Segmental Duplications Flank the Multiple Sclerosis Locus on Chromosome 17q

摘要: The emerging information on the structure of human genome has provided an entirely new view to landscape. Large structural repeats, inversions, and other type rearrangements add a level complexity set challenges for detailed understanding normal disease-associated abnormal functions individual genes regions (Subramanian et al. 2001; Eichler Sankoff 2003). We have applied mapping positional cloning strategy identify genetic loci multiple (MS) sclerosis using study samples collected nationwide from isolated population Finland. Population isolates generally possess certain advantages in studies diseases, even those with complex, polygenic background (Peltonen 2000). Within Finland, Southern Ostrobothnian region represents high-risk area MS, showing exceptional familial clustering MS cases. This particular sample thus offers several including high incidence disease, number cases, proportion progressive-type (Sumelahti 2000, 2003). Our genome-wide search previous identified four main candidate MS: HLA locus 6p, Myelin Basic Protein (MBP) 18q, two relatively wide 5p12–p14 17q22–q24 (Tienari 1992, 1998; Kuokkanen 1997). Interestingly, 17q also been implicated linkage scans performed more heterogeneous populations (Ebers 1996; Sawcer Dyment 2001). biological significance this is further emphasized by fact that syntenic mouse experimental allergic encephalomyelitis (Eae) Chromosome 11 (Butterfield 1998) rat Eae 10 (Jagodic We recently strengthened evidence region, as well restricted critical haplotype association analysis Finnish multiplex families 3.0 Mb, between markers D17S1792 ATA43A10 (Saarela 2002). For fine locus, we confirmed physical map radiation (RH) panels observed significant variation positive clones each marker. interpreted suggestive duplicated sequence structures. hypothesis stimulated extensive FISH comparison different databases. It became evident contained abundance interchromosomal intrachromosomal segmental duplications, known duplicons or low-copy repeat sequences 2002). Such often demarcate genomic instability associated within recurrent chromosomal disease (Stankiewicz Lupski 17 among chromosomes represent duplications presents special challenge (Bailey 2002a). 17q22–24 large segment >300 numerous duplications. These can potentially lead loss gain dosage-sensitive gene disruption its regulatory elements. One example putative role such complex 8p (Giglio positioned common submicroscopic inversion (26% European descent), rearrangement involved pathogenesis diseases like bipolar mapped 2001). In used techniques tools computational refine precisely part process aiming characterize molecular MS. obtained data exemplify landscape position long-range raising interesting possibility architecture may contribute