Browsing by Subject "Cell Adhesion Molecules, Neuronal"
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Item Open Access Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.(PLoS Genet, 2009-06) Bucan, Maja; Abrahams, Brett S; Wang, Kai; Glessner, Joseph T; Herman, Edward I; Sonnenblick, Lisa I; Alvarez Retuerto, Ana I; Imielinski, Marcin; Hadley, Dexter; Bradfield, Jonathan P; Kim, Cecilia; Gidaya, Nicole B; Lindquist, Ingrid; Hutman, Ted; Sigman, Marian; Kustanovich, Vlad; Lajonchere, Clara M; Singleton, Andrew; Kim, Junhyong; Wassink, Thomas H; McMahon, William M; Owley, Thomas; Sweeney, John A; Coon, Hilary; Nurnberger, John I; Li, Mingyao; Cantor, Rita M; Minshew, Nancy J; Sutcliffe, James S; Cook, Edwin H; Dawson, Geraldine; Buxbaum, Joseph D; Grant, Struan FA; Schellenberg, Gerard D; Geschwind, Daniel H; Hakonarson, HakonThe genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.Item Open Access Thousands of human mobile element fragments undergo strong purifying selection near developmental genes.(Proceedings of the National Academy of Sciences of the United States of America, 2007-05) Lowe, Craig B; Bejerano, Gill; Haussler, DavidAt least 5% of the human genome predating the mammalian radiation is thought to have evolved under purifying selection, yet protein-coding and related untranslated exons occupy at most 2% of the genome. Thus, the majority of conserved and, by extension, functional sequence in the human genome seems to be nonexonic. Recent work has highlighted a handful of cases where mobile element insertions have resulted in the introduction of novel conserved nonexonic elements. Here, we present a genome-wide survey of 10,402 constrained nonexonic elements in the human genome that have all been deposited by characterized mobile elements. These repeat instances have been under strong purifying selection since at least the boreoeutherian ancestor (100 Mya). They are most often located in gene deserts and show a strong preference for residing closest to genes involved in development and transcription regulation. In particular, constrained nonexonic elements with clear repetitive origins are located near genes involved in cell adhesion, including all characterized cellular members of the reelin-signaling pathway. Overall, we find that mobile elements have contributed at least 5.5% of all constrained nonexonic elements unique to mammals, suggesting that mobile elements may have played a larger role than previously recognized in shaping and specializing the landscape of gene regulation during mammalian evolution.