the IOth'Internationd Mouse Genome Conference. We want to specidy acknowledge the help and the very active assistance of B6nidicte fioutb. We specid1y thank Isabelle Fleurmce adCatherine Renard for the administrative part of the meeting, Dominique Simon and Xavier Montagutelli have helped for writing the booklet.

This meeting was supported by the &titut National de la Sat6 et de la Recherche M6dicale (INSERM).

In the United States this meeting was funded, in part, by the Office of HumanGenome Research of the National Institutes of Health and the U.S. Department of Energy, Office of Healtli?&d Environment Research. Support was also received from the International Mammalian Genome Society and the Journal Mammal@ Genome. .Chr President/Chair 1 Michael F. Seldk 2 Lmda D. Siracusa Catherine M. Abbott 3 Edward K. Wakeland Michael seldin 4 Berverly Mock Fred Fiedorck, Jr 5 Christine Kozak DennisT. A. Stephenson 6 Rosemary Elliott Karen Moore Brilliant 7 Murray Robert W.Wi 8 JeByCeci 9 Kenji Imai 10 Benjamin Taylor Margit Burmeister 11 Arthur Bwhberg 12 Peter D'Eustachio Roy Riblet 13 Monica Justice Dennis A. Stephenson 14 Joseph Nadeau 15 Konrad Huppi 16 Roger Reeves Deborah Win 17 ReIlataHamvas Jiri Fotejt 18 KemethR Johnson Muriel T. Davisson 19 Jean-Louis Guinet X Yvonne Boyd GailHm E. Bishop Michael Mitchell I I Y Colin Com&swn Internationale de Nomenclature G6n6tique de la Souris International Commiftee on Stizn&r&d Genetic Nomenclaturefor Mice

Muriel T. Davisson, WsidentefC-s USA S.D.M. Brown, England C.M. Abbott, England P. R Avner, France S. Camper, RW. Elliott, J.T. Eppig, USA USA USA M. J. Justice J.-L.Guknet, France IJ. Jackson, Scotland K. Moore, USA K. Moriwaki, Japan J. Peters, England H. Germany L.M.Silver, USA C: Szpjrer, Belgium Winking, Commission HUGOhYUGO Codee

Philip R Avner Yvonne Boyd Stephen D.M. Brown Eva M. Eicher Janan T. Eppig Jemy Friedman David Kingsley HansLehrach Mary F. Lyon Miriam TO&,&&Oshitokhi Meisler Kazuo Moriwaki Secritaria flecretarht

Philip R. Avner RudiBalling . Stephen D.M. Brown Jean Louis Guknet Mary F. Lyon Meisler -1 Kazuo Moriwaki Joseph H. N~WU I;" *. t- !

2:oo pJn. Chromosome Cornmiace Chairs and Co-Chairs 4:Oo Nomenclature Cornmiaet 5:oo Registration at the Centre dlnformation Scientifique 6:30 Welcome Party in the Main Lobby

Tuesday October 8 Morning Sawn: Mutation identif&n

8:30 am. Jean-Louis Gutnet WeIcome 8:45 Jean Weissenbach The hman genome project :fiom mapping to sequencing ml) 9:30 David Beia Generation of a expressed sequence map of the moue using SingIe-Strand Confonnarion Polymorphism @CP) mapping of cDNk (69) 9:45 Sally camper AnaIysir of mutant micc reveak the hierarchy of trmcriptionfators that control pituitary deveIopment (93) 1o:oo KiranChada The pygmy gene is an architecturalfator invotved in tumorigenesis (I 4)

10:15 Coffee

10:45 MariaBarbosa Positional cIoning of the beige and Chediak-Higashi qndrome genes, homologow loci that regularc IysosomaIprotein traflcking (21) 11:Oo Karen Moore The beige gene is the murine od~logueof the hwMn Chediok Higashi worn(37) 11:15 Steve Brown * b@osin ~muta!a*onsin the we:dissecting thefunction of a cnticd “hybrid” motor molede in sensoty hau cells (2s) 11:30 Nancy Jenkins Moleculcrr genetic dissection of momunconvem*onal myosin V 153) 11:45 Eirikur SteingrimssoIl Moledargenetic analysis of b-€iZH-Z&proteins related to microphthalmia (72) 1200 noon Lunchfirst service - Poster session - Computa Demonmatiom 1:30 p.m. Lunch secondsentice - Poster session - Computer Demommtionr A#emoon SssiOn: Gat& md PhysWMapping

230 MargitBurmei Comporotivc genetic and physical mqps of mowe Chromosome IO and hyMn 19~13.3(6) 2:45 Roger Reeves From pWaImaps to sequence: Chr 16 Scgvcncing Conrmkin 0) 3:oo Amir ZUM &net& dp&icd mopphg of the H3 trmuplantanbnrejecrion locw a mOwe Chromosome 2 (13) 3:15 KirstenFischaLiidahl lkendofH2: complcrccomg~mrd~clPvZgenrrvbfmrut~12fi 3:30 Christophe Chevillard Estoblirhmmt of aphysiccrl map of the entire moue Igh Iocut 6y th fiagmetoticn of a complete YAC andmR4C comg and the rhrmficmu*r of a partiaI RAC conti2 (131) 3:45 RobatErickron A high molution mcq?.dpmtial YAC of the Nicnatmn-Prkk C npim 31 Chromosome 18 (S7) 4:oo Genevi&eGourdon CTG repeat changes in tramgcnk micr cmrying thc genomic DMrrpra 1202) 415 Coffee

445 MarieGhristine Siia Analysis of a 94kb genomic scqwncc WiiAin the XIC region (I 7) I 5:Oo Paul Deany PWaImapping of the meX cbomasome (29) 5:15 YasuShiOkazald A genetic Iinkagt map of thr syrh hamtar andloCalirotion ofcad- locw on chromosome 9qd.I-bI using RuiSspot-inqping (16) I 530 Jii Fonjt Towardpitional cloning of the hybridstuiI@y I (Hstl) gem an Chawcw 17 (ss) 5:45 Ryo Kominami Genetic am&& of T cell ljmphoma inriiccrd by 7 -r& irradimforr (I 28) --

6:OO MichaelRh&s Eucu: a high mdvtion miutxatzl&e mr~,of tht m4w cu) . 615 mranLevan Recent devliopments in the rat gem map and compmotivr mrqDping WWthe moue (73) 6:30 Chromosome Committee meetings 7:30 End of working sessionr

Wednesday October 9 Morning seiswn: QuantaotivC Inheriiance and Mulligenlc Traits Quantit&e genetics cocaine induced stereolyw (30) 8:30 am. Christos Bdas of QTLr and 09) 1 a possible mutation qfecting contextual memory 8:45 Lorraine Flaherty (1 9:30 HiroshiMasuya ,UultigeniC control of the anteroposteriw axisjiormrrtion in moue limb development (6s) 9:45 Robert Williams QlLF controlling normal variation in neuron munber and brain weight (IS) 1o:oo SharmilaBasu Gene* basis of retinalphenotypemadificarion in the ocular retardotion mouse (4)

10:15 Coffee

10:45 Richard Mural Exon prediction, pail, and the challenge of automated annotation of DNA sequences (B2) 11:30 Anne Pud Mapping of the genu conbibatring to high and low antib4 responsiveness in Bioi& mice (75) j Roxmary Elliott At least two loci affect &sterilw between mafedonicus and C57BU6 1 11:45 Mus I (12s) 12:OO noon Lunch fint service - Poster session - Computer DcmoNtrotons 1:30 p.m. Lunch secondservice - Poster session - Computer Dcmo~atim Ajlanoon Session I: 2:30 HCltne Courvok A major quantita!ive &ai! locw injluencu h.ymactivity in the WKHA rat (1 02) 245 MarieDarnon Intcrstraindrmnca in thepkmbarbircrl rupoiuivenur of detarication fknctiont in mouse liver (135) GtoIge carkan Moch@rs ofthephewindvcrdbyAkheimeromyloidpcw~aprotein 3:oo ('P) ('P) owre;Vmssion in trmgenic mice (5) 't. 3:15 Edward Wakeland Functional dissection of SLEpgthogtM with congtnic swim 180) 3:30 AlanAttie Sjwrgisrn between BTER adB57BU6 alleles prodvcu an dinrvirrance syn&om in (BTBRx B57BU6) FI mice (146) 3:45 €vie Melanitou ConrbYctonof congenic lines segrrgming a Trpc 1 -ma ~UISI(IK.allels cf mouse chromome 6 in a NOD background (90) AncJysir qfdtigenic 400 Benjamin A Taylor obuity in Strain crassu (163) 415 coffa Afiemoon Skssbn R" 445 . 5:oo 5:lS 530 545 600 230 8:30 am. High-eJ4ciencyjkll-lengthcDNA cloning by biorinyrorrd C4.P pqp (18) 8:45 Pier0 Carninci. 9:30 John Schimenti Chromosomal Deletion Comp1cc-e~in Mice by Radiaion of Embryo& srcm Cells (201) 945 Martine Cohen Salmon Molecular barir of &a&#: I&n@c~*oonof cccMear-speclfic ,.,, mmecochlear substrated cDNA librmy: lindcntandingof thep”hosenv of the Usher type LB Jyndrome (205) 1o:oo Christine Disteche Altered trmmptional regularion of Ch4associated with tk d$&,, chromosomal location in MUSsprecu~ and laboratoty straitu ofmice a4 10:15 coffee J. Martin SHIRPA -A standarakedprotocolfor phcnogypic assu~ment(140) 10:45 E. 11:oo Majs Bum Phenow- andgenow-baed screenfor novel Erm-inducd mutatiom in rh mme (66) albino and pink-@ diIution (p) of mouse mo&hfi 11:15 Monica Justice nte (c) ngiom Chr 7: ~~fknctionalgenomicr(74) coriiicvemet lk STAR genefamily 1k30 quaking (145) Meisler Two models of inherited newownuculm in the (I) 1k45 Miriam &caw mwe 12:OO noon Lunchfinr service - Poster session - Computer LkmonrirOtiOnr 1:30 pa Lunch second service - Poster session - Computer De~atio?~ Afternoon Sessio~~ Imprinting andMutotfon Idmiyzcettorr

2:30 Josephine Peters A new imprihg region in disrcrl mouse Chromosome 2 (203) 2:45 Luisa Dandolo Imprinting mrd the Hl9-1@ locus (SI) 3:oo Bruce cattanach A modelfw Angelman Jyndiomr in thr moue (108) 3:15 Neal Copeland Position effimututiom: the Wand SI loci (7@ Combined nqatirement of Phap&l@ae C beta1 and betad, 3:30 Hee-Sup Shin isoqme.~, fw postnatal pwth and dntelopment of the moue (374) Positional cIonhg of mutottering a modrl fwhwnnn epilep@taria (77) 3:45 Colin FIetcha Compmative mapping of hwuur chr~osomc19 region and identificarionof a 400 Johannah DoyIe candidoic gene for the mowe tom mutation (I 16)

4:15 Coffee Thc Ye- Genome Prmfiamthe sequenct to thefknctional anorySis and 4:45 Banard Dujon bEvond W3) 5:oo LiiStubbs Mouse translocation mutanff as took for anchoring diseasuehtcd phenop to the nunue and humun gene& andpmmaps (114) major intrinricprotcin (blip) is mvtotrdgrna in the HFI mow 5:lS Duslca 1. Sidjanin ntc gene a (2M) 5:30 StephalH8rdia Mus qxetus-specijik LlN51 hybnXzationprobes dctlct introgression oFru, sprrtus alkk inro Mus muscuhls domestiau fro) 6:OO General &causion.-fktwr meetings 7:30 BANQUET ABB0-n Tel 441316511049 4 Catherine M. Fax 44131 651 1059 E-mail ~Qsnr0.med.edXuk wrnburgh EH42XUUK

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Sharmih University Of Michigan Fax 313.7474130 205ZinaPrtcherPIaca E-mail sharmih@’rarich.ed~

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'+ 6

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I~ ~ I Mammalian Genome 8.461463 (1997).

Meeting report: 10th International Mouse Genome Conference

Sally A. Camper, Miriam H. Meisler

Department of Human Genetics. University of Michigan. Ann Arbor, Michigan 48109-0618. USA Received: 27 February 1997 / Accepted 3 March 1997 Ten years after hosting the First International Mammalian Genome nah Doyle (Oak Ridge National Laboratory) predicted that the Conference in Paris in 1986. Dr. Jean-Louis GuCnet presided over same gene would be mutated in the human disorders Familial the Tenth Conference at the Pasteur Institute, October 7-10, 1996. Hemiplegic Migraine and Episodic Ataxia 2. a prediction that was The 1986 conference was a satellite to the Human Gene Mapping recently confirmed [6]. A defect in the major intrinsic protein gene Workshop and had approximately 50 attendees. The 1996 meeting Mip was shown to be associated with cataract development in the was attended by 300 scientists from around the world. In the Hfi mouse by Duska Sidjamin (Univ. Pennsylvania). Jonathan interim, the number of mapped loci in the mouse increased from Stoye (Mill Hill) described the cloning of the Fvl gene responsible 1,000 to over 20,000. The contributions of Dr. GuCnet to this for resistance to the murine leukemia virus (MLV). This locus decade of progress include more than 60 published gene mapping encodes a product with homology to retroviral gag genes, suggest- reports, the development of interspecific backcrosses for high- ing that endogenous mammalian retroviruses may serve unsus- resolution genetic mapping [ I], and ongoing investigations of pected biological functions. mouse models of human neuromuscular disorders. A screening program for identification of mutations affecting This Conference was dedicated to the memory of Dr. George vision and hearing was described by Muriel Davisson (Jackson D, Snell(1903-1996). Dr. Snell received the Nobel Prize in 1980 Laboratory). Seventeeh new vision and 15 new vestibular variants for fundamental contributions to the field of-immunogenetics. His have already been identified. A Mutagenesis Handbook Database pioneering work at The Jackson Laboratory provided the basis for with protocols, screening techniques. and updates on projects in understanding the graft rejection process and the development of progress is under development at the MRC. Hanvell (http:ll human organ transplantation. Identification of individual genes www.mgu.har.mrc.ac.uk/MGU-welcome.htm1).Maya Bucan contributing to the multifactorial inheritance of transplant toler- (Univ. Pennsylvania) described the screeningpf lo00 offspring of ance was a formidable challenge in 1942, when only 8 linkage ENU mutagenized males, using a protocol that combines a whole groups and 23 mouse loci had been identified [2]. Dr. Snell estab- genome screen for dominant behavioral traits with a hemizygous lished the first localization of a histocompatibility gene, on what is screen for novel mutations within the W'9H deletion on Chr 5. now known as Chromosome (Chr) 17 [3]. The subsequent map- Physical and genetic maps. A genetically anchored YAC frame- ping of more than 40 histocompatibility loci has contributed sig- work map of the mouse X Chr was described by Paul Denny nificantly to the development of the mouse genetic map. (MRC, Hanvell) and represents the first step towards a complete This brief review highlights a few of the more than 200 papers physical map of this 160-Mb chromosome. Results of a large-scale presented in Paris. sequence spanning 94 kb around the Xist locus were presented by International Mouse Chromosome Committee meetings. Issues Marie-Christine Simmler (Pasteur Institute), including identifica- related to the generation of consensus genetic maps from multiple tion of a unique transcript expressed in testis, and comparison of independent crosses and the development of new formats for pre- methods for sequence analysis. Substantial progress on the physi- sentation of genetic and physical data were discussed at this year's cal map and DNA sequencing of mouse Chr 16 was reported by committee meetings. Software for on-line editing of the maps was Roger Reeves (Johns Hopkins. Baltimore, Md.). Sequence com- introduced by The Jackson Laboratory informatics group. Hence- parison with human Chr 21 led to the identification of genes not forth, the Committee Maps will be continuously updated by com- recognized by computer software. Analysis of a 2-Mb contig of the mittee members. The committee-generated consensus maps can be H2 major histocompatibility region revealed an ancient family of accessed electronically at (http://www.informatics.jax.orgl eight MHC class I genes (Kirsten Fischer Lindahl, University of mgd.htm1). Matnmalian Genome will continue to publish a printed Texas southwestern, Dallas). version on an annual basis, with the next issue scheduled for Genetic mapping of expressed sequence tags in the mouse publication in August 1997. complements DNA sequence analysis and provides access to Mutant generation and identification. The discovery of the ly- cDNA libraries from early developmental time points and diverse sosomal trafficking regulator gene Lyst responsible for the mouse tissues. The chromosomal mapping of >lo00 brain cDNAs using beige mutation and the human Chediak Higashi syndrome was SSCP to detect interstrain variation was reported by David Beier described by Maria Barbosa (University of Florida) and Karen (Harvard Medical School, Boston). Greg Lennon (Lawrence Moore (Millenium). The two groups initially identified nonover- Livermore, California) described the mouse EST project of the lapping cDNAs that were later shown to be 5' and 3' portions of I.M.A.G.E. consortium. Forty thousand cDNAs from 22 cDNA the large Lysf transcript [4,5]. Identification of the calcium channel . libraries. including normalized libraries prepared by Bento Soares, alpha subunit gene responsible for the allelic neurological muta- have been sequenced at Washington University. St. Louis and tions tottering and leaner was reported by Colin Fletcher (Freder- deposited into dbEST (http://www-bio.llnl.gov/bbrp/image/ ick Cancer Center, Md.). This work was facilitated by a congenic image.html). The goal is to complete 400,OOO sequences in 2 years, strain that narrowed the nonrecombinant interval and the availabil- and the donation of additional mouse cDNA libraries for this proj- ity of two independent alleles. From comparative mapping, Johan- ect was requested. Systematic mapping of the mouse ESTs is not yet planned. The fact that 80% of the positionally cloned human Correspondence IO: M.H. Meisler disease genes are represented in the human EST database (51/62) I. I @.-*-2-- -- - .-

I ment. Miroshi Masuya Japan) demibed loci indicates that completion of the mouse EST project will have a (Mishima, two that major impact on positional cloning. modify the preaxial polydactyly phenotype of Rim4 mutant mice New technology and resources. A novel two-step method for as well as several classic limb mutants, suggesting an iqmtant generating nested deletions a locus described by John role in formation of the alltenopostenor axis of the limb. Ed Wake- Schimenti (Jackson Laboratory).around After targetedwas integration of a land (U. Florida, Gainesville) described the phenotypes of four negatively selectable marker in ES cells, cells are irradiated to congenic lines generated by marker-assisted selection to separate generate random chromosomal deletions and grown in selective the components of susceptibility to systemic lupus erythematosus medium to isolate clones that have lost the marker. The length and (SLE) in the NZM2410 moue strain. extent of the resulting set of nested deletions can be determined by Guest lectures. Jean Weissenbach (Pasteur Institute) reported on PCR assay for loss of heterozygosity, with ES cells derived from the current status of the human genome project, including the an F, hybrid between two inbred strains. The SHIRPA protocol for mapping of more than 15,000 ESTs by a consortium of American standardized evaluation of new mutants was described by J. E. and European laboratories [9]. The genetic length of the CEPH- Martin (Royal London Hospital). One person can evaluate 100 based human genetic map is 3700 cM. Mutations in microsatellite mice per day with 5-step protocol that includes assessment of body markers were found to be responsible for some apparent double posturc, spontaneous activity, transfer arousal, piloerection. startle recombinants. The future role of silicon chip-based mutation de- response, gait, mobility, grip strength, pinna and corneal reflex, tection for genetic disorders was also discussed. Bernard Dujon and response to toe pinch and handling. Adoption of a standardized (Pasteur Institute) described the challenge of deriving functional protocol would provide objective, reproducible data and would information from the complete sequence of the yeast genome [lo]. facilitate comparison of mutant phenotypes described in different This genome contains approximately 6OOO protein coding genes. laboratodes. CAP trapper, an efficient method for constructing only % of which were recognized prior to the sequence analysis. full-length cDNA libraries on the basis of chemical introduction of The EUROFAN project, with 138 participating laboratones, will a biotin group into the diol residue of the cap site followed by focus on functional analysis of the 2000 yeast genes whose func- selection for full-length cDNA with streptavidin-coated magnetic tion is currently unpredictable. Since a significant fraction of yeast beads, was described by P. Carninci (RIKEN, Japan). genes have sequence similarity to mammalian genes, the func- Chromatin structure and gene regulation. On the basis of analy- tional genomics of the yeast will have profound implications for sis of mild alleles at the Steel locus that are located at distances up mammalian genetics. Richard Mural (Oak Ridge National Labo- to 180 kb from the MCGF structural gene, Neal Copeland (Fred- ratory) described improvements in the GRAIL software for exon erick Cancer Center, Md.) proposed that long-distance position prediction, and demonstrated the powerful analytical and graphical effects may be more common in the mammalian genome than has programs now available for genomic sequence (1 1). He empha- been recognized [7]. Bruce Cattanach (Hanvell, UK) presented a sized the importance of developing new methods of annotation that mouse model for the Angelman and Prader Willi syndromes that would enable investigators to contribute data from experimental affect imprinted loci; the relationship is supported by expression analysis of gene function as additions to sequence entries in the studies, comparative mapping, and phenotypic analysis. A new databases. imprinted region of mouse Chr 2 was described by Jo Peters (Har- Future meetings: The Eleventh Mouse Genome Conference. or- well, UK). Analysis of targeted mutations of Puxl by Rudi Balling ganized by Edward Wakeland (U. Florida, Gainesville). will be (Munich) demonstrated that the severe spontaneous alleles of un- held from October 12 to 16 in St. Petersburg. Florida. Registration information is available electronically at the website (http:ll dulated that involve sizable deletions are likely to disrupt addi- tional genes. mcbio.med.buffalo.edu/l limgd) and by email (dmiller@mcbio. med.buffalo.edu). Membership .in the International Mammalian Rat and hamster genetic maps. A complete genetic map of the hamster genome was generated with the RLGS two-dimensional Genome Society (BIGS), which sponsors these Conferences, is DNA technology by Yasushi Okazaki with Yoshihide Hayashizaki open to all interested investigators. Special membership rates are Japan). The map was used to localize a cardiomyopathy available for conference registration and subscriptions to Mammh- (RIKEN, lian Genome. To become a member of the IMGS, contact Darla locus and will facilitate genetic analysis of other hamster mutants [8]. Recent progress on the genetic map of the rat includes estab- Miller, IMGS Administrative Manager, Department of Molecular lishment of the database RATMAP (http://ratmap.gen.g.se) and Biology, Roswell Park Cancer Institute, Buffalo, New York organization of a Rat Genetic Nomenclature Committee. Goran 14263, USA. Levan (Goteborg University, Sweden) reported that 1600 genes have been mapped to rat chromosomes by linkage analysis and Achwfedgmnts. This conference was funded by the Institut National de FISH, providing 85% coverage of the genome. la Sante et de la Recherche Medicale (INSERM), the U. S. National Center MRC Hanvell's new web site (http:l/ Informatics and databases. for Human Genome Research (HGoo756). and the U. S. Department of www.mgu.har.mrc.ac.uk/MGU-welcome.html)will provide ge- Energy. Support was also received from the International Mammalian Ge- netic imprinting maps, chromosomal aberrations, searchable lists nome Society and from Mmmdiun Genom. of mouse frozen embryo and mutant stocks. and a mutagenesis handbook (Mark Shivens, MRC hell).Judith Blake and Janan References Eppig (The Jackson Laboratory) described the evolving status of the Mouse Genome Database. a comprehensive database for ge- 1. Avner P. Amar I, Dandolo L. Gutnet J-L (1988) Genetic analysis of netic and biological data and the the mouse using interspecific crosses. Trends Genet 4.18-23 (http.J/www/ihfoxmatics.jax.org), history of genetics. Annu Rev Genet Gene Expression Database for Mouse Development (GXD)(hwJ 2. Russell ES (1985) A mouse 19. /www.informatics.jax.or~~~html),a database containing images 1-28 of embryonic expression data. 3. Gorer PA, Lyman S, Snell GD (1948) Studies on the genetic and antigenic basis of transplantation. Linkage histocom- trait Several groups reported progress in tumour between Quantitative analysis. patibiiity gene mice. Proc Ser B 135. identification loci and fused in R Soc London and refined localization of quantitative trait 499-505 (QTLs). Phenotypes currently under investigation include obesity, 4. Barbosa MDFS. Nguyen QA, Tchemev JA. Ashley JA. Detter JC. diabetes, insulin resistance, hyperactivity in the rat, weimer Blaydes Brandt Chotai Hodgman C. Solari RCE bVeK disease, brain and retinal development, antibody responsiveness, SM. SJ. D. M. Kingsmore SF (1996) Identification of the homologous beige and and psychomotor response to cocaine. Lorraine Flaherty (Albany, Chediak-Higashi syndrome genes. Nature 382 262-265 Nu) identified loci affecting contextual memory in crosses be- 5. Perou CM, Moore KJ, Nagle DL, Misumi DJ, Woolf EA. McGrail SH. ' tween inbred strains and also in progeny of a mutagenesis expen- Holmgren L. Brody TH, Dussault BJ, Jr. MomCA. Duyk GM. S.A. Camper, M.H. Meislec Meeting Report 463

Y Genetic-linkage map of the hamster and Plyor W, Li L, Justice MJ. Kaplan J (1996) Identification of the ashizaki (1996) syrian murine beige gene by YAC complementation and positional cloning. localization of cardiomyopathy ~ocuson chromosome 9QA2.1-Bi US- Nature Genet 13. 303-308 ing RLGS spot-mapping. Nature Genet 13. 87-90 Ophoff RA, Terwindt GM, Vergouwe MN. van Eijk et (1996) 9. Weissenbach J (19%) Landing on the human genome. Science 274. 6. R. d. 2055-2070 Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Caz' channel gene CACNLIA4. Cell 87.543-552 B (1996) The yeast genome project-what did we learn? Trends IO. DujonGenet 12,363-270 7. Bedell MA, Jenkins NA. Copeland NG (1996) Good genes in bad neighborhoods. Nature Genet 12.229-232 11. Uberbacher EC. Xu Y. RJ Mural (1996) Discovering and understand- 8. Okazaki Y. Okuizumi Ohsumi T, Nomura 0.Takada Kamiya M. ing genes in human DNA sequence using GRAIL. Methods Enzymol H. S. 266.259-28 1 Sasaki N. Matsuda Y, Nishimura M, Tagaya 0. Muramatsu M. Hay- 6

Am. 1. Hum. Genet. 59:764-771, 1996

REVIEW ARTICLE The Role of the laboratory Mouse in the Human Genome Project Miriam H. Meisler Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor

human and mouse genomes contain -150 conserved Introduction segments with nearly identical gene content. The iden- tified conserved linkage groups now span almost 90% The long-term goal of the human genome project is to of the genome, and new mapping data are rapidly identify and establish the function of each of the esti- filling the gaps (Dietrich et al. 1995; Nadeau et al. mated 100,000 genes in the genome. The gene-discovery 1995; Debry and Seldin 1996). Conserved linkage re- phase of the project is proceeding rapidly, via large-scale lationships make it possible to use gene identification sequencing of genomic and cDNA clones. Establishing and map position in one species to predict location in the functional roles for these genes is the challenge for the other and to recognize true homologies between the future, New methods have improved the power of mouse mutants and human disease. A small portion the laboratory mouse to address questions of gene func- of the Debrybeldin comparative map, showing the tion and have attracted many investigators to the field. short arm of human chromosome 2, is reproduced in There has been dramatic progress in the efficiency of posi- figure 1. The 27 genes that have been mapped in both tional cloning of mutant mouse genes, induction of new species fall into four conserved linkage groups that mutants by chemical mutagenesis, targeted mutation of are located on mouse chromosomes 6, 11, 12, and cloned genes by homologous recombination, strategies 17. The indicated gene order is derived from meiotic for analysis of polygenic traits, and comparative mapping mapping of the mouse genes, since most human genes of the human and mouse chromosomes. The contents of are mapped cytogenetically and are not ordered within recent issues of the journals Human Molecular Genetics, chromosome bands. Nature Genetics, and Genomics demonstrate the striking Physical mapping has provided high-resolution sompar- extent to which mouse genes and mouse mutants now isons for a few regions of the human and mouse genomes. occupy the attention of human geneticists. This paper For example, the relative positions of six known genes in provides a brief survey of recent developments with par- the 600-kb interval between LDHC and 5lYODl are ticular relevance to human genetics and the analysis of clearly conserved (fig. 2).Large-scale comparmvr genomic gene function. sequencing of intervals like this one could rewlt in Sene Two useful reference books have recently been pub- discovery based on conservation of function~lquences. lished. The excellent textbook by Silver (1995) provides At an average spacing of 30 kb per gene. kcimpratwe historical background and an up-to-date account of cur- sequencing might idenufy an additional 1 5-20 wnc- lo- rent methods in mouse genetics. The third edition of cated between LDHC and MYODl. Genetic Variants and Strains of the Laboratory Mouse Mouse mapping has been facilitated by the Jc, clop- (Lyon et al. 1996) provides comprehensive information, ment of cumulative mapping panels whow \h.ircd use including descriptions of mouse strains,' mutants, poly- is similar to that of the human CEPH pedigree\. c\Lcpt morphisms, and chromosome variants. that linkage phase is known and every meici\i\ I\ ifitor- mative. The widely used BSB'and BSS hhcro\tes The Human Mouse Comparative Map from the Jackson Laboratory, with 94 mciow\ cxh, The key to establishing relationships between hu- have been typed for >1,500 genes and m.irker\ Kowe man and mouse genes is the comparative map. The et al. 1994). The European Community Irirrr\rccitic Backcross contains 1,000 meioses (European H.1c.k- cross Collaborative Group 1994). A large nirniivr tzf genes have been mapped on other backcro\\c\ in rhe Received June 21, 1996; accepted for publication July 11,1996. Address for correspondence and reprints: Dr. Miriam H. Meisler, laboratories of Nancy Jenkins and Ne~lC tq-elJnd, and Michael Seldin and Christine Kozak. ;Iiiwnsus Department of Human Genetics, 4708 Medical Sciences II, Box 0618, University of Michigan, Ann Arbor, MI 48109-0618. E-mail: maps are compiled by the International 5lou\e hro- [email protected] mosome Committees and published as dn .i:iiiii.iI tap- 0 1996 by The American Society of Human Genetics. All rights reserved. 0002-9297/96/5904-0005$02.00 plement to the journal Mammalian Genomr. ( lii line . Meisler: Role of Avouse in Human Genome Project 765

IN SITU HUMAN Mouse Map Chr ogists for decades and are now proving to be a valuable 2p25 Acpl S I2 resource for identification of the underlying molecular 2~25.~24 TPO f 5.0 I2 disorders. Of the 600 spontaneous mouse mutants de- 2~25.~24 Rrm2 7.0 12 2p25 o& 6.0 I2 scribed in the new edition of the Mouse Locus Catalog 2p23 Pomcl 4.0 12 (Doolittle et al. 1996), 70 have been cloned within the 2p24. I Nmyc I 4.0 12 past few years, and >50 additional cloning projects are 2p24-p22 AD33 Adcy3 S 12 ?p24-p23 AFOB Apob 2.0 12 in progress. Several mouse mutants have led to the iden- 2D SDC I Syndl I .o 12 tification of homologous human disease genes (table 2). 2pi2 REG I A Regla S 12 The current success in positional cloning mouse 2p22-pZI hSOSl Sosl 44.0 -17 of Pk S 17 mutants can be attributed to the efficiency of high-reso- Msh2 45.9 17 lution genetic mapping, the density of genetic markers, 2D21 LHCGR ucgr 46.5 17 2b22 )(MI Xdh 49.0 -17 and the availability of physical mapping resources. 2P21 SPTBNI Spnb2 12.0 I1 Crosses segregating the mutant of interest and con- ZP 15-p12 Re1 13.0 11 REL .**A* taining several thousand informative meioses can be 2pl3 ANX4 ,A+aAa--.-4 Anx4 39.0 6 2p13 TGFA 'a*AAh*---A Tgfa 39.0 6 readily generated, localizing the mutant genes to inter- 2p13 EGR4 Egr4 38.5 6 >=:-la: vals of kb. The 6,600 microsatellites developed 2p13-pI2 MAD .:a:-:-:*:~ Mad 35.0 6

2P sFTp3 ~ ~ Sfrp3 32.0 6 essential polymorphic markers for high-resolution ge- 2p12 CDBA 1. CdBa 31.5 6 netic mapping mutants (Dietrich et al. 1996). Many 2p12 CD8B I ',*aAAa**AA Cd8b 31.5 6 of 2pll FABPl >:-:-:-:e: . Fabpl 30.0 6 of these microsatellites are polymorphic between in bred 2p12 IGK I*-A**-A-A~ kk 30.0 6 strains, as well as in the more distantly related Mus Figure 1 Comparative gene map of the short arm of human musculus castaneus and M. spretus. Independent map- chromosome 2 with four conserved linkage groups on mouse chromo- ping of candidate genes contributed to many of the suc- somes 6, 11, 12, and 17. Mouse map positions are given in centi- cessful positional cloning projects, and knowledge of morgans from the centromere. The complete comparative map can be the humadmouse conserved linkage groups has been accessed electronically at http://www3.ncbi.nlm.nih.gov/RIomologyl. important for recognition of candidate genes. Physical Adapted from Debry and Seldin (1996) with permission. S = syntenic, subchromosomal location not known. resources for positional cloning in the mouse include >10 genome equivalents of YAC clones, as well as PI sources of updated information for crosses, compara- and bacterial artificial chromosome libraries that can be tive humadmouse maps, and related data are listed screened commercially. The mouse expressed sequence in table 1. tag (EST) project at Washington University plans to gen- erate 5' end sequences from 200,000 to 400,000 cDNAs Conserved linkage and Isolation of the Usher from embryonic and adult tissues. By focusing on coding I B Gene sequence and on tissues and embryonic stages not An example of the practical value of the comparative readily available from human sources, it is anticipated chromosome map is provided by the isolation of the that many novel genes will be identified. Mapping these gene responsible for Usher syndromelB, the most fre- ESTs in mouse and man would enhance their value for quent cause of deaf-blindness in humans. Usher 1B and positional cloning efforts in both species. the mouse deafness mutant shaker2 had previously been A number of interesting mouse genes have been iso- mapped to a conserved linkage group on mouse chromo- lated from insertional mutants caused by random inte- some 7 and human chromosome llq13, suggesting that gration of microinjected uansgenes (table 31. The they might be caused by mutations in orthologous genes. transgene provides a probe for isolation of the disrupted The shaker1 gene was isolated in 1995 by positional gene (Meisler 1992; Meisler et al. 1996). Approximately cloning. The mutated gene, Myosin 7a, encodes an un- 3% of transgene insertion sites are,associated wlch visi- conventional myosin expressed in the hair cells of the ble, viable mutations, and another 10% result in prena- inner ear (Gibson et al. 1995). Within a short time, tal lethality. Although some transgene insertion sites mutations were also identified in the MY07A gene of have deletions that may span several centimorgans (Kel- Usher patients (Weil et al. 1995), and the papers describ- ler et al. 1994), insertions have already facilitated the ing the mouse and human mutations were published cloning of several novel genes. back to back. This paradigm motivates much of the current effort in positional cloning of mouse mutants. Chemical Mutagenesis and Genetic Dissection of ' Positional Cloning of Spontaneous Mouse Mutants Complex Pathways: The Clock Mutation The array of abnormal phenotypes associated with Most of the classical mouse mutants arose spontane- single-gene mutations in the mouse have fascinated biol- ously or were induced by radiation. The success of posi- 766 Am. J. Hum. Genet. 59:764-71, 19%

LDHC LDHA SAA * TPH KCNCI .UYODI Human llp15.1 EIHH B k;?;>;?;j I I I I I I 0 200 400 600 800

LdhJLdhl Sua* Tph Kcncl Myodl pg#q a &$:$:j Mouse 7 I I I I I 0 200 400 600

Figure 2 Comparative physical map of genes in the interval between LDHC and MYODl on human chromosome 1 1 p 15. I Jnd prouirii.11 mouse chromosome 7. The human map was derived by partial digest mapping of overlapping YAC clones (Sellar et al. 199-1). The rnouw m.ip was determined by long-range restriction mapping of genomic DNA (Stubbs et al. 1994). Box width represents the inrerval to which rhr gcnc was mapped, not the size of the gene. Distances are given in kilobases. The clustering of human SAr\l, SAAZ, SAA3, and SA44 rlndir.irrd 17, asterisks ['I) was recently shown to be conserved in the mouse (de Beer et al. 1996)

tional cloning has regenerated interest in mutagenesis to (LMcDonald et al. 1990). It has also been applied to the provide genetic access to novel pathways. An exciting generation of new alleles of existing mutants such .is the indicator of future possibilities was the recent identifi- circling mutant kreisler (Cordes and Barsh 1994). High cation of the clock mutation affecting circadian rhythm. mutation rates are also obtained with the mutagen shlor- Vitaterna et a1 (1994) monitored the wheel-running be- ambucil (Flaherty et al. 1992), which produces small havior of 304 offspring of males mutagenized with N- deletions that may be amenable to cloning by represcnra- ethyl, N-nitrosourea (ENU). One animal had an ex- tional difference analysis (Baldocchi et at. 1996). Trans- tended periodicity that was 6 SD units above the mean. locations induced by alkylating agents provide phpical Homozygotes for this mutation demonstrate a complete markers that facilitate cloning (Rutledge et '11. 1986; loss of periodicity when maintained in constant dark- Woychik et al. 1990). Preliminary studies indic.ite that ness. This is the first mammalian gene controlling diur- as many as 15% of induced translocations dre ,iccoliipa- nal rhythms to be identified, and it paves the way for nied by easily detectable phenotypes (W. Gencrou, ,ind genetic identification of novel mammalian genes affect- L. Stubbs, personal communication). ing other behavioral and regulatory processes. Positional The variety of chemical mutagens now dt our Jiyx)xil cloning of the clock gene is in progress. is likely to initiate a renaissance of interest iii iiiJiiced Application of chemical mutagenesis to the mamma- mutations that will enrich our knowledge ot' Imic lvology lian genome required the development of mutagenesis and human genetic disease. Potential targets for iiiur.ipm- protocols with high mutation rates (on the order of sis screening include the visual, immune, ;inJ iic'ur(III Icic.il per locus per generation), to permit identification of mu- systems. A pilot project for the production niiJ ~Ii~~riI~iirion tants in any locus by analysis of a few thousand animals. of ENU mutagenized male mice or their oifspriii~rc1 iiircr- ENU has one of the highest in vivo mutation rates (Rus- ested investigators is under discussion (hl. Bus.in. pr\c1ii,iI sell et al. 1979). Use of EN was pioneered by Bill Dove communication).The combination of cherntc.11 iiiwwiie- and colleagues to generate models of phenylketonuria sis with positional cloning should permit the ivhriilii (it

Table 1 On-line Information Sources

~~ ~~ Source Uniform Resource Locator

Mouse Genom: Database hrrp~/www.informatics.jax.org/mgd.hrml Mouse Locus Catalog Chromosome Committee reports DebryISeldin Humadmouse homology map http://~3.ncbi.nlm.nih.gov/Momology/ Jackson Laboratory Backcross http://www.informatics.jax.org/crossdata.html EUCIB Backcross http://www.hgmp.mrc.ac.uWMBx/MBxHomepage.hrrnl Mouse genetic nomenclature http://www.informatics.jax.ocg/nomen/ Mouse genetic and physical maps hrrp://www.genome.wi.mit.edulcgi-binlmousdindex Meisler: Role of Mouse in Human Genome Project 767

Table 2

Recently Cloned Spontaneous Mouse Mutants and Homologous Human Disorders COSSERVEDLISKACE GROUP

MOUSE MJ-rAsr (SYalBoL) HUMANDISORDER GESEPRODUCT Human Mouse

beige (bg) Chediak Higashi syndrome Vesicle protein, WD40 domain lq44 13 didbetes (d6) ... Leptin hormone receptor 4 dominant white spotting (W) Piebaldism MCGF receptor 4ql2 5 dwarf, Snell (dw) Panhypopituitarism Pir-1 transcription factor 3pll 16 extra toes (Xt) Cephalopolys yndactyly . GLU transcription factor 7p13 13 Hypodactyly (Hd) ... Hoxal3 7p14 6 kidney and retinal degeneration (Krd) Renal coloboma syndrome Pax2 haploinsufficiency lOq2S 19 motor endplate disease (med) ... Sodium channel Scnla 12q13 15 mottled (mo), Menkes disease ATP7il xq13 x * multiple intestinal neoplasia (min) hdenomatous polyposis coli APC 5q21 18 obesity (ob) .. Leptin, peptide hormone 7q32 6 ocular retardation (or) .. ChxlO homeobox gene (14q2.I) 12 osteopetrosis (oc) ... Transporter, 12 T.M type llq13 19 reeler (rl) ... Reelin, ECF motif protein (7q21-36) 5 retinal degeneration slow (rd2) Retinitis pigmentosa Peripherin 2 6p21-cen 17 shaker1 (shl) Usher 1B Myosin VIIA llq13 7 small eye (sey) Aniridia Pax6 llp13 2 Snell’s Waltzer (deafness) (sv) ... .Myosin VI (6p12-91 2) 9 spasmodic (spd) Hyperekplexia Glycine receptor alpha 1 subunit Sq32 11 spastic (spa) ... Glycine receptor beta subunit 4q32 3 splotch (sp) Waardenberg syndrome 1 Pax1 2Opt 1 2 staggerer (sg) ... RORa, retinoic acid receptor 9 testicular feminization (tfm) Androgen insensitivity Androgen receptor Xqll-q12 X tight skin (tsk) Marfan Fibrillin 1 15q21.1 .-7 trembler (tr) Charcot-Marie-Tooth Ih Peripheral myelin protein 17~12-11.2 11 weaver (wv) ... Potassium channel GIRK2 2lq 16 X-linked immune deficiency (xid) Agammaglobulinemia Bruton tyrosine kinase Xq2 1-q22 X

NoTE.-Predicted human locations that have not been confirmed experimentally are italicized in parentheses. Ellipses (. . .) indicate human disorder nor identified.

novel genes affecting any phenotype of interest for which loci that influence disease severity (Rozmahel et al. a robust assay can be developed. Analysis of chemically 1996). Several hundred targeted knockouts of individual induced mutants may be as important in the future as genes have also been generated to provide basic informa- spontaneous mutations have been in the past. tion about in vivo functions (Bronson and Smithies 1994). Some unanticipated results of knockout experi- Targeted Mutation by Homologous Recombination: ments include the discovery of the role of the Src onco- Disease Models and Gene Function gene in tooth formation (H. Varmus, personal communi- cation) and the importance of the epithelial sodium The ability to introduce specific alterations into the transport gene for newborn lung function (Hummler et germ line of the mouse is one of the most dramatic al. 1996). developments in modern biology. This technique has been used to create precise molecular models for human Contiguous Gene Syndromes and single-gene disorders such as cystic fibrosis and Tay “Designer Deletions’’ Sachs disease (table .4); twenty-six disease-related tar- geted mutations are included in the recent review by Deletions are a common source of human inherited Majzoub and Muglia (1996). Although the physiologi- disorders. Deletions that were induced by radiation and cal abnormalities in the mouse are frequently not identi- chemicals have been used to identify regions of im- cal to those in human patients, these mouse models can printing in the mouse genome (Cattanach and Jones be extremely valuable for testing interventions (Searle 1994). In 1995, a general method for inducing deletions et al. 1994), evaluating constructs for gene therapy (Cox 3 or 4 cM in length with predetermined ends was de- et al. 1993; Phelps et al. 1995), and identifying modifier scribed (Ramirez-Solis et al. 1995). The procedure in- 768 Am. J. Hum. Genet. S9:764-771, 1996 Table 3

Mouse Mutants Cloned from Transgene Insertion Sites - CONSERVEDLIXKACE GROUP

.MOUSE !dUTAbT (SYMBOL) PHENO~PE GENEPRODUCT Human, Mouse dystonia muscularis (dt) ,Muscle weakness Dystonin, BPAGl 6~12-p11 1 Fused (Fu) Skeleral, neurological Transcriprion factor (16~13-22) 17 HP58 Early developmenr Yeasr homolog IO limb deformity (Id) . Fused radiudulna Formin, structural protein 15q13.3-ql4 2 microopthalmia (mi) Small eyes, deaf Transcription factor MITF 3~14.1-p12.3 6 motor endplare disease (med) Ataxia, paralysis Sodium channel Scnla 12q13 15 polycycstic kidney disease Kidney disease TPR repeat protein (14m 14 Pygmy (Pd Small size HMGI-C . (12913-14) 10 reeler (rl) Ataxia Reelin (7921-36) 5

Non.-Predicred human locations that have not been confirmed experimentally are italicized in parentheses. volves four gene-targeting events by homologous recom- for a genome scan to chromosomally map each new bination in embryonic stem cells. This method will make mutant and can generate multiple alleles of each locus it possible to produce precise mouse models of contigu- that include gain of function as well as loss of function. ous gene syndromes. Induced deletions can also be used Saturation mutagenesis with ENU could in principle in combination with chemical mutagenesis to identify identify all of the functional elements within a target functional genetic elements within a specified deleted region, although there is some evidence of differential interval. gene sensitivity to mutagenesis. Several efforts to apply this approach are in progress; regions for which dense Combination of Deletions with Mutagenesis for transcript maps are already available would be particu- Functional Analysis of Defined Chromosome Intervals larly productive targets. An efficient strategy for identification and localization Tumor-Suppressor Genes and Loss of Heterozygosity of functional genetic elements is to cross chemically mu- tagenized mice with mice carrying induced deletions, so (LOHI that recessive mutations located within the deletion are Detection of LOH during tumorigenesis is facilitated visible in the offspring. This approach was pioneered by in the mouse because large numbers of independent tu- Gene Rinchik at the Oak Ridge National Laboratory, mors can be generated on a uniform heterozygous ge- using a radiation-induced deletion around the albino netic background with readily distinguishable alleles. locus (Rinchik et al. 1990). Analysis of 3,000 offspring The wild mouse-derived inbred strains SPRETEi and of EN-treated males resulted in identification of many CASTEi carry unique alleles that differ from other labo- distinct functional elements within the deletion (Rinchik ratory strains at most microsatellite markers (Dierrich et al. 1993a, 19936). This method eliminates the need et al. 1994). All heterozygous F1 mice produced from

Table 4

Molecular Models of Human Inherited Disorders Generated by Homologus Recombination Human Disorder Targeted Gene Mouse Phenotype

Cystic fibrosis Cystic fibrosis transmembrane receptor Gastrointestinal and pancreatic abnormalities Neurofibromarosis 1 NF1 Neural crest-derived and myeloid tumors Hemophilia A. Factor VIlI Clomng defect Tay Sachs Disease &hexosaminidase A , Neuronal storage defect Niemann-Pick Type A Acid sphyingomyelinase Neurodegeneration Gaucher’s Disease P-glucocerebrosidase Glucocerebroside storage Retino blastoma RB phosphoprotein Pituitary tumors Glycogen-storage disease Glucose 6 phosphatase Glycogen storage; hepatomegaly, enlarged kidney Lipid-storage diseases Sphingolipid activator protein (SA) Sphingolipid storage disease, leukodystrophy ~ a

Meisler: Role of bfousc in Human Genome Project 769

crosses between laboratory strains and C STEi or ing combinations of mutants (Smithies and hiaeda SPRETEi are genetically identical. LMuItiple tumors can 1995). Combining mutations in PoxI and Pdgfra pro- be generated in each mouse by treatment with carcino- duced spina bifida, a novel phenotype found in neither gens or crossing with transgenic mice with constitutive single mutation (Helwig et al. 1995). Experimental ma- expression of an activated oncogene, This approach has nipulations of this type are likely to be important in been used to identify LOH in a variety of tumor types, the future investigation of complex physiological and including insulinomas (Dietrich et al. 1994; Parangi et developmental processes. al. 1995), hepatocarcinomas (Davis et al. 1994; Manenti et al. 1995), and lung tumors (Herzog et al. 1995). LOH Comparative Sequencing and Gene Discovery can be detected using microsatellite markers spanning the genome or by the restriction landmark method (Oh- In the course of the 160 million years of separate sumi et al. 1995). Sets of microsatellite markers with evolution of the human and mouse genomes, functional resolution of 10 cM and 30 cM, as well as a genotyping sequences have been highly conserved, and nonfunc- service, are available from Research Genetics. Analysis tional sequences have diverged with a mutation rate of of LOH in hybrid mice holds great promise for the iden- roughly 1% per million years. As a result, direct compar- tification of genes involved in the complex progression ison of genomic sequence can distinguish exons and from hyperplasia to tumor. other functional elements from nonfunctional regions. The comparative maps are a guide to appropriate con- served regions for sequence comparison, such that Gene Interaction and Complex Traits ‘IS shown in figure 2. The largest published comparative The same factors that facilitate detection of LOH in DNA sequence is a 100-kb region of T-cell receptor gene hybrid mice also make the mouse a powerful system family (Koop and Hood 1994); the LI~USU~III~high level for identification of quantitative trait loci (QTLs). John of conservation in intergenic regions of this sene family Todd pioneered the use of microsatellites and mapped may be related to the history of gene duplications in the four loci contributing to insulin dependent diabetes (Idd) region. Comparative sequencing was used successfully (Todd et al. 1991). The mapping of QTLs associated to identify the intensively sought gene D.LI.-\HP tDh1 with hypertension in the rat by Eric Lander and his locus-associated homeodomain protein) that IF located colleagues was another early demonstration of this ap- downstream of the expanded trinucleoriclc rcpcat in proach to an important human disease (Jacob et al. myotonic dystrophy (Boucher et al. l99.i). .4lrcrc.J ex- 1991).Polygenic interstrain differences in cancer suscep- pression of DMAHP may be responsible for \oiiic of the tibility and aging have also been identified. Some of the clinical features of this disorder. mouse QTLs appear to correspond with independently One unexpected result of comparative wqiiciiLiiig has mapped human QTLs (Debry and Seldin 1996). been the discovery of conserved seqilenic IiloiLs mc‘ral Interstrain variation has been used to map quantita- kilobases in length that do not contain coiiwr\td pro- tive modifiers of major disease genes such as cystic fi- tein-coding information (Hood et al. 199 ;: ( trittith et brosis (Rozmahel et al. 1996) and colon cancer (Dietrich al. 1996; R. Reeves, personal cornrnunic.iriciii 1. !’I Irctitial et al. 1993); these modifiers may play a role in the vari- roles for these conserved, noncoding wqiimch iiiLlude able course of the human diseases. Although efficient generating RNA products, contributing [(I Iiriwio\orne strategies for positional cloning of QTLs will require function, or regulating gene expression .I\ mh.iii,c.r\ or further development, several interesting candidate genes locus control regions. have been identified within QTL intervals, including the defective Fc receptor near the Idd3 locus affecting auto- Conclusions immune diabetes (Prins et al. 1993) and the phospholi- pase gene as a potential modifier of colon cancer We are entering an exciting era of iiircr.icritiii I.l.r\scc.n (MacPhee et al. 1995). Once identified, candidate genes human and mouse genetics. Tens of tholi\,liiJ~III iiovel can be rigorously evaluated by a variety of methods. human genes will be identified by I;iryt*-\L.ilt*w:oniic Crosses between mutant mice can be used to examine and cDNA sequencing during the next fctv !c.irx. \ii.iIy- directly the combinatorial effects of mutations in indi- sis of spontaneous and induced moiisc‘ iiiut.itit til- will vidual genes. The effects of quantitive changes in expres- play a major role in characterization oi quit tuiicti(in. sion of ApoE, ApoAl, and the LDL receptor on athero-’ and experimental manipulation of the iiic~iixc\\ :II sclerosis have been examined in crosses between tribute to analysis of gene interaction ,inJ clic i:ihl ric.~nce overexpressing transgenic mice and mice carrying tar- of polygenic phenotypes. Comparative ~cqiiciicliit:of geted “knockout” mutations (Smithies and klaeda human and mouse genomic DNA coulcl 1d.1~III ,in- 1995). A direct correlation between blood pressure and portant role in gene discovery. The inoiiw t \ I pwct plasma levels of angiotensinogen was demonstrated us- will contribute to identification of gent\ c \p.x81d in 770 Am. J. Hum. Gener. 59:764-771, 1996 stages of development and in tissues not readily obtain- status and future prospects. Proc Natl Acad Sci USA 92: able from human sources. 10849-10853 ' Dietrich WF, Lander ES, Smith JS, Moser AR, Could KA, Luongo C, Borenstein N, et a1 (1993) Genetic identification Acknowledgments of Mom-2, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75:631-639 This paper is dedicated to the memory of Verne M. Dietrich WF, Miller JC, Steen R, Merchant MA, Damron- Chapman ( 1938-1995), who made many contributions to the Boles D, Husain Dredge R, et al(l996)A comprehensive of genetics its applications. I Z, development mouse and human genetic map of the mouse genome. Nature 380:149- 152 am grateful to Sally Camper for careful review of the manu- Dietrich WF, Radany EH, Smith JS, Bishop JM, Hanahan D, script and to Thomas Gelehrter, Thomas Glaser, Thomas Lander ES (1994) Genome-wide search for loss of heterozy- Glover, and the members of my laboratory for valuable discus- gosity in transgenic mouse tumors reveals candidate tumor sions and assistance. Jane Santoro provided expert editorial suppressor genes chromosomes 9 and 16. Proc Natl Acad assistance. I regret that relevant work by many investigators on Sci USA 91:9451-9455 could not be cited, because of space limitations. Preparation Doolittle DP, Davisson IMT, GuidiJN, Green IMC (1996)Cat- of this manuscript was supported by National Institutes of alog of mutant genes and polymorphic loci. Lyon Health (NIH) grant GM24872. Many of these topics were In: .MF, discussed at the 9th International Mouse Genome Conference Rastan S, Brown SDM (eds) Genetic variants and strains of held in Ann Arbor, MI, November 12-16,1995, with support the laboratory mouse, 3d ed. Vol 1 in: Lyon IMF, Rastan 5, from the U.S. Department of Energy (grant DEFGOZ Brown (eds) Genetic variants and strains of the laboratory 95ER62050) and the NIH (grant HG00756). mouse, 3d ed. Oxford University Press, New York. pp I7- 854 European Backcross Collaborative Group ( 1994) Towards References high resolution maps of the mouse and human genomes: a facility for ordering markers to 0.1 cM resolution. Hum Baldocchi RA, Tartaglia KE, Bryda ED, Flaherty L (1996) Mol Genet 3:621-627 Recovery of probes linked to the jcpk locus on mouse chro- Flaherty L, Messer A, Russell LB, Rinchik EM ( 1992) Chlor- mosome 10 by the use of an improved representational dif- ambucil-induced mutations in mice recovered in homozy- ference analysis technique. 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