Lengeling, Andreas

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     Edinburgh Research Explorer                                      From man to mice - from mice to manCitation for published version:Lengeling, A 2002, 'From man to mice - from mice to man' Gene Function & Disease, vol 3, no. 3-4, pp. 67-68.Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Preprint (usually an early version)Published In:Gene Function & DiseaseGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 20. Feb. 2015Gene Funct. Dis. 2002, Vol. 3, 3-4, 6768 67Guest EditorialFrom man to mice  from mice to manWe have reached a new landmark in mouse genetics,functional genome annotation and comparative gen-omics. The sequence and analysis of more than 95%of the mouse genome has been published for the firsttime in Nature (Vol. 420, 5th December 2002). Thebiomedical research community has now this superband freely available tool at their fingertips to tackle thecomplexities of human disease by using the mouseas a model.After the publication of the human genome draft se-quence a year ago, progress in sequencing hasmeanwhile covered approximately 98% of the humangenome with about 95% in finished form. This re-source has now been used for comparisons with themouse draft sequence. The results provide new im-portant insights into structure and contents of bothgenomes, with some unexpected surprises. The mostimportant findings are: Approximately 99% of all mouse genes have de-tectable homologues in the human genome. The human and mouse gene catalogue containsabout 30,000 protein-coding genes, supporting theearlier gene number estimates made from the hu-man draft sequence. But the mouse genome is14 % smaller than the human genome (2.5 Gbcompared with 2.9 Gb). About 1,200 new genes have been detected in thehuman genome by comparisons of mouse and hu-man sequences. Approximately 9,000 genes havebeen found in the mouse for the first time. The analysis of the mouse transcriptome by theFANTOM consortium of the RIKEN Institute hasrevealed an unexpectedly large number of non-co-ding RNAs, indicating that non-coding RNA is themajor component of the transcriptome. Some gene families have experienced a massiveexpansion in the mouse lineage since the diver-gence of rodents and humans. Mice have moregenes in gene families involved in olfaction, repro-duction, immunity and host defence, reflecting dif-ferent selection forces for these biological func-tions in the two species. By comparing the draft sequence of the inbredstrain C57BL/6J with sequences generated from WILEY-VCH Verlag GmbH, 69451 Weinheim, 2002 0173-0835/02/0601-0067 $17.50+.50/0other inbred mouse strains, about 80.000 singlenucleotide polymorphisms (SNPs) have beenidentified. These SNPs are not evenly distributedover the genome. They occur in large blocks, indi-cating that the founder populations of laboratorymouse strains were extremely limited. The con-clusion is that the genetic variation among inbredstrains is much smaller than expected.How will this sequencing endeavour change our dailywork? What impact will the mouse genome sequencehave on the elucidation of vertebrate gene functions?Impact on gene targeting experimentsThe key to understanding the function of a gene ismutagenesis. By using knockout approaches throughhomologous recombination in embryonic stem (ES)cells, thousands of medically important loss-of-func-tion mutations in mice have been generated. One ofthe most time-consuming steps in the knockout busi-ness is still the design and cloning of the targetingconstruct. With the mouse sequence available, tedi-ous restriction site mapping can be avoided. Tar-geting vectors can be designed from the locus se-quence in silico. Thus, the process of generatingtransgenic mice will be sped-up tremendously. More-over, sequence annotated C57BL/6J-BAC clones canbe directly ordered at genome resource centers andused as DNA cloning resources for targeting con-structs. In combination with C57BL/6J-ES cell linesknockout and knockin alleles can be engineered fromthe beginning in a homogeneous inbred backgroundand will render further extensive backcrosses dis-pensable.Impact on large-scale mutagenesis projectsPhenotype-driven large-scale mutagenesis projectshave opened a new avenue in the systematic pro-duction of new mouse mutants. At least ten bigmouse mutagenesis centers have embarked on ran-dom chemical mutagenesis by using ethylnitrosourea(ENU) as an effective mutagen. Hundreds of novelmouse mutant lines have been recovered by world-wide mutagenesis screens. All these mutants are now68 Gene Funct. Dis. 2002, Vol. 3, 3-4, 6768waiting for the positional cloning of the underlying mo-lecular gene lesion. With the complete mouse se-quence at hand, every gene in a critical mapping in-terval will be known, allowing a very effective candi-date gene approach to find the mutation.The same is true for several large-scale gene-trapprogrammes that are underway to add more mutantsto the worldwide collection of mutant lines. The avail-ability of the genome sequence will facilitate the de-termination of the precise integration site of the “genetrap reporter construct”. This allows a better selectionof targeted ES cells that can be subsequently used togenerate interesting mutants.Revolutionizing the analysis of quantitative traitsOne of the exciting brake-throughs can be expectedfor the genetic characterization of multigenic andquantitative traits in mice. Most of the medically im-portant human diseases like diabetes, hypertension,autoimmunity disorders, susceptibility to cancer andinfectious diseases are believed to be determined bycomplex interactions of multiple genes. Many of thesecomplex traits can also be observed in crosses be-tween inbred strains of mice that serve as animal mo-dels for such disorders. The analysis of SNP distri-butions among inbred strains has now shown that twothirds of the mouse genome have a very low polymor-phism rate, due to ancestral haplotypes which havebeen inherited since the divergence of mouse sub-strains. This means that positional cloning initiativesof quantitative trait loci (QTLs) should focus on chro-mosomal subregions of high SNP rates between par-ental strains. More than 95% of the total geneticvariation will be found in these regions. By makinguse of linkage disequilibrium between a phenotypeand particular ancestral haplotypes, it might be pos-sible to identify a critical region where the causativegene should be located. If QTLs have been mappedin several strain combinations, a comparison ofhaplotype distributions among the strains should al-low to narrow the critical region to an even smallerchromosomal interval.Tasks for the futureTo use the full potential of mouse inbred strains in thegenetic dissection of important traits, SNP data haveto be generated systematically in all commonly usedstrains. This is a requirement to explore the fine struc-ture of ancestral haplotypes at a resolution highenough for QTL cloning. In addition, the valuableresource of inbred strains needs to be systematicallyphenotyped for as many physiologically and medi-cally relevant parameters as possible. The recentlystarted Mouse Phenome project at the JacksonLaboratory is an important new tool to make thosekinds of data freely available to the scientific com-munity.Not every human phenotype or disorder can be ex-actly replicated in mouse models. The elucidation ofboth genome sequences will further an improvedunderstanding of observed differences between miceand man. But all comparative studies will depend onthe to-and-fro between the two genomes, the guidingprinciple will be maintained - from man to mice andback again from mice to man.Andreas Lengeling Braunschweig

From man to mice - from mice to man

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