TRENDS in Genetics Vol.17 No.2 February 2001http://tig.trends.com93ReviewReviewhttp://tig.trends.com 0168-9525/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0168-9525(00)02180-6ReviewReviewthrough extensive genome replicationaccompanied by chromosome fusions and frequentrearrangements. Genetics 150, 1217–12286 Lagercrantz, U. and Lydiate, D. (1996)Comparative genome mapping in Brassica.Genetics 144, 1903–19107 Leitch, I.J. and Bennett, M.D. (1997) Polyploidyin angiosperms. Trends Plant Sci. 2, 470–4768 Wendel, J.F. (2000) Genome evolution inpolyploids. Plant Mol. Biol. 42, 225–2499 Mayer, K. et al. (1999) Sequence and analysis ofchromosome 4 of the plant Arabidopsis thaliana.Nature 402, 769–77710 Lin, X. et al. (1999) Sequence and analysis ofchromosome 2 of the plant Arabidopsis thaliana.Nature 402, 761–76811 Theologis, A. et al. (20000 Sequence and analysis ofchromosome 1 of Arabidopsisthaliana. Nature 408, 816–82012 Salanoubat, M. et al. (2000) Sequence andanalysis of chromosome 3 of Arabidopsis thaliana.Nature 408, 820–82213 Tabata, S. et al. (2000) Sequence and analysis ofchromosome 5 of Arabidopsis thaliana. Nature408, 823–82614 Bancroft, I. (2000) Insights into the structural andfunctional evolution of plant genomes afforded bythe nucleotide sequences of chromosomes 2 and 4of Arabidopsis thaliana. Yeast 17, 1–515 The Arabidopsis Genome Initiative (2000)Analysis of the genome sequence of the floweringplantArabidopsis thaliana. Nature 408, 796–81516 Bevan, M.W. et al. (1998) Analysis of 1.9 Mb ofcontiguous sequence from chromosome 4 ofArabidopsis thaliana. Nature 391, 485–48817 Blanc, G. et al. (2000) Extensive duplication andreshuffling in the Arabidopsis genome. Plant Cell12, 1093–110118 van Dodeweerd, A-M. et al. (1999) Identification andanalysis of homologous segments of the genomes ofrice and Arabidopsis thaliana. Genome 42, 887–89219 Ku, H-M. et al. (2000) Comparing sequencedsegments of the tomato and Arabidopsis genomes:Large-scale duplication followed by selective geneloss creates a network of synteny. Proc. Natl.Acad. Sci. U. S. A. 97, 9121–912620 Acarkan, A. et al. (2000) Comparative genomeanalysis reveals extensive conservation of genomeorganization for Arabidopsis thaliana andCapsella rubella. Plant J. 23, 55–6221 O’Neill, C. and Bancroft, I. (2000) Comparativephysical mapping of segments of the genome ofBrassica oleracea var alboglabra that arehomologous to sequenced regions of thechromosomes 4 and 5 of Arabidopsis thaliana.Plant J. 23, 233–24322 Song, K. et al. (1995) Rapid genome change insynthetic polyploids of Brassica and itsimplications for polyploid evolution. Proc. Natl.Acad. Sci. U. S. A. 92, 7719–772323 Michelmore, R.W. and Meyers, B.C. (1998)Clusters of resistance genes in plants evolve bydivergent selection and a birth-and-death process.Genome Res. 8, 1113–113024 Noel, L. et al. (1999) Pronounced intraspecifichaplotype divergence at the RPP5 complexdisease resistance locus of Arabidopsis. Plant Cell11, 2099–211125 Tarchini, R. et al. (2000) The complete sequence of340 kb of DNA around the rice Adh1–Adh2 regionreveals interrupted colinearity with maizechromosome 4. Plant Cell 12, 391–39126 Pichersky, E. (1990) Nomad DNA – A model formovement and duplication of DNA sequences inplant genomes. Plant Mol. Biol. 15, 437–44827 Bennetzen, J.L. (2000) Transposable elementcontributions to plant gene and genome evolution.Plant Mol. Biol. 42, 251–26928 Moore, G. et al. (1995) Grasses, line up and form acircle. Curr. Biol. 5, 737–73929 Chen, M. et al. (1998) Sequence organization andconservation in sh2/a1-homologous regions ofsorghum and rice. Genetics 148, 435–44330 Tikhonov, A.P. et al. (1999) Colinearity and itsexceptions in orthologous adh regions of maizeand sorghum. Proc. Natl. Acad. Sci.U. S. A.96, 7409–741431 Gaut, B.S. and Doebley, J.F. (1997) DNAsequence evidence for the segmentalallotetraploid origin of maize. Proc. Natl. Acad.Sci. U. S. A. 94, 6809–681432 Vision, J. et al. (2000) The origins of genomicduplications in Arabidopsis. Science290, 2114–2117ReviewType 1 diabetes, rheumatoid arthritis, multiplesclerosis and Graves’ disease are all autoimmunediseases, to name but a few, probably resulting froman inappropriate immune response to self-proteins.Apart from being characterized by loss ofimmunological tolerance to self, these diseases shareother important characteristics. First, they are allcomplex diseases where multiple genes andenvironmental factors act in concert in theiraetiology. Second, at least one of the genetic factorsinvolved in the development of these diseases islocated in the HLA complex on chromosome 6(Ref. 1).The genes within this complex that are involved indisease are frequently difficult to identify. In thisarticle, we focus on progress made in establishingwhich HLA genes are directly involved and discussmethodological aspects that are important to considerwhen studying the effects of this gene complex. Wefocus directly on type 1 diabetes because studies ofthis disease have implications for the understandingof other HLA associated diseases.Type 1 diabetesDiabetes mellitus is a group of heterogeneous disorderscharacterized by hyperglycaemia (high blood sugar).The incidence of these disorders is increasing worldwide.The predisposition to develop a majority of autoimmune diseases is associatedwith specific genes within the human leukocyte antigen (HLA) complex.However, it is frequently difficult to determine which of the many genes of theHLA complex are directly involved in the disease process.The main reasons forthese difficulties are the complexity of associations where several HLAcomplex genes might be involved,and the strong linkage disequilibrium thatexists between the genes in this complex. The latter phenomenon leads tosecondary disease associations, or what has been called ‘hitchhikingpolymorphisms’.Here, we give an overview of the complexity of HLAassociations in autoimmune disease,focusing on type 1 diabetes and trying toanswer the question:how many and which HLA genes are directly involved?HLA complex genes in type 1 diabetesand other autoimmune diseases.Which genes are involved?Dag E. Undlien,Benedicte A. Lie and Erik ThorsbyD.E.Undlien*B.A.LieE.ThorsbyInstitute of Immunology,The National Hospital andUniversity of Oslo, N-0027 Oslo, Norway.*e-mail:[email protected] in Genetics Vol.17 No.2 February