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1591. Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk

Title Tesim:
Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk
Creator:
Wang, Zefeng, Liu, Yan, Burd, Christin E., Sanoff, Hanna K., Jeck, William R., and Sharpless, Norman E.
Date of publication:
2010
Abstract Tesim:
Human genome-wide association studies have linked single nucleotide polymorphisms (SNPs) on chromosome 9p21.3 near the INK4/ARF (CDKN2a/b) locus with susceptibility to atherosclerotic vascular disease (ASVD). Although this locus encodes three well-characterized tumor suppressors, p16INK4a, p15INK4b, and ARF, the SNPs most strongly associated with ASVD are ∼120 kb from the nearest coding gene within a long non-coding RNA (ncRNA) known as ANRIL (CDKN2BAS). While individuals homozygous for the atherosclerotic risk allele show decreased expression of ANRIL and the coding INK4/ARF transcripts, the mechanism by which such distant genetic variants influence INK4/ARF expression is unknown. Here, using rapid amplification of cDNA ends (RACE) and analysis of next-generation RNA sequencing datasets, we determined the structure and abundance of multiple ANRIL species. Each of these species was present at very low copy numbers in primary and cultured cells; however, only the expression of ANRIL isoforms containing exons proximal to the INK4/ARF locus correlated with the ASVD risk alleles. Surprisingly, RACE also identified transcripts containing non-colinear ANRIL exonic sequences, whose expression also correlated with genotype and INK4/ARF expression. These non-polyadenylated RNAs resisted RNAse R digestion and could be PCR amplified using outward-facing primers, suggesting they represent circular RNA structures that could arise from by-products of mRNA splicing. Next-generation DNA sequencing and splice prediction algorithms identified polymorphisms within the ASVD risk interval that may regulate ANRIL splicing and circular ANRIL (cANRIL) production. These results identify novel circular RNA products emanating from the ANRIL locus and suggest causal variants at 9p21.3 regulate INK4/ARF expression and ASVD risk by modulating ANRIL expression and/or structure.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/pf54-z486
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pgen.1001233, PMID: 21151960, PMCID: PMC2996334, and Onescience id: 176db115dab07eb6d57dc1052ec5bb0544c1cc94
ISSN:
1553-7390 and 1553-7404
Journal Issue:
12
Journal Title:
PLoS Genetics
Journal Volume:
6
Keyword:
RNA Splicing, Atherosclerosis, Cyclin-Dependent Kinase Inhibitor p15, Exons, RNA, Untranslated, Cyclin-Dependent Kinase Inhibitor p16, Humans, Risk Factors, Nucleic Acid Conformation, Gene Expression, Cell Line, Tumor, DNA, Circular, and Genome-Wide Association Study
Language Label:
English
Page Start:
e1001233
Person:
Wang, Zefeng, Liu, Yan, Burd, Christin E., Sanoff, Hanna K., Jeck, William R., and Sharpless, Norman E.
Rights Statement Label:
In Copyright
Source:
vt150s27g

1592. Analysis of the Basidiomycete Coprinopsis cinerea Reveals Conservation of the Core Meiotic Expression Program over Half a Billion Years of Evolution

Title Tesim:
Analysis of the Basidiomycete Coprinopsis cinerea Reveals Conservation of the Core Meiotic Expression Program over Half a Billion Years of Evolution
Creator:
Stajich, Jason E., Wilke, Sarah K., Burns, Claire, Pukkila, Patricia J., Zolan, Miriam E., Rechtsteiner, Andreas, Lilly, Walt W., Hanlon, Sean E., Gathman, Allen C., Savytskyy, Oleksandr P., Lieb, Jason D., and Casselton, Lorna
Date of publication:
2010
Abstract Tesim:
Coprinopsis cinerea (also known as Coprinus cinereus) is a multicellular basidiomycete mushroom particularly suited to the study of meiosis due to its synchronous meiotic development and prolonged prophase. We examined the 15-hour meiotic transcriptional program of C. cinerea, encompassing time points prior to haploid nuclear fusion though tetrad formation, using a 70-mer oligonucleotide microarray. As with other organisms, a large proportion (∼20%) of genes are differentially regulated during this developmental process, with successive waves of transcription apparent in nine transcriptional clusters, including one enriched for meiotic functions. C. cinerea and the fungi Saccharomyces cerevisiae and Schizosaccharomyces pombe diverged ∼500–900 million years ago, permitting a comparison of transcriptional programs across a broad evolutionary time scale. Previous studies of S. cerevisiae and S. pombe compared genes that were induced upon entry into meiosis; inclusion of C. cinerea data indicates that meiotic genes are more conserved in their patterns of induction across species than genes not known to be meiotic. In addition, we found that meiotic genes are significantly more conserved in their transcript profiles than genes not known to be meiotic, which indicates a remarkable conservation of the meiotic process across evolutionarily distant organisms. Overall, meiotic function genes are more conserved in both induction and transcript profile than genes not known to be meiotic. However, of 50 meiotic function genes that were co-induced in all three species, 41 transcript profiles were well-correlated in at least two of the three species, but only a single gene (rad50) exhibited coordinated induction and well-correlated transcript profiles in all three species, indicating that co-induction does not necessarily predict correlated expression or vice versa. Differences may reflect differences in meiotic mechanisms or new roles for paralogs. Similarities in induction, transcript profiles, or both, should contribute to gene discovery for orthologs without currently characterized meiotic roles.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/aatv-c415
Identifier:
Onescience id: 53b8a23aeb24944242eb391ae5512e64a177e869, Publisher DOI: https://doi.org/10.1371/journal.pgen.1001135, PMID: 20885784, and PMCID: PMC2944786
ISSN:
1553-7404 and 1553-7390
Journal Issue:
9
Journal Title:
PLoS Genetics
Journal Volume:
6
Keyword:
History, Ancient, Cluster Analysis, Conserved Sequence, Time Factors, Gene Expression Regulation, Fungal, Gene Expression Profiling, Cell Nucleus, Basidiomycota, Genes, Fungal, Fungal Proteins, Saccharomyces cerevisiae, Schizosaccharomyces, Evolution, Molecular, Multigene Family, and Meiosis
Language Label:
English
Page Start:
e1001135
Person:
Stajich, Jason E., Wilke, Sarah K., Burns, Claire, Pukkila, Patricia J., Zolan, Miriam E., Rechtsteiner, Andreas, Lilly, Walt W., Hanlon, Sean E., Gathman, Allen C., Savytskyy, Oleksandr P., Lieb, Jason D., and Casselton, Lorna
Rights Statement Label:
In Copyright
Source:
rj430c34s

1593. Systematic Identification of Balanced Transposition Polymorphisms in Saccharomyces cerevisiae

Title Tesim:
Systematic Identification of Balanced Transposition Polymorphisms in Saccharomyces cerevisiae
Creator:
Jones, Corbin D., Vision, Todd J., Ganko, Eric W., McCoach, Caroline, Lieb, Jason D., Hanlon, Sean E., Faddah, Dina A., Mieczkowska, Joanna O., Pickrell, Joseph K., and Mann, Frederick G.
Date of publication:
2009
Abstract Tesim:
High-throughput techniques for detecting DNA polymorphisms generally do not identify changes in which the genomic position of a sequence, but not its copy number, varies among individuals. To explore such balanced structural polymorphisms, we used array-based Comparative Genomic Hybridization (aCGH) to conduct a genome-wide screen for single-copy genomic segments that occupy different genomic positions in the standard laboratory strain of Saccharomyces cerevisiae (S90) and a polymorphic wild isolate (Y101) through analysis of six tetrads from a cross of these two strains. Paired-end high-throughput sequencing of Y101 validated four of the predicted rearrangements. The transposed segments contained one to four annotated genes each, yet crosses between S90 and Y101 yielded mostly viable tetrads. The longest segment comprised 13.5 kb near the telomere of chromosome XV in the S288C reference strain and Southern blotting confirmed its predicted location on chromosome IX in Y101. Interestingly, inter-locus crossover events between copies of this segment occurred at a detectable rate. The presence of low-copy repetitive sequences at the junctions of this segment suggests that it may have arisen through ectopic recombination. Our methodology and findings provide a starting point for exploring the origins, phenotypic consequences, and evolutionary fate of this largely unexplored form of genomic polymorphism.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/9941-5s71
Identifier:
PMID: 19503594, Onescience id: 41b47375eb9f419b70cabdde60f274d44261eb91, Publisher DOI: https://doi.org/10.1371/journal.pgen.1000502, and PMCID: PMC2682701
ISSN:
1553-7390 and 1553-7404
Journal Issue:
6
Journal Title:
PLoS Genetics
Journal Volume:
5
Keyword:
DNA, Fungal, Gene Dosage, Saccharomyces cerevisiae, Genome, Fungal, Models, Genetic, Polymorphism, Genetic, Comparative Genomic Hybridization, and DNA Transposable Elements
Language Label:
English
Page Start:
e1000502
Person:
Jones, Corbin D., Vision, Todd J., Ganko, Eric W., McCoach, Caroline, Lieb, Jason D., Hanlon, Sean E., Faddah, Dina A., Mieczkowska, Joanna O., Pickrell, Joseph K., and Mann, Frederick G.
Rights Statement Label:
In Copyright
Source:
tm70n326t

1594. NRXN3 Is a Novel Locus for Waist Circumference: A Genome-Wide Association Study from the CHARGE Consortium

Title Tesim:
NRXN3 Is a Novel Locus for Waist Circumference: A Genome-Wide Association Study from the CHARGE Consortium
Creator:
Pankow, James S., Aspelund, Thor, Fu, Mao, Monda, Keri L., Bielinski, Suzette J., Eiriksdottir, Gudny, Gyllensten, Ulf, Launer, Lenore J., Haritunians, Talin, Mitchell, Braxton D., Rotter, Jerome I., Harris, Tamara B., Demerath, Ellen W., Heard-Costa, Nancy L., Psaty, Bruce M., Amin, Najaf, McArdle, Patrick F., McKnight, Barbara, Boerwinkle, Eric, Pattaro, Cristian, Arnold, Alice M., Shuldiner, Alan R., Chen, Yii-Der Ida, Garcia, Melissa, Campbell, Harry, Glazer, Nicole L., Feitosa, Mary F., Pramstaller, Peter P., Zillikens, M. Carola, Brancati, Fred, Smith, Albert V., and Johansson, Åsa
Date of publication:
2009
Abstract Tesim:
Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/svd7-zw53
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pgen.1000539, PMID: 19557197, PMCID: PMC2695005, and Onescience id: 1ff0933c28d85a6208f75099fd538245b2e66f21
ISSN:
1553-7404 and 1553-7390
Journal Issue:
6
Journal Title:
PLoS Genetics
Journal Volume:
5
Keyword:
/dk/atira/pure/subjectarea/asjc/1300/1306, Nutrition/Obesity, /dk/atira/pure/subjectarea/asjc/1300/1312, Ecology, Evolution, Behavior and Systematics, Genetic Predisposition to Disea, complex traits, genetics and genomics, Genetics and Genomics/Complex Traits, nutrition, Genetics, QH426-470, /dk/atira/pure/subjectarea/asjc/2700/2716, obesity, Humans, Research Article, Obesity, Molecular Biology, /dk/atira/pure/subjectarea/asjc/1300/1311, Cancer Research, /dk/atira/pure/subjectarea/asjc/1100/1105, and Genetics(clinical)
Language Label:
English
Page Start:
e1000539
Person:
Pankow, James S., Aspelund, Thor, Fu, Mao, Monda, Keri L., Bielinski, Suzette J., Eiriksdottir, Gudny, Gyllensten, Ulf, Launer, Lenore J., Haritunians, Talin, Mitchell, Braxton D., Rotter, Jerome I., Harris, Tamara B., Demerath, Ellen W., Heard-Costa, Nancy L., Psaty, Bruce M., Amin, Najaf, McArdle, Patrick F., McKnight, Barbara, Boerwinkle, Eric, Pattaro, Cristian, Arnold, Alice M., Shuldiner, Alan R., Chen, Yii-Der Ida, Garcia, Melissa, Campbell, Harry, Glazer, Nicole L., Feitosa, Mary F., Pramstaller, Peter P., Zillikens, M. Carola, Brancati, Fred, Smith, Albert V., and Johansson, Åsa
Rights Statement Label:
In Copyright
Source:
gt54kw07f

1595. Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?

Title Tesim:
Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?
Creator:
Humphries, Steve E., Järvelin, Marjo-Riita, Heid, Iris M., Loos, Ruth J. F., Hinney, Anke, Kronenberg, Florian, Boeing, Heiner, Kaakinen, Marika, Hebebrand, Johannes, Dina, Christian, Corella, Dolores, Hu, Frank B., Hoehe, Margret R., Francès, Francesc, Cooper, Jackie A., Kollerits, Barbara, Fisher, Eva, Bouchard, Claude, Froguel, Philippe, Ardlie, Kristin, Anand, Sonia S., Huth, Cornelia, Bjerregaard, Peter, Hunt, Steven C., Adamkova, Vera, Illig, Thomas, Hubacek, Jaroslav A., Krude, Heiko, Ciullo, Marina, Biebermann, Heike, Engert, James C., and Hegele, Robert A.
Date of publication:
2009
Abstract Tesim:
The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (‘healthy population’, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/7ckk-t323
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pgen.1000694, Onescience id: 37cd7a5d17cc009993de671ecfd929432f041eee, PMCID: PMC2757909, and PMID: 19851442
ISSN:
1553-7390 and 1553-7404
Journal Issue:
10
Journal Title:
PLoS Genetics
Journal Volume:
5
Keyword:
BODY-MASS, Population, POLYMORPHISM, GENETICS & HEREDITY, Life Sciences & Biomedicine, Genetics, METABOLIC SYNDROME, LIVER, Intracellular Signaling Peptides and Proteins, PROTEIN, Humans, EXPRESSION, Science & Technology, COMMON GENETIC VARIANT, Female, UPSTREAM, Male, Membrane Proteins, POPULATION, Genetics & Heredity, Middle Aged, Obesity, Genome-Wide Association Study, INSULIN, Adult, and Adolescent
Language Label:
English
Page Start:
e1000694
Person:
Humphries, Steve E., Järvelin, Marjo-Riita, Heid, Iris M., Loos, Ruth J. F., Hinney, Anke, Kronenberg, Florian, Boeing, Heiner, Kaakinen, Marika, Hebebrand, Johannes, Dina, Christian, Corella, Dolores, Hu, Frank B., Hoehe, Margret R., Francès, Francesc, Cooper, Jackie A., Kollerits, Barbara, Fisher, Eva, Bouchard, Claude, Froguel, Philippe, Ardlie, Kristin, Anand, Sonia S., Huth, Cornelia, Bjerregaard, Peter, Hunt, Steven C., Adamkova, Vera, Illig, Thomas, Hubacek, Jaroslav A., Krude, Heiko, Ciullo, Marina, Biebermann, Heike, Engert, James C., and Hegele, Robert A.
Rights Statement Label:
In Copyright
Source:
0g354p187

1596. Genome-Wide uH2A Localization Analysis Highlights Bmi1-Dependent Deposition of the Mark at Repressed Genes

Title Tesim:
Genome-Wide uH2A Localization Analysis Highlights Bmi1-Dependent Deposition of the Mark at Repressed Genes
Creator:
Zhang, Yi, Kallin, Eric M., Jothi, Raja, Zhao, Keji, Cao, Ru, Xia, Kai, and Cui, Kairong
Date of publication:
2009
Abstract Tesim:
Polycomb group (PcG) proteins control organism development by regulating the expression of developmental genes. Transcriptional regulation by PcG proteins is achieved, at least partly, through the PRC2-mediated methylation on lysine 27 of histone H3 (H3K27) and PRC1-mediated ubiquitylation on lysine 119 of histone H2A (uH2A). As an integral component of PRC1, Bmi1 has been demonstrated to be critical for H2A ubiquitylation. Although recent studies have revealed the genome-wide binding patterns of some of the PRC1 and PRC2 components, as well as the H3K27me3 mark, there have been no reports describing genome-wide localization of uH2A. Using the recently developed ChIP-Seq technology, here, we report genome-wide localization of the Bmi1-dependent uH2A mark in MEF cells. Gene promoter averaging analysis indicates a peak of uH2A just inside the transcription start site (TSS) of well-annotated genes. This peak is enriched at promoters containing the H3K27me3 mark and represents the least expressed genes in WT MEF cells. In addition, peak finding reveals regions of local uH2A enrichment throughout the mouse genome, including almost 700 gene promoters. Genes with promoter peaks of uH2A exhibit lower-level expression when compared to genes that do not contain promoter peaks of uH2A. Moreover, we demonstrate that genes with uH2A peaks have increased expression upon Bmi1 knockout. Importantly, local enrichment of uH2A is not limited to regions containing the H3K27me3 mark. We describe the enrichment of H2A ubiquitylation at high-density CpG promoters and provide evidence to suggest that DNA methylation may be linked to uH2A at these regions. Thus, our work not only reveals Bmi1-dependent H2A ubiquitylation, but also suggests that uH2A targeting in differentiated cells may employ a different mechanism from that in ES cells.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/1eb2-xq82
Identifier:
PMID: 19503595, PMCID: PMC2683938, Onescience id: d71dbebeb7ff0b6d7cbe342b06b5e1c143b91cba, and Publisher DOI: https://doi.org/10.1371/journal.pgen.1000506
ISSN:
1553-7390 and 1553-7404
Journal Issue:
6
Journal Title:
PLoS Genetics
Journal Volume:
5
Keyword:
Proto-Oncogene Proteins, Nuclear Proteins, Transcription Initiation Site, Histones, Polycomb-Group Proteins, CpG Islands, Repressor Proteins, Genome, DNA Methylation, Promoter Regions, Genetic, Animals, Bmi1 protein, mouse, Polycomb Repressive Complex 1, Cells, Cultured, and Mice
Language Label:
English
Page Start:
e1000506
Person:
Zhang, Yi, Kallin, Eric M., Jothi, Raja, Zhao, Keji, Cao, Ru, Xia, Kai, and Cui, Kairong
Rights Statement Label:
In Copyright
Source:
3b591h57z

1597. Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

Title Tesim:
Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes
Creator:
Cantor, Rita M., Bradfield, Jonathan P., Minshew, Nancy J., Wassink, Thomas H., Imielinski, Marcin, Sigman, Marian, Kustanovich, Vlad, Lindquist, Ingrid, Li, Mingyao, Alvarez Retuerto, Ana I., Wang, Kai, Bucan, Maja, Hadley, Dexter, Kim, Junhyong, Glessner, Joseph T., Sweeney, John A., Sonnenblick, Lisa I., Nurnberger, John I., Gidaya, Nicole B., McMahon, William M., Kim, Cecilia, Owley, Thomas, Singleton, Andrew, Hutman, Ted, Buxbaum, Joseph D., Sutcliffe, James S., Herman, Edward I., Coon, Hilary, Cook, Edwin H., Abrahams, Brett S., Dawson, Geraldine, and Lajonchere, Clara M.
Date of publication:
2009
Abstract Tesim:
The 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 = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), 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.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/dvnt-qn64
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pgen.1000536, PMID: 19557195, Onescience id: 36d9f7392943797995a0b44396b62b6bd6104966, and PMCID: PMC2695001
ISSN:
1553-7390 and 1553-7404
Journal Issue:
6
Journal Title:
PLoS Genetics
Journal Volume:
5
Keyword:
Cell Adhesion Molecules, Genetic Predisposition to Disease, Journal Article, Ubiquitin-Protein Ligases, Child, Female, Neuronal, Exons, Nerve Tissue Proteins, Pedigree, Preschool, Gene Duplication, Autistic Disorder, Male, Cohort Studies, Gene Dosage, Sequence Deletion, Adolescent, Genome-Wide Association Study, Case-Control Studies, Young Adult, and Humans
Language Label:
English
Page Start:
e1000536
Person:
Cantor, Rita M., Bradfield, Jonathan P., Minshew, Nancy J., Wassink, Thomas H., Imielinski, Marcin, Sigman, Marian, Kustanovich, Vlad, Lindquist, Ingrid, Li, Mingyao, Alvarez Retuerto, Ana I., Wang, Kai, Bucan, Maja, Hadley, Dexter, Kim, Junhyong, Glessner, Joseph T., Sweeney, John A., Sonnenblick, Lisa I., Nurnberger, John I., Gidaya, Nicole B., McMahon, William M., Kim, Cecilia, Owley, Thomas, Singleton, Andrew, Hutman, Ted, Buxbaum, Joseph D., Sutcliffe, James S., Herman, Edward I., Coon, Hilary, Cook, Edwin H., Abrahams, Brett S., Dawson, Geraldine, and Lajonchere, Clara M.
Rights Statement Label:
In Copyright
Source:
rv043283q

1598. Arabidopsis CULLIN3 Genes Regulate Primary Root Growth and Patterning by Ethylene-Dependent and -Independent Mechanisms

Title Tesim:
Arabidopsis CULLIN3 Genes Regulate Primary Root Growth and Patterning by Ethylene-Dependent and -Independent Mechanisms
Creator:
Genschik, Pascal, Scheres, Ben, Dumbliauskas, Eva, Lechner, Esther, Thomann, Alexis, Hansen, Maureen, Parmentier, Yves, and Kieber, Joe
Date of publication:
2009
Abstract Tesim:
CULLIN3 (CUL3) together with BTB-domain proteins form a class of Cullin-RING ubiquitin ligases (called CRL3s) that control the rapid and selective degradation of important regulatory proteins in all eukaryotes. Here, we report that in the model plant Arabidopsis thaliana, CUL3 regulates plant growth and development, not only during embryogenesis but also at post-embryonic stages. First, we show that CUL3 modulates the emission of ethylene, a gaseous plant hormone that is an important growth regulator. A CUL3 hypomorphic mutant accumulates ACS5, the rate-limiting enzyme in ethylene biosynthesis and as a consequence exhibits a constitutive ethylene response. Second, we provide evidence that CUL3 regulates primary root growth by a novel ethylene-dependant pathway. In particular, we show that CUL3 knockdown inhibits primary root growth by reducing root meristem size and cell number. This phenotype is suppressed by ethylene-insensitive or resistant mutations. Finally, we identify a function of CUL3 in distal root patterning, by a mechanism that is independent of ethylene. Thus, our work highlights that CUL3 is essential for the normal division and organisation of the root stem cell niche and columella root cap cells.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/7115-4922
Identifier:
PMCID: PMC2607017, PMID: 19132085, Publisher DOI: https://doi.org/10.1371/journal.pgen.1000328, and Onescience id: 797cd8b732751fe9ad1ac8b6de2408001400867d
ISSN:
1553-7404 and 1553-7390
Journal Issue:
1
Journal Title:
PLoS Genetics
Journal Volume:
5
Keyword:
Plant Roots, Ethylenes, Arabidopsis Proteins, Carrier Proteins, Gene Expression Regulation, Plant, Cotyledon, Cell Line, Lyases, Oligonucleotide Array Sequence Analysis, Arabidopsis, and Mutation
Language Label:
English
Page Start:
e1000328
Person:
Genschik, Pascal, Scheres, Ben, Dumbliauskas, Eva, Lechner, Esther, Thomann, Alexis, Hansen, Maureen, Parmentier, Yves, and Kieber, Joe
Rights Statement Label:
In Copyright
Source:
td96k9537

1599. The Histone H3K79 Methyltransferase Dot1L Is Essential for Mammalian Development and Heterochromatin Structure

Title Tesim:
The Histone H3K79 Methyltransferase Dot1L Is Essential for Mammalian Development and Heterochromatin Structure
Creator:
Bajko, Jeffrey, Su, Hui, Li, En, Zhai, Huili, Gonzalo, Susana, Chen, Taiping, Hevi, Sarah, Kadam, Shilpa, Lei, Hong, Valdez, Reginald, Bhat, Audesh, Baltus, Gretchen A., Jones, Brendan, and Zhang, Yi
Date of publication:
2008
Abstract Tesim:
Dot1 is an evolutionarily conserved histone methyltransferase specific for lysine 79 of histone H3 (H3K79). In Saccharomyces cerevisiae, Dot1-mediated H3K79 methylation is associated with telomere silencing, meiotic checkpoint control, and DNA damage response. The biological function of H3K79 methylation in mammals, however, remains poorly understood. Using gene targeting, we generated mice deficient for Dot1L, the murine Dot1 homologue. Dot1L-deficient embryos show multiple developmental abnormalities, including growth impairment, angiogenesis defects in the yolk sac, and cardiac dilation, and die between 9.5 and 10.5 days post coitum. To gain insights into the cellular function of Dot1L, we derived embryonic stem (ES) cells from Dot1L mutant blastocysts. Dot1L-deficient ES cells show global loss of H3K79 methylation as well as reduced levels of heterochromatic marks (H3K9 di-methylation and H4K20 tri-methylation) at centromeres and telomeres. These changes are accompanied by aneuploidy, telomere elongation, and proliferation defects. Taken together, these results indicate that Dot1L and H3K79 methylation play important roles in heterochromatin formation and in embryonic development.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/tsbp-gv67
Identifier:
Onescience id: 3c87f2b12cfd0f7af7204d3d255e358d1b5fe3f8, Publisher DOI: https://doi.org/10.1371/journal.pgen.1000190, PMID: 18787701, and PMCID: PMC2527135
ISSN:
1553-7404 and 1553-7390
Journal Issue:
9
Journal Title:
PLoS Genetics
Journal Volume:
4
Keyword:
Embryonic Stem Cells, Female, Heterochromatin, Methyltransferases, Histone-Lysine N-Methyltransferase, Histones, Centromere, Animals, Aneuploidy, Mutation, Embryo, Mammalian, Mice, Transgenic, Lysine, Mice, Phenotype, and Models, Genetic
Language Label:
English
Page Start:
e1000190
Person:
Bajko, Jeffrey, Su, Hui, Li, En, Zhai, Huili, Gonzalo, Susana, Chen, Taiping, Hevi, Sarah, Kadam, Shilpa, Lei, Hong, Valdez, Reginald, Bhat, Audesh, Baltus, Gretchen A., Jones, Brendan, and Zhang, Yi
Rights Statement Label:
In Copyright
Source:
73666c63g

1600. The Genomic Distribution and Function of Histone Variant HTZ-1 during C. elegans Embryogenesis

Title Tesim:
The Genomic Distribution and Function of Histone Variant HTZ-1 during C. elegans Embryogenesis
Creator:
Zhang, Xinmin, McClinic, Karissa N., Ercan, Sevinc, Lieb, Jason D., Green, Roland D., Kelly, William G., and Whittle, Christina M.
Date of publication:
2008
Abstract Tesim:
In all eukaryotes, histone variants are incorporated into a subset of nucleosomes to create functionally specialized regions of chromatin. One such variant, H2A.Z, replaces histone H2A and is required for development and viability in all animals tested to date. However, the function of H2A.Z in development remains unclear. Here, we use ChIP-chip, genetic mutation, RNAi, and immunofluorescence microscopy to interrogate the function of H2A.Z (HTZ-1) during embryogenesis in Caenorhabditis elegans, a key model of metazoan development. We find that HTZ-1 is expressed in every cell of the developing embryo and is essential for normal development. The sites of HTZ-1 incorporation during embryogenesis reveal a genome wrought by developmental processes. HTZ-1 is incorporated upstream of 23% of C. elegans genes. While these genes tend to be required for development and occupied by RNA polymerase II, HTZ-1 incorporation does not specify a stereotypic transcription program. The data also provide evidence for unexpectedly widespread independent regulation of genes within operons during development; in 37% of operons, HTZ-1 is incorporated upstream of internally encoded genes. Fewer sites of HTZ-1 incorporation occur on the X chromosome relative to autosomes, which our data suggest is due to a paucity of developmentally important genes on X, rather than a direct function for HTZ-1 in dosage compensation. Our experiments indicate that HTZ-1 functions in establishing or maintaining an essential chromatin state at promoters regulated dynamically during C. elegans embryogenesis.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/vp80-ad73
Identifier:
PMID: 18787694, PMCID: PMC2522285, Publisher DOI: https://doi.org/10.1371/journal.pgen.1000187, and Onescience id: 9ec5b1d32ff7e4e509896437409bf1061a5fe797
ISSN:
1553-7404 and 1553-7390
Journal Issue:
9
Journal Title:
PLoS Genetics
Journal Volume:
4
Keyword:
Transcription Initiation Site, Operon, Animals, Fluorescent Antibody Technique, RNA Interference, Histones, Genome, Helminth, Female, Models, Genetic, Embryonic Development, RNA Polymerase II, Dosage Compensation, Genetic, Promoter Regions, Genetic, Caenorhabditis elegans, and Caenorhabditis elegans Proteins
Language Label:
English
Page Start:
e1000187
Person:
Zhang, Xinmin, McClinic, Karissa N., Ercan, Sevinc, Lieb, Jason D., Green, Roland D., Kelly, William G., and Whittle, Christina M.
Rights Statement Label:
In Copyright
Source:
zw12zd38c