Recent studies of the human genome have revealed large blocks of almost identical sequences in particular chromosomal regions, comprising about 5 percent of the human genomic sequence. Non-allelic homologous recombination between these paralogous sequences results in changes of genomic structure creating inversions and other types of chromosomal rearrangements. Variation in chromosomal architecture, such as submicroscopical inversions, is more widespread in the human genome than previously thought. One example of a common inversion polymorphism is identified on chromosome 8p23. The main goal of this proposal is to characterize the 8p23 inversion region and develop tools for genome-wide investigation of similar rearrangements. The 8p23 rearrangement, an inversion polymorphism spanning about a 4Mb region flanked by paralogous sequences, was only recently recognized on different haptotypes. The region surrounding or including the inversion on chromosome 8p has been implicated by several independent mapping studies of complex phenotypes including schizophrenia, bipolar disorder, Tourette syndrome, harm avoidance, and prostate cancer susceptibility. Understanding the underlying structure and history of the 8p inversion region is needed to study its role in genome evolution and investigation of these putative loci also requires molecular characterization of the 8p inversion region. Little is known about common inversions. We will conduct detailed analysis of the flanking paralogous sequences and investigate the presence of haplotypes blocks for this region; this will reveal the phylogenetic history of these duplicated segments and enable us to reconstruct the most likely ancestral configuration. Expression profiles will be established for different inversion haplotypes to test the hypothesis that 8p inversion events may affect local or more global gene expression. We will develop a simple assay in order to screen large numbers of samples for the presence of the 8p inversion. Additionally, this and similar inversions may affect the results of statistical genetic analyses; we will investigate the possible implications of these rearrangements on mapping studies, develop statistical methods for linkage and linkage disequilibrium mapping to integrate inversion information for each chromosome, and re-analyze prior genotype data for the different traits that were previously associated with this region. Furthermore, tools will be developed and applied to predict and identify additional genome regions with similar variability, further expanding the possible link between chromosomal architecture and complex traits.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068875-04
Application #
7073331
Study Section
Genome Study Section (GNM)
Program Officer
Anderson, Richard A
Project Start
2003-06-05
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$327,616
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Rao, P N; Li, W; Vissers, L E L M et al. (2010) Recurrent inversion events at 17q21.31 microdeletion locus are linked to the MAPT H2 haplotype. Cytogenet Genome Res 129:275-9
van Es, Michael A; van Vught, Paul W J; Blauw, Hylke M et al. (2008) Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat Genet 40:29-31
Blauw, Hylke M; Veldink, Jan H; van Es, Michael A et al. (2008) Copy-number variation in sporadic amyotrophic lateral sclerosis: a genome-wide screen. Lancet Neurol 7:319-26
Mehan, Michael R; Almonte, Maricel; Slaten, Erin et al. (2007) Analysis of segmental duplications reveals a distinct pattern of continuation-of-synteny between human and mouse genomes. Hum Genet 121:93-100
van Es, Michael A; Van Vught, Paul W; Blauw, Hylke M et al. (2007) ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study. Lancet Neurol 6:869-77
Wessman, Maija; Terwindt, Gisela M; Kaunisto, Mari A et al. (2007) Migraine: a complex genetic disorder. Lancet Neurol 6:521-32
Chen, Gary K; Slaten, Erin; Ophoff, Roel A et al. (2006) Accommodating chromosome inversions in linkage analysis. Am J Hum Genet 79:238-51
Mehan, Michael R; Freimer, Nelson B; Ophoff, Roel A (2004) A genome-wide survey of segmental duplications that mediate common human genetic variation of chromosomal architecture. Hum Genomics 1:335-44