JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
The age related markers lipofuscin and apoptosis show different genetic architecture by QTL mapping in short-lived Nothobranchius fish.
Aging (Albany NY)
PUBLISHED: 08-06-2014
Show Abstract
Hide Abstract
Annual fish of the genus Nothobranchius show large variations in lifespan and expression of age-related phenotypes between closely related populations. We studied N. kadleci and its sister species N. furzeri GRZ strain, and found that N.kadleci is longer-lived than the N. furzeri. Lipofuscin and apoptosis measured in the liver increased with age in N. kadleci with different profiles: lipofuscin increased linearly, while apoptosis declined in the oldest animals. More lipofuscin (P<0.001) and apoptosis (P<0.001) was observed in N. furzeri than in N. kadleci at 16w age. Lipofuscin and apoptotic cells were then quantified in hybrids from the mating of N. furzeri to N. kadleci. F?individuals showed heterosis for lipofuscin but additive effects for apoptosis. These two age-related phenotypes were not correlated in F? hybrids. Quantitative trait loci analysis of 287 F? fish using 237 markers identified two QTL accounting for 10% of lipofuscin variance (P<0.001) with overdominance effect. Apoptotic cells revealed three significant- and two suggestive QTL explaining 19% of variance (P<0.001), showing additive and dominance effects, and two interacting loci. Our results show that lipofuscin and apoptosis are markers of different age-dependent biological processes controlled by different genetic mechanisms.
Related JoVE Video
16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy.
Hum. Mol. Genet.
PUBLISHED: 06-16-2014
Show Abstract
Hide Abstract
Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.
Related JoVE Video
Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.
Hepatology
PUBLISHED: 01-17-2013
Show Abstract
Hide Abstract
Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 × 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 × 10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis.
Related JoVE Video
A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals.
Mech. Ageing Dev.
PUBLISHED: 06-14-2011
Show Abstract
Hide Abstract
We conducted a case-control genome-wide association study (GWAS) of human longevity, comparing 664,472 autosomal SNPs in 763 long-lived individuals (LLI; mean age: 99.7 years) and 1085 controls (mean age: 60.2 years) from Germany. Only one association, namely that of SNP rs4420638 near the APOC1 gene, achieved genome-wide significance (allele-based P=1.8×10(-10)). However, logistic regression analysis revealed that this association, which was replicated in an independent German sample, is fully explicable by linkage disequilibrium with the APOE allele ?4, the only variant hitherto established as a major genetic determinant of survival into old age. Our GWAS failed to identify any additional autosomal susceptibility genes. One explanation for this lack of success in our study would be that GWAS provide only limited statistical power for a polygenic phenotype with loci of small effect such as human longevity. A recent GWAS in Dutch LLI independently confirmed the APOE-longevity association, thus strengthening the conclusion that this locus is a very, if not the most, important genetic factor influencing longevity.
Related JoVE Video
A tissue-specific landscape of sense/antisense transcription in the mouse intestine.
BMC Genomics
PUBLISHED: 06-10-2011
Show Abstract
Hide Abstract
The intestinal mucosa is characterized by complex metabolic and immunological processes driven highly dynamic gene expression programs. With the advent of next generation sequencing and its utilization for the analysis of the RNA sequence space, the level of detail on the global architecture of the transcriptome reached a new order of magnitude compared to microarrays.
Related JoVE Video
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.
, Stephen Sawcer, Garrett Hellenthal, Matti Pirinen, Chris C A Spencer, Nikolaos A Patsopoulos, Loukas Moutsianas, Alexander Dilthey, Zhan Su, Colin Freeman, Sarah E Hunt, Sarah Edkins, Emma Gray, David R Booth, Simon C Potter, An Goris, Gavin Band, Annette Bang Oturai, Amy Strange, Janna Saarela, Celine Bellenguez, Bertrand Fontaine, Matthew Gillman, Bernhard Hemmer, Rhian Gwilliam, Frauke Zipp, Alagurevathi Jayakumar, Roland Martin, Stephen Leslie, Stanley Hawkins, Eleni Giannoulatou, Sandra D'Alfonso, Hannah Blackburn, Filippo Martinelli Boneschi, Jennifer Liddle, Hanne F Harbo, Marc L Perez, Anne Spurkland, Matthew J Waller, Marcin P Mycko, Michelle Ricketts, Manuel Comabella, Naomi Hammond, Ingrid Kockum, Owen T McCann, Maria Ban, Pamela Whittaker, Anu Kemppinen, Paul Weston, Clive Hawkins, Sara Widaa, John Zajicek, Serge Dronov, Neil Robertson, Suzannah J Bumpstead, Lisa F Barcellos, Rathi Ravindrarajah, Roby Abraham, Lars Alfredsson, Kristin Ardlie, Cristin Aubin, Amie Baker, Katharine Baker, Sergio E Baranzini, Laura Bergamaschi, Roberto Bergamaschi, Allan Bernstein, Achim Berthele, Mike Boggild, Jonathan P Bradfield, David Brassat, Simon A Broadley, Dorothea Buck, Helmut Butzkueven, Ruggero Capra, William M Carroll, Paola Cavalla, Elisabeth G Celius, Sabine Cepok, Rosetta Chiavacci, Françoise Clerget-Darpoux, Katleen Clysters, Giancarlo Comi, Mark Cossburn, Isabelle Cournu-Rebeix, Mathew B Cox, Wendy Cozen, Bruce A C Cree, Anne H Cross, Daniele Cusi, Mark J Daly, Emma Davis, Paul I W de Bakker, Marc Debouverie, Marie Beatrice D'hooghe, Katherine Dixon, Rita Dobosi, Bénédicte Dubois, David Ellinghaus, Irina Elovaara, Federica Esposito, Claire Fontenille, Simon Foote, Andre Franke, Daniela Galimberti, Angelo Ghezzi, Joseph Glessner, Refujia Gomez, Olivier Gout, Colin Graham, Struan F A Grant, Franca Rosa Guerini, Hakon Hakonarson, Per Hall, Anders Hamsten, Hans-Peter Hartung, Rob N Heard, Simon Heath, Jeremy Hobart, Muna Hoshi, Carmen Infante-Duarte, Gillian Ingram, Wendy Ingram, Talat Islam, Maja Jagodic, Michael Kabesch, Allan G Kermode, Trevor J Kilpatrick, Cecilia Kim, Norman Klopp, Keijo Koivisto, Malin Larsson, Mark Lathrop, Jeannette S Lechner-Scott, Maurizio A Leone, Virpi Leppä, Ulrika Liljedahl, Izaura Lima Bomfim, Robin R Lincoln, Jenny Link, Jianjun Liu, Aslaug R Lorentzen, Sara Lupoli, Fabio Macciardi, Thomas Mack, Mark Marriott, Vittorio Martinelli, Deborah Mason, Jacob L McCauley, Frank Mentch, Inger-Lise Mero, Tania Mihalova, Xavier Montalban, John Mottershead, Kjell-Morten Myhr, Paola Naldi, William Ollier, Alison Page, Aarno Palotie, Jean Pelletier, Laura Piccio, Trevor Pickersgill, Fredrik Piehl, Susan Pobywajlo, Hong L Quach, Patricia P Ramsay, Mauri Reunanen, Richard Reynolds, John D Rioux, Mariaemma Rodegher, Sabine Roesner, Justin P Rubio, Ina-Maria Rückert, Marco Salvetti, Erika Salvi, Adam Santaniello, Catherine A Schaefer, Stefan Schreiber, Christian Schulze, Rodney J Scott, Finn Sellebjerg, Krzysztof W Selmaj, David Sexton, Ling Shen, Brigid Simms-Acuna, Sheila Skidmore, Patrick M A Sleiman, Cathrine Smestad, Per Soelberg Sørensen, Helle Bach Søndergaard, Jim Stankovich, Richard C Strange, Anna-Maija Sulonen, Emilie Sundqvist, Ann-Christine Syvänen, Francesca Taddeo, Bruce Taylor, Jenefer M Blackwell, Pentti Tienari, Elvira Bramon, Ayman Tourbah, Matthew A Brown, Ewa Tronczynska, Juan P Casas, Niall Tubridy, Aiden Corvin, Jane Vickery, Janusz Jankowski, Pablo Villoslada, Hugh S Markus, Kai Wang, Christopher G Mathew, James Wason, Colin N A Palmer, H-Erich Wichmann, Robert Plomin, Ernest Willoughby, Anna Rautanen, Juliane Winkelmann, Michael Wittig, Richard C Trembath, Jacqueline Yaouanq, Ananth C Viswanathan, Haitao Zhang, Nicholas W Wood, Rebecca Zuvich, Panos Deloukas, Cordelia Langford, Audrey Duncanson, Jorge R Oksenberg, Margaret A Pericak-Vance, Jonathan L Haines, Tomas Olsson, Jan Hillert, Adrian J Ivinson, Philip L De Jager, Leena Peltonen, Graeme J Stewart, David A Hafler, Stephen L Hauser, Gil McVean, Peter Donnelly, Alastair Compston.
Nature
PUBLISHED: 02-04-2011
Show Abstract
Hide Abstract
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Related JoVE Video
Maternal epigenetic pathways control parental contributions to Arabidopsis early embryogenesis.
Cell
PUBLISHED: 01-21-2011
Show Abstract
Hide Abstract
Defining the contributions and interactions of paternal and maternal genomes during embryo development is critical to understand the fundamental processes involved in hybrid vigor, hybrid sterility, and reproductive isolation. To determine the parental contributions and their regulation during Arabidopsis embryogenesis, we combined deep-sequencing-based RNA profiling and genetic analyses. At the 2-4 cell stage there is a strong, genome-wide dominance of maternal transcripts, although transcripts are contributed by both parental genomes. At the globular stage the relative paternal contribution is higher, largely due to a gradual activation of the paternal genome. We identified two antagonistic maternal pathways that control these parental contributions. Paternal alleles are initially downregulated by the chromatin siRNA pathway, linked to DNA and histone methylation, whereas transcriptional activation requires maternal activity of the histone chaperone complex CAF1. Our results define maternal epigenetic pathways controlling the parental contributions in plant embryos, which are distinct from those regulating genomic imprinting.
Related JoVE Video
A duplication in 1q21.3 in a family with early onset and childhood absence epilepsy.
Epilepsia
PUBLISHED: 09-24-2010
Show Abstract
Hide Abstract
Early onset absence epilepsy (EOAE) starting before the age of 4 years constitutes a rare subgroup of the idiopathic generalized epilepsies (IGEs). A strong genetic component in IGE has been suggested by twin and family studies. We describe a boy with absence seizures starting at the age of 9 months whose parents both had childhood absence epilepsy. A 192-kb duplication in 1q21.3 was identified in the proband and his father, encompassing the gene CHRNB2 coding for the ?-2 subunit of the nicotinic acetylcholine receptor and the gene ADAR coding for adenosine deaminase, an enzyme responsible for RNA editing. Both are candidate genes for seizure disorders. The duplication was not identified in 191 independent IGE patients (93 EOAE; 98 classical IGE) or in 1,157 population controls.
Related JoVE Video
CNVineta: a data mining tool for large case-control copy number variation datasets.
Bioinformatics
PUBLISHED: 07-06-2010
Show Abstract
Hide Abstract
Copy number variation (CNV), a major contributor to human genetic variation, comprises >/= 1 kb genomic deletions and insertions. Yet, the identification of CNVs from microarray data is still hampered by high false negative and positive prediction rates due to the noisy nature of the raw data. Here, we present CNVineta, an R package for rapid data mining and visualization of CNVs in large case-control datasets genotyped with single nucleotide polymorphism oligonucleotide arrays. CNVineta is compatible with various established CNV prediction algorithms, can be used for genome-wide association analysis of rare and common CNVs and enables rapid and serial display of log(2) of raw data ratios as well as B-allele frequencies for visual quality inspection. In summary, CNVineta aides in the interpretation of large-scale CNV datasets and prioritization of target regions for follow-up experiments. Availability and Implementation: CNVineta is available as an R package and can be downloaded from http://www.ikmb.uni-kiel.de/CNVineta/; the package contains a tutorial outlining a typical workflow. The CNVineta compatible HapMap dataset can also be downloaded from the link above.
Related JoVE Video
Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.
Nat. Genet.
PUBLISHED: 06-20-2010
Show Abstract
Hide Abstract
Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10?¹? and P = 4.1 × 10??, respectively).
Related JoVE Video
Meta-analysis and imputation refines the association of 15q25 with smoking quantity.
Jason Z Liu, Federica Tozzi, Dawn M Waterworth, Sreekumar G Pillai, Pierandrea Muglia, Lefkos Middleton, Wade Berrettini, Christopher W Knouff, Xin Yuan, Gérard Waeber, Peter Vollenweider, Martin Preisig, Nicholas J Wareham, Jing Hua Zhao, Ruth J F Loos, Inês Barroso, Kay-Tee Khaw, Scott Grundy, Philip Barter, Robert Mahley, Antero Kesäniemi, Ruth McPherson, John B Vincent, John Strauss, James L Kennedy, Anne Farmer, Peter McGuffin, Richard Day, Keith Matthews, Per Bakke, Amund Gulsvik, Susanne Lucae, Marcus Ising, Tanja Brueckl, Sonja Horstmann, H-Erich Wichmann, Rajesh Rawal, Norbert Dahmen, Claudia Lamina, Ozren Polašek, Lina Zgaga, Jennifer Huffman, Susan Campbell, Jaspal Kooner, John C Chambers, Mary Susan Burnett, Joseph M Devaney, Augusto D Pichard, Kenneth M Kent, Lowell Satler, Joseph M Lindsay, Ron Waksman, Stephen Epstein, James F Wilson, Sarah H Wild, Harry Campbell, Veronique Vitart, Muredach P Reilly, Mingyao Li, Liming Qu, Robert Wilensky, William Matthai, Hakon H Hakonarson, Daniel J Rader, Andre Franke, Michael Wittig, Arne Schäfer, Manuela Uda, Antonio Terracciano, Xiangjun Xiao, Fabio Busonero, Paul Scheet, David Schlessinger, David St Clair, Dan Rujescu, Gonçalo R Abecasis, Hans Jörgen Grabe, Alexander Teumer, Henry Völzke, Astrid Petersmann, Ulrich John, Igor Rudan, Caroline Hayward, Alan F Wright, Ivana Kolčić, Benjamin J Wright, John R Thompson, Anthony J Balmforth, Alistair S Hall, Nilesh J Samani, Carl A Anderson, Tariq Ahmad, Christopher G Mathew, Miles Parkes, Jack Satsangi, Mark Caulfield, Patricia B Munroe, Martin Farrall, Anna Dominiczak, Jane Worthington, Wendy Thomson, Steve Eyre, Anne Barton, , Vincent Mooser, Clyde Francks, Jonathan Marchini.
Nat. Genet.
PUBLISHED: 03-18-2010
Show Abstract
Hide Abstract
Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.
Related JoVE Video
Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL).
Nat. Genet.
PUBLISHED: 02-19-2010
Show Abstract
Hide Abstract
We performed a genome-wide association analysis of 1,897,764 SNPs in 1,043 German ulcerative colitis (UC) cases and 1,703 controls. We discovered new associations at chromosome 7q22 (rs7809799) and at chromosome 22q13 in IL17REL (rs5771069) and confirmed these associations in six replication panels (2,539 UC cases and 5,428 controls) from different regions of Europe (overall study sample P(rs7809799) = 8.81 x 10(-11) and P(rs5771069) = 4.21 x 10(-8), respectively).
Related JoVE Video
Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance.
Hum. Mol. Genet.
PUBLISHED: 07-10-2009
Show Abstract
Hide Abstract
Microdeletion at chromosomal position 15q13.3 has been described in intellectual disability, autism spectrum disorders, schizophrenia and recently in idiopathic generalized epilepsy (IGE). Using independent IGE cohorts, we first aimed to confirm the association of 15q13.3 deletions and IGE. We then set out to determine the relative occurrence of sporadic and familial cases and to examine the likelihood of having seizures for individuals with the microdeletion in familial cases. The 15q13.3 microdeletion was identified in 7 of 539 (1.3%) unrelated cases of IGE using quantitative PCR or SNP arrays and confirmed by array comparative genomic hybridization analysis using probes specific to the 15q13.3 region. The inheritance of this lesion was tracked using family studies. Of the seven microdeletions identified in probands, three were de novo, two were transmitted from an unaffected parent and in two cases the parents were unavailable. Non-penetrance of the microdeletion was identified in 4/7 pedigrees and three pedigrees included other family members with IGE who lacked the 15q13.3 deletion. The odds ratio is 68 (95% confidence interval 29-181), indicating a pathogenic lesion predisposing to epilepsy with complex inheritance and incomplete penetrance for the IGE component of the phenotype in multiplex families.
Related JoVE Video
Systematic evaluation of the effect of common SNPs on pre-mRNA splicing.
Hum. Mutat.
PUBLISHED: 02-05-2009
Show Abstract
Hide Abstract
The evolutionary and biomedical importance of differential mRNA splicing is well established. Numerous studies have assessed patterns of differential splicing in different genes and correlated these patterns to the genotypes for adjacent single-nucleotide polymorphisms (SNPs). Here, we have chosen a reverse approach and screened dbSNP for common SNPs at either canonical splice sites or exonic splice enhancers (ESEs) that would be classified as putatively splicing-relevant by bioinformatic tools. The 223 candidate SNPs retrieved from dbSNP were experimentally tested using a previously established panel of 92 matching DNAs and cDNAs. For each SNP, 16 cDNAs providing a balanced representation of the genotypes at the respective SNP were investigated by nested RT-PCR and subsequent sequencing. Putative allele-dependent splicing was verified by the cloning of PCR products. The positive predictive value of the bioinformatics tools turned out to be low, ranging from 0% for ESEfinder to 9% (in the case of acceptor-site SNPs) for a recently reported neural network. The results highlight the need for a better understanding of the sequence characteristics of functional splice-sites to improve our ability to predict in silico the splicing relevance of empirically observed DNA sequence variants.
Related JoVE Video
15q13.3 microdeletions increase risk of idiopathic generalized epilepsy.
Nat. Genet.
PUBLISHED: 01-11-2009
Show Abstract
Hide Abstract
We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.
Related JoVE Video
From next-generation sequencing alignments to accurate comparison and validation of single-nucleotide variants: the pibase software.
Nucleic Acids Res.
Show Abstract
Hide Abstract
Scientists working with single-nucleotide variants (SNVs), inferred by next-generation sequencing software, often need further information regarding true variants, artifacts and sequence coverage gaps. In clinical diagnostics, e.g. SNVs must usually be validated by visual inspection or several independent SNV-callers. We here demonstrate that 0.5-60% of relevant SNVs might not be detected due to coverage gaps, or might be misidentified. Even low error rates can overwhelm the true biological signal, especially in clinical diagnostics, in research comparing healthy with affected cells, in archaeogenetic dating or in forensics. For these reasons, we have developed a package called pibase, which is applicable to diploid and haploid genome, exome or targeted enrichment data. pibase extracts details on nucleotides from alignment files at user-specified coordinates and identifies reproducible genotypes, if present. In test cases pibase identifies genotypes at 99.98% specificity, 10-fold better than other tools. pibase also provides pair-wise comparisons between healthy and affected cells using nucleotide signals (10-fold more accurately than a genotype-based approach, as we show in our case study of monozygotic twins). This comparison tool also solves the problem of detecting allelic imbalance within heterozygous SNVs in copy number variation loci, or in heterogeneous tumor sequences.
Related JoVE Video
Genome-wide association analysis reveals 12q13.3-q14.1 as new risk locus for sarcoidosis.
Eur. Respir. J.
Show Abstract
Hide Abstract
Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability. To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages. After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p=0.0215) in the validation panel and yielded a p-value of 9.22 × 10(-8) (OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p = 0.024; OR 1.14). Fine-mapping and mRNA expression studies pointed to osteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor. The OS9 protein plays an important role in endoplasmic reticulum-associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses of OS9 mRNA provide evidence for a functional mechanism underlying the detected association signal.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.