Center for Genomic science

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Center for Genomic science

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Cheng G.,1 F Hong Kong Jockey Club Building for Interdisciplinary Research | Chung P.H.-Y.,1 F Hong Kong Jockey Club Building for Interdisciplinary Research | Chan E.K.-W.,Chinese University of Hong Kong | So M.-T.,1 F Hong Kong Jockey Club Building for Interdisciplinary Research | And 10 more authors.
BMC Medical Genomics | Year: 2017

Background: Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved by the integrative analysis of genotype and phenotype. We aim to explore the BA phenotypic features and to delineate the source of its variance. Methods: The study is a cross-sectional observational study collating with case/control association analysis. One-hundred-and-eighty-one type III non-syndromic BA patients and 431 controls were included for case-control association tests, including 89 patients (47.19% males, born June 15th, 1981 to September 17th, 2007) have detailed clinical records with follow-up of the disease course (median ~17.2 years). BA-association genes from the genome-wide gene-based association test on common genetic variants (CV) and rare copy-number-variants (CNVs) from the genome-wide survey, the later comprise only CNVs > 100 kb and found in the BA patients but not in the local population (N = 1,381) or the database (N = 11,943). Hereby comorbidity is defined as a chronic disease that affects the BA patients but has no known relationship with BA or with the BA treatment. We examined genotype-phenotype correlations of CNVs, connectivity of these novel variants with BA-associated CVs, and their role in the BA candidate gene network. Results: Of the 89 patients, 41.57% have comorbidities, including autoimmune-allergic disorders (22.47%). They carried 29 BA-private CNVs, including 3 CNVs underpinning the carriers’ immunity comorbidity and one JAG1 micro-deletion. The BA-CNV-intersected genes (N = 102) and the CV-tagged genes (N = 103) were both enriched with immune-inflammatory pathway genes (FDR q < 0.20), and the two gene sets were interconnected (permutation p = 0.039). The molecular network representing CVs and rare-CNV association genes fit into a core/periphery structure, the immune genes and their related modules are found at the coherence core of all connections, suggesting its dominant role in the BA pathogenesis pathway. Conclusions: The study highlights a patient-complexity phenomenon as a novel BA phenotypic feature, which is underpinned by rare-CNVs that biologically converge with CVs into the immune-inflammatory pathway and drives the BA occurrence and the likely BA association with immune diseases in clinics. © 2017 The Author(s).


Cheung C.-L.,University of Hong Kong | Cheung C.-L.,Center for Genomic science | Lam K.S.L.,University of Hong Kong | Cheung B.M.Y.,University of Hong Kong
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2015

Background. Sarcopenia is commonly defined as loss of muscle mass with limited muscle function or strength. Different cutpoints of low lean mass and slow gait speed have been proposed by different professional working groups. We compared the performance of different cutpoints of low lean mass and slow gait speed in predicting death. Methods. We analyzed data of participants aged 65 years or older from the continuous National Health and Nutrition Examination Survey 1999-2004 (N = 2,841), and the subsequent follow-up data on mortality up to December 31, 2006. For low lean mass, cutpoints based on appendicular lean mass (ALM) alone, ALM adjusted for body mass index (ALMBMI), and ALM adjusted for height squared (ALMH2) were evaluated. For slow gait speed, the cutpoints based on 0.8 and 1.0 m/s were evaluated. A Cox-proportional hazard regression model with adjustment for multiple confounding factors was used for the association analyses. Results. For low lean mass, the cutpoints based on ALMBMI (<0.512 in women and <0.789 in men) showed the most significant association and highest hazard ratio with death (hazard ratio = 1.72; 95% CI: 1.28-2.29). For slow gait speed, all cutpoints tested showed significant association with death in the full model (p <. 001), while the cutpoint 0.8 m/s showed the highest hazard ratio (2.32; 95% CI: 1.58-3.39). Conclusions. Low lean mass defined by ALMBMI showed the strongest association with death; while slow gait speed showed significant association with death, with the strongest association being observed for the cutpoint of 0.8 m/s. Further studies validating the cutpoints are warranted before using them in clinical settings. © 2015 The Author.


Long K.B.,Drexel University | Burgwin C.M.,Drexel University | Sassi-Gaha S.,Drexel University | Earl J.P.,Center for Genomic science | And 5 more authors.
Journal of Investigative Dermatology | Year: 2015

Systemic sclerosis (SSc) is a polygenic, autoimmune disorder of unknown etiology, characterized by the excessive accumulation of extracellular matrix (ECM) proteins, vascular alterations, and autoantibodies. The tight skin (Tsk)2/+ mouse model of SSc demonstrates signs similar to SSc including tight skin and excessive deposition of dermal ECM proteins. By linkage analysis, we mapped the Tsk2 gene mutation to <3 megabases on chromosome 1. We performed both RNA sequencing of skin transcripts and genome capture DNA sequencing of the region spanning this interval in Tsk2/+ and wild-type littermates. A missense point mutation in the procollagen III amino terminal propeptide segment (PIIINP) of collagen, type III, alpha 1 (Col3a1) was found to be the best candidate for Tsk2; hence, both in vivo and in vitro genetic complementation tests were used to prove that this Col3a1 mutation is the Tsk2 gene. All previously documented mutations in the human Col3a1 gene are associated with the Ehlers-Danlos syndrome, a connective tissue disorder that leads to a defect in type III collagen synthesis. To our knowledge, the Tsk2 point mutation is the first documented gain-of-function mutation associated with Col3a1, which leads instead to fibrosis. This discovery provides insight into the mechanism of skin fibrosis manifested by Tsk2/+ mice. © 2015 The Society for Investigative Dermatology.


PubMed | Center for Individualized Medicine, Center for Genomic science, Tsinghua University, University of Hong Kong and 2 more.
Type: Journal Article | Journal: Bioinformatics (Oxford, England) | Year: 2016

Prediction and prioritization of human non-coding regulatory variants is critical for understanding the regulatory mechanisms of disease pathogenesis and promoting personalized medicine. Existing tools utilize functional genomics data and evolutionary information to evaluate the pathogenicity or regulatory functions of non-coding variants. However, different algorithms lead to inconsistent and even conflicting predictions. Combining multiple methods may increase accuracy in regulatory variant prediction.Here, we compiled an integrative resource for predictions from eight different tools on functional annotation of non-coding variants. We further developed a composite strategy to integrate multiple predictions and computed the composite likelihood of a given variant being regulatory variant. Benchmarked by multiple independent causal variants datasets, we demonstrated that our composite model significantly improves the prediction performance.We implemented our model and scoring procedure as a tool, named PRVCS, which is freely available to academic and non-profit usage at http://jjwanglab.org/PRVCS CONTACT: wang.junwen@mayo.edu, jliu@stat.harvard.edu, or limx54@gmail.comSupplementary data are available at Bioinformatics online.


PubMed | University of Aalborg, Center for Genomic science, Copenhagen University and Allegheny Singer Research Institute
Type: Journal Article | Journal: BMC infectious diseases | Year: 2016

Necrotizing soft tissue infections (NSTIs) are a group of infections affecting all soft tissues. NSTI involves necrosis of the afflicted tissue and is potentially life threatening due to major and rapid destruction of tissue, which often leads to septic shock and organ failure. The gold standard for identification of pathogens is culture; however molecular methods for identification of microorganisms may provide a more rapid result and may be able to identify additional microorganisms that are not detected by culture.In this study, tissue samples (n=20) obtained after debridement of 10 patients with NSTI were analyzed by standard culture, fluorescence in situ hybridization (FISH) and multiple molecular methods. The molecular methods included analysis of microbial diversity by 1) direct 16S and D2LSU rRNA gene Microseq 2) construction of near full-length 16S rRNA gene clone libraries with subsequent Sanger sequencing for most samples, 3) the Ibis T5000 biosensor and 4) 454-based pyrosequencing. Furthermore, quantitative PCR (qPCR) was used to verify and determine the relative abundance of Streptococcus pyogenes in samples.For 70% of the surgical samples it was possible to identify microorganisms by culture. Some samples did not result in growth (presumably due to administration of antimicrobial therapy prior to sampling). The molecular methods identified microorganisms in 90% of the samples, and frequently detected additional microorganisms when compared to culture. Although the molecular methods generally gave concordant results, our results indicate that Microseq may misidentify or overlook microorganisms that can be detected by other molecular methods. Half of the patients were found to be infected with S. pyogenes, but several atypical findings were also made including infection by a) Acinetobacter baumannii, b) Streptococcus pneumoniae, and c) fungi, mycoplasma and Fusobacterium necrophorum.The study emphasizes that many pathogens can be involved in NSTIs, and that no specific NSTI causing combination of species exists. This means that clinicians should be prepared to diagnose and treat any combination of microbial pathogens. Some of the tested molecular methods offer a faster turnaround time combined with a high specificity, which makes supplemental use of such methods attractive for identification of microorganisms, especially for fulminant life-threatening infections such as NSTI.


PubMed | Yonsei University, SNP Genetics Inc., University of Ulsan, Center for Genomic science and 9 more.
Type: | Journal: Human molecular genetics | Year: 2016

Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal obstruction. It is characterized by the absence of ganglia in the nerve plexuses of the lower gastrointestinal tract. So far, three common disease-susceptibility variants at the RET, SEMA3 and NRG1 loci have been detected through genome-wide association studies (GWAS) in Europeans and Asians to understand its genetic etiologies. Here we present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putatively causal variants to 99% credible sets. We also demonstrate that the effects of RET and NRG1 are universal across European and Asian ancestries. In contrast, we detected a European-specific association of a low-frequency variant, rs80227144, in SEMA3 [odds ratio (OR) = 5.2, P=4.7 10


PubMed | Center for Genomic science and Drexel University
Type: Journal Article | Journal: The Journal of investigative dermatology | Year: 2015

Systemic sclerosis (SSc) is a polygenic, autoimmune disorder of unknown etiology, characterized by the excessive accumulation of extracellular matrix (ECM) proteins, vascular alterations, and autoantibodies. The tight skin (Tsk)2/+ mouse model of SSc demonstrates signs similar to SSc including tight skin and excessive deposition of dermal ECM proteins. By linkage analysis, we mapped the Tsk2 gene mutation to <3 megabases on chromosome 1. We performed both RNA sequencing of skin transcripts and genome capture DNA sequencing of the region spanning this interval in Tsk2/+ and wild-type littermates. A missense point mutation in the procollagen III amino terminal propeptide segment (PIIINP) of collagen, type III, alpha 1 (Col3a1) was found to be the best candidate for Tsk2; hence, both in vivo and in vitro genetic complementation tests were used to prove that this Col3a1 mutation is the Tsk2 gene. All previously documented mutations in the human Col3a1 gene are associated with the Ehlers-Danlos syndrome, a connective tissue disorder that leads to a defect in type III collagen synthesis. To our knowledge, the Tsk2 point mutation is the first documented gain-of-function mutation associated with Col3a1, which leads instead to fibrosis. This discovery provides insight into the mechanism of skin fibrosis manifested by Tsk2/+ mice.


PubMed | Red Cross, Taichung Veterans General Hospital, Shandong Academy of Sciences, National Taiwan University Hospital and 50 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2016

Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings.


Cai S.,CAS Institute of Microbiology | Li J.,CAS Institute of Microbiology | Ze Hu F.,Allegheny Singer Research Institute | Zhang K.,CAS Institute of Microbiology | And 6 more authors.
Applied and Environmental Microbiology | Year: 2010

Cellulosilyticum ruminicola 111 is a newly described bacterium isolated from yak (Bos grunniens) rumen and is characterized by its ability to grow on a variety of hemicelluloses and degrade cellulosic materials. In this study, we performed the whole-genome sequencing of C. ruminicola 111 and observed a comprehensive set of genes encoding the enzymes essential for hydrolyzing plant cell wall. The corresponding enzymatic activities were also determined in strain H1; these included endoglucanases, cellobiohydrolases, xylanases, mannanase, pectinases, and feruloyl esterases and acetyl esterases to break the interbridge cross-link, as well as the enzymes that degrade the glycosidic bonds. This bacterium appears to produce polymer hydrolases that act on both soluble and crystal celluloses. Approximately half of the cellulytic activities, including cellobiohydrolase (50%), feruloyl esterase (45%), and one third of xylanase (31%) and endoglucanase (36%) activities were bound to cellulosic fibers. However, only a minority of mannase (6.78%) and pectinase (1.76%) activities were fiber associated. Strain H1 seems to degrade the plant-derived polysaccharides by producing individual fibrolytic enzymes, whereas the majority of polysaccharide hydrolases contain carbohydrate-binding module. Cellulosome or cellulosomelike protein complex was never isolated from this bacterium. Thus, the fibrolytic enzyme production of strain H1 may represent a different strategy in cellulase organization used by most of other ruminal microbes, but it applies the fungal mode of cellulose production. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

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