The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and play an essential role in self/nonself immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune disease1. Yet identification of causal variants is problematic due to linkage disequilibrium (LD) that extends across multiple HLA and non-HLA genes in the MHC2,3. We therefore set out to characterize the LD patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common single nucleotide polymorphisms (SNPs) and deletion/insertion polymorphisms (DIPs) across four population samples. The analysis provides informative tag SNPs that capture some of the variation in the MHC region and that could be used in initial Corresponding author: John D. Rioux, Montreal Heart Institute, 5000 Rue Bélanger, Montréal, Québec, Canada, H1T 1C8, E-mail: rioux@broad.mit.edu. 16 These authors contributed equally All data will be available at the following sites: http://www.broad.mit.edu/mpg/idrg/projects/hla/ http://www.sanger.ac.uk/HGP/Chr6/ http://www.glovar.org COMPETING FINANCIAL INTEREST STATEMENTThe authors declare that they have no competing financial interests. Numerous studies have demonstrated association between HLA alleles and disease susceptibility (a partial list is provided in Table 1 and Supplementary Table 1), but the interpretation of these results is confounded by the strong correlation between alleles at neighboring HLA and non-HLA genes. Major efforts have therefore been directed at cataloguing the gene and variation content of the entire MHC4-6. In addition, previous studies in European-derived populations have examined the distribution of LD across the region and have suggested that SNPs could help dissect causal variation within the MHC2,3,7-10. Here, we have created a resource to guide future association studies by genotyping genetic variants across the extended MHC region of 7.5 Mb at a higher density and in more DNA samples than previously reported. In 361 individuals of African (YRI), European (CEU), Chinese (CHB), and Japanese (JPT) ancestry, the inferred haplotype structure across the region shows that LD is systematically higher in CEU, CHB and JPT samples than in the YRI sample (Fig. 1). Alleles across the different classical HLA loci demonstrate strong correlation (Supplementary Table 2). These high levels of LD among SNPs and DIPs and among HLA alleles suggest that SNPs outside the HLA genes are informative about HLA types (Fig. 2a), and that a few, well chosen SNPs may capture common classical HLA variation at several loci. Europe PMC Funders GroupWe examined the association between HLA types and single SNPs across the entire region. Fig. 2b shows the results for HLA-C (see Supplementary Fig. 1 for the other HLA genes). In the four populations studied, 34-44% of the HLA alleles present are strongly associa...

Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.

Background: Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders.

Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.