Elucidating the Genetic Basis of Canine Progressive Retinal Atrophies in Several Breeds of Dog

Canine progressive retinal atrophies (PRA) are a group of hereditary diseases characterised by rod and cone photoreceptor cell death in the retina. This study sought to elucidate novel PRA-associated variants of distinct forms of PRA in three breeds of dog: the Lhasa Apso (LA), Giant Schnauzer (GS) and Shetland Sheepdog (SS). A genome-wide association study identified a 1.3 Mb disease-associated region on canine chromosome 33 in LA dogs. Whole genome sequencing (WGS) analysis of a PRA-affected LA revealed a long interspersed nuclear element-1 (LINE-1) insertion in the predicted promoter region of the retinal candidate gene, IMPG2. Validation of the LINE-1 insertion determined it segregated with disease and was likely to be private to LA dogs. Comprehensive WGS analyses alone were utilised to determine PRA-associated mutations in a family of GS dogs, and in a single SS. For the GS breed, WGS was performed on two affected siblings and both non-affected parents. Successive filtering, for autosomal recessive deleterious variants, against 568 canine genomes identified a single nucleotide variant (SNV) in the gene encoding NECAP endocytosis associated 1 (NECAP1): c.544G>A (p.G182R). Screening 5,130 canids revealed only the three PRA-affected GS were homozygous for the SNV, yet heterozygotes were identified in the GS breed and in other breeds of German ancestry. NECAP1 has not previously been associated with retinal degeneration; however, these findings, in parallel with known gene function, indicate NECAP1 should be considered as a strong candidate for retinal degeneration research in other species. Following WGS analysis of the single SS against 176 controls of other breeds, a c.1222G>C (p.A408P) SNV in the Bardet-Biedl syndrome 2 gene (BBS2) was identified. In addition to PRA, homozygotes exhibited features including an upturned nose, unusual coat and dental defects, proposing a novel syndromic form of canine PRA. This research has elucidated three novel PRA-associated mutations for which diagnostic DNA tests have been developed, offering breeders the opportunity to avoid producing PRA-affected dogs. Since PRA shares clinical features to human retinitis pigmentosa (RP) and other phenotypically similar retinal diseases, this study may offer novel insights for consideration in human as well as canine retinal degeneration research and gene therapies

Ontologies and Computational Methods for Traditional Chinese Medicine

Perinteinen kiinalainen lääketiede (PKL) on tuhansia vuosia vanha hoitomuoto, jonka tarkoituksena on terveyden ylläpito, tautien ennaltaehkäisemisen ja terveydellisten ongelmien hoito. Useat vuosittain julkaistavat tutkimukset tukevat hoitojen tehokkuutta ja PKL onkin jatkuvasti kasvattamassa suosiotaan maailmanlaajuisesti. Kiinassa PKL ollut suosittu hoitomuoto jo pitkään ja nykyään sitä harjoitetaan rinnakkain länsimaisen lääketieteen kanssa. Viime vuosikymmeninä tapahtuneen tietotekniikan kehityksen ja yleistymisen myötä myös PKL:n menetelmät ovat muuttuneet ja tietotekniikkaa on alettu hyödyntämään PKL:n tutkimuksessa. PKL:n tietoa on tallennettu digitaaliseen muotoon, minkä seurauksena on syntynyt suuri määrä erilaisia tietokantoja. Tieto on jakautunut eri tietokantoihin, joiden terminologia ei ole yhtenevää. Tämä aiheuttaa ongelmia tiedon löytämisessä ja tietoa hyödyntävien sovellusten kehittämisessä. Tässä työssä selvitetään, mitä PKL on, ja mikä sen asema on nykyään Kiinassa ja muualla maailmalla. Työn tarkoituksena on tutkia PKL:n tietoteknisten sovelluksen kehittämistä ja siihen liittyviä haasteita. Työssä perehdytään PKL:n ontologioiden ja semanttisten työkalujen toimintaan, sekä PKL:n laskennallisiin menetelmiin ja niiden tarjoamiin mahdollisuuksiin. Lisäksi kerrotaan uusimmista kansainvälisesti merkittävistä projekteista ja pohditaan tulevaisuuden näkymiä. Jo kehitetyt PKL:n tietotekniset sovellukset tarjoavat uusia mahdollisuuksia tiedon etsimiseen ja parantavat tutkijoiden mahdollisuutta jakaa tietoa ja tehdä yhteistyötä. Tietokoneavusteiset diagnoosityökalut ja asiantuntijajärjestelmät tarjoavat mahdollisuuksia lääkärin tekemän diagnoosin varmistamiseen. Tulevaisuudessa laskennallisia menetelmiä hyödyntäen voitaisiin tarjota terveyttä ja hyvinvointia edistäviä palveluja verkossa.Traditional Chinese Medicine (TCM) has been used for thousands of years in China for the purposes of health maintenance, disease prevention and treatment of health problems. Several published studies support the effectiveness of TCM treatments and the global use of TCM is constantly increasing. In China, Western and Chinese medicine are practiced in parallel. During the past few decades, the use of information technology in medicine has increased rapidly. The development of information technology has opened up new possibilities for information storage and sharing, as well as communication and interaction between people. Along with the growing use of information technology, a wide variety of patient databases and other electronic sources of information have emerged. However, the information is fragmented and dispersed, and the terminology is ambiguous. The objective of the thesis is to examine the position of TCM today, and to find out what changes and new opportunities the modern information technology brings for different aspects of TCM. This study describes how ontologies and semantic tools can be utilized when collecting existing knowledge and combining different databases. Also different computational methods and TCM expert systems are introduced. Finally, the most recent projects in the field of TCM are discussed and the future challenges are reflected. The computational methods for TCM, such as diagnostic tools and expert systems, could be very useful in anticipating and preventing health problems. E-science and knowledge discovery offer new ways for knowledge sharing and cooperation. TCM expert systems can be used to generate diagnosis or automatic clinical alerts. In the future, a comprehensive and easily accessible online health service system could be developed and used to improve the health and well-being of people

Human genome meeting 2016 : Houston, TX, USA. 28 February - 2 March 2016

: O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder A. K. Srivastava, Y. Wang, R. Huang, C. Skinner, T. Thompson, L. Pollard, T. Wood, F. Luo, R. Stevenson O2 Phenome-wide association study for smoking- and drinking-associated genes in 26,394 American women with African, Asian, European, and Hispanic descents R. Polimanti, J. Gelernter O3 Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort X. Lin, I. Y. Lim, Y. Wu, A. L. Teh, L. Chen, I. M. Aris, S. E. Soh, M. T. Tint, J. L. MacIsaac, F. Yap, K. Kwek, S. M. Saw, M. S. Kobor, M. J. Meaney, K. M. Godfrey, Y. S. Chong, J. D. Holbrook, Y. S. Lee, P. D. Gluckman, N. Karnani, GUSTO study group O4 High-throughput identification of specific qt interval modulating enhancers at the SCN5A locus A. Kapoor, D. Lee, A. Chakravarti O5 Identification of extracellular matrix components inducing cancer cell migration in the supernatant of cultivated mesenchymal stem cells C. Maercker, F. Graf, M. Boutros O6 Single cell allele specific expression (ASE) IN T21 and common trisomies: a novel approach to understand DOWN syndrome and other aneuploidies G. Stamoulis, F. Santoni, P. Makrythanasis, A. Letourneau, M. Guipponi, N. Panousis, M. Garieri, P. Ribaux, E. Falconnet, C. Borel, S. E. Antonarakis O7 Role of microRNA in LCL to IPSC reprogramming S. Kumar, J. Curran, J. Blangero O8 Multiple enhancer variants disrupt gene regulatory network in Hirschsprung disease S. Chatterjee, A. Kapoor, J. Akiyama, D. Auer, C. Berrios, L. Pennacchio, A. Chakravarti O9 Metabolomic profiling for the diagnosis of neurometabolic disorders T. R. Donti, G. Cappuccio, M. Miller, P. Atwal, A. Kennedy, A. Cardon, C. Bacino, L. Emrick, J. Hertecant, F. Baumer, B. Porter, M. Bainbridge, P. Bonnen, B. Graham, R. Sutton, Q. Sun, S. Elsea O10 A novel causal methylation network approach to Alzheimer’s disease Z. Hu, P. Wang, Y. Zhu, J. Zhao, M. Xiong, David A Bennett O11 A microRNA signature identifies subtypes of triple-negative breast cancer and reveals MIR-342-3P as regulator of a lactate metabolic pathway A. Hidalgo-Miranda, S. Romero-Cordoba, S. Rodriguez-Cuevas, R. Rebollar-Vega, E. Tagliabue, M. Iorio, E. D’Ippolito, S. Baroni O12 Transcriptome analysis identifies genes, enhancer RNAs and repetitive elements that are recurrently deregulated across multiple cancer types B. Kaczkowski, Y. Tanaka, H. Kawaji, A. Sandelin, R. Andersson, M. Itoh, T. Lassmann, the FANTOM5 consortium, Y. Hayashizaki, P. Carninci, A. R. R. Forrest O13 Elevated mutation and widespread loss of constraint at regulatory and architectural binding sites across 11 tumour types C. A. Semple O14 Exome sequencing provides evidence of pathogenicity for genes implicated in colorectal cancer E. A. Rosenthal, B. Shirts, L. Amendola, C. Gallego, M. Horike-Pyne, A. Burt, P. Robertson, P. Beyers, C. Nefcy, D. Veenstra, F. Hisama, R. Bennett, M. Dorschner, D. Nickerson, J. Smith, K. Patterson, D. Crosslin, R. Nassir, N. Zubair, T. Harrison, U. Peters, G. Jarvik, NHLBI GO Exome Sequencing Project O15 The tandem duplicator phenotype as a distinct genomic configuration in cancer F. Menghi, K. Inaki, X. Woo, P. Kumar, K. Grzeda, A. Malhotra, H. Kim, D. Ucar, P. Shreckengast, K. Karuturi, J. Keck, J. Chuang, E. T. Liu O16 Modeling genetic interactions associated with molecular subtypes of breast cancer B. Ji, A. Tyler, G. Ananda, G. Carter O17 Recurrent somatic mutation in the MYC associated factor X in brain tumors H. Nikbakht, M. Montagne, M. Zeinieh, A. Harutyunyan, M. Mcconechy, N. Jabado, P. Lavigne, J. Majewski O18 Predictive biomarkers to metastatic pancreatic cancer treatment J. B. Goldstein, M. Overman, G. Varadhachary, R. Shroff, R. Wolff, M. Javle, A. Futreal, D. Fogelman O19 DDIT4 gene expression as a prognostic marker in several malignant tumors L. Bravo, W. Fajardo, H. Gomez, C. Castaneda, C. Rolfo, J. A. Pinto O20 Spatial organization of the genome and genomic alterations in human cancers K. C. Akdemir, L. Chin, A. Futreal, ICGC PCAWG Structural Alterations Group O21 Landscape of targeted therapies in solid tumors S. Patterson, C. Statz, S. Mockus O22 Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma S. N. Nikolaev, X. I. Bonilla, L. Parmentier, B. King, F. Bezrukov, G. Kaya, V. Zoete, V. Seplyarskiy, H. Sharpe, T. McKee, A. Letourneau, P. Ribaux, K. Popadin, N. Basset-Seguin, R. Ben Chaabene, F. Santoni, M. Andrianova, M. Guipponi, M. Garieri, C. Verdan, K. Grosdemange, O. Sumara, M. Eilers, I. Aifantis, O. Michielin, F. de Sauvage, S. Antonarakis O23 Identification of differential biomarkers of hepatocellular carcinoma and cholangiocarcinoma via transcriptome microarray meta-analysis S. Likhitrattanapisal O24 Clinical validity and actionability of multigene tests for hereditary cancers in a large multi-center study S. Lincoln, A. Kurian, A. Desmond, S. Yang, Y. Kobayashi, J. Ford, L. Ellisen O25 Correlation with tumor ploidy status is essential for correct determination of genome-wide copy number changes by SNP array T. L. Peters, K. R. Alvarez, E. F. Hollingsworth, D. H. Lopez-Terrada O26 Nanochannel based next-generation mapping for interrogation of clinically relevant structural variation A. Hastie, Z. Dzakula, A. W. Pang, E. T. Lam, T. Anantharaman, M. Saghbini, H. Cao, BioNano Genomics O27 Mutation spectrum in a pulmonary arterial hypertension (PAH) cohort and identification of associated truncating mutations in TBX4 C. Gonzaga-Jauregui, L. Ma, A. King, E. Berman Rosenzweig, U. Krishnan, J. G. Reid, J. D. Overton, F. Dewey, W. K. Chung O28 NORTH CAROLINA macular dystrophy (MCDR1): mutations found affecting PRDM13 K. Small, A. DeLuca, F. Cremers, R. A. Lewis, V. Puech, B. Bakall, R. Silva-Garcia, K. Rohrschneider, M. Leys, F. S. Shaya, E. Stone O29 PhenoDB and genematcher, solving unsolved whole exome sequencing data N. L. Sobreira, F. Schiettecatte, H. Ling, E. Pugh, D. Witmer, K. Hetrick, P. Zhang, K. Doheny, D. Valle, A. Hamosh O30 Baylor-Johns Hopkins Center for Mendelian genomics: a four year review S. N. Jhangiani, Z. Coban Akdemir, M. N. Bainbridge, W. Charng, W. Wiszniewski, T. Gambin, E. Karaca, Y. Bayram, M. K. Eldomery, J. Posey, H. Doddapaneni, J. Hu, V. R. Sutton, D. M. Muzny, E. A. Boerwinkle, D. Valle, J. R. Lupski, R. A. Gibbs O31 Using read overlap assembly to accurately identify structural genetic differences in an ashkenazi jewish trio S. Shekar, W. Salerno, A. English, A. Mangubat, J. Bruestle O32 Legal interoperability: a sine qua non for international data sharing A. Thorogood, B. M. Knoppers, Global Alliance for Genomics and Health - Regulatory and Ethics Working Group O33 High throughput screening platform of competent sineups: that can enhance translation activities of therapeutic target H. Takahashi, K. R. Nitta, A. Kozhuharova, A. M. Suzuki, H. Sharma, D. Cotella, C. Santoro, S. Zucchelli, S. Gustincich, P. Carninci O34 The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs J. J. Mulvihill, G. Baynam, W. Gahl, S. C. Groft, K. Kosaki, P. Lasko, B. Melegh, D. Taruscio O36 Performance of computational algorithms in pathogenicity predictions for activating variants in oncogenes versus loss of function mutations in tumor suppressor genes R. Ghosh, S. Plon O37 Identification and electronic health record incorporation of clinically actionable pharmacogenomic variants using prospective targeted sequencing S. Scherer, X. Qin, R. Sanghvi, K. Walker, T. Chiang, D. Muzny, L. Wang, J. Black, E. Boerwinkle, R. Weinshilboum, R. Gibbs O38 Melanoma reprogramming state correlates with response to CTLA-4 blockade in metastatic melanoma T. Karpinets, T. Calderone, K. Wani, X. Yu, C. Creasy, C. Haymaker, M. Forget, V. Nanda, J. Roszik, J. Wargo, L. Haydu, X. Song, A. Lazar, J. Gershenwald, M. Davies, C. Bernatchez, J. Zhang, A. Futreal, S. Woodman O39 Data-driven refinement of complex disease classification from integration of heterogeneous functional genomics data in GeneWeaver E. J. Chesler, T. Reynolds, J. A. Bubier, C. Phillips, M. A. Langston, E. J. Baker O40 A general statistic framework for genome-based disease risk prediction M. Xiong, L. Ma, N. Lin, C. Amos O41 Integrative large-scale causal network analysis of imaging and genomic data and its application in schizophrenia studies N. Lin, P. Wang, Y. Zhu, J. Zhao, V. Calhoun, M. Xiong O42 Big data and NGS data analysis: the cloud to the rescue O. Dobretsberger, M. Egger, F. Leimgruber O43 Cpipe: a convergent clinical exome pipeline specialised for targeted sequencing S. Sadedin, A. Oshlack, Melbourne Genomics Health Alliance O44 A Bayesian classification of biomedical images using feature extraction from deep neural networks implemented on lung cancer data V. A. A. Antonio, N. Ono, Clark Kendrick C. Go O45 MAV-SEQ: an interactive platform for the Management, Analysis, and Visualization of sequence data Z. Ahmed, M. Bolisetty, S. Zeeshan, E. Anguiano, D. Ucar O47 Allele specific enhancer in EPAS1 intronic regions may contribute to high altitude adaptation of Tibetans C. Zeng, J. Shao O48 Nanochannel based next-generation mapping for structural variation detection and comparison in trios and populations H. Cao, A. Hastie, A. W. Pang, E. T. Lam, T. Liang, K. Pham, M. Saghbini, Z. Dzakula O49 Archaic introgression in indigenous populations of Malaysia revealed by whole genome sequencing Y. Chee-Wei, L. Dongsheng, W. Lai-Ping, D. Lian, R. O. Twee Hee, Y. Yunus, F. Aghakhanian, S. S. Mokhtar, C. V. Lok-Yung, J. Bhak, M. Phipps, X. Shuhua, T. Yik-Ying, V. Kumar, H. Boon-Peng O50 Breast and ovarian cancer prevention: is it time for population-based mutation screening of high risk genes? I. Campbell, M.-A. Young, P. James, Lifepool O53 Comprehensive coverage from low DNA input using novel NGS library preparation methods for WGS and WGBS C. Schumacher, S. Sandhu, T. Harkins, V. Makarov O54 Methods for large scale construction of robust PCR-free libraries for sequencing on Illumina HiSeqX platform H. DoddapaneniR. Glenn, Z. Momin, B. Dilrukshi, H. Chao, Q. Meng, B. Gudenkauf, R. Kshitij, J. Jayaseelan, C. Nessner, S. Lee, K. Blankenberg, L. Lewis, J. Hu, Y. Han, H. Dinh, S. Jireh, K. Walker, E. Boerwinkle, D. Muzny, R. Gibbs O55 Rapid capture methods for clinical sequencing J. Hu, K. Walker, C. Buhay, X. Liu, Q. Wang, R. Sanghvi, H. Doddapaneni, Y. Ding, N. Veeraraghavan, Y. Yang, E. Boerwinkle, A. L. Beaudet, C. M. Eng, D. M. Muzny, R. A. Gibbs O56 A diploid personal human genome model for better genomes from diverse sequence data K. C. C. Worley, Y. Liu, D. S. T. Hughes, S. C. Murali, R. A. Harris, A. C. English, X. Qin, O. A. Hampton, P. Larsen, C. Beck, Y. Han, M. Wang, H. Doddapaneni, C. L. Kovar, W. J. Salerno, A. Yoder, S. Richards, J. Rogers, J. R. Lupski, D. M. Muzny, R. A. Gibbs O57 Development of PacBio long range capture for detection of pathogenic structural variants Q. Meng, M. Bainbridge, M. Wang, H. Doddapaneni, Y. Han, D. Muzny, R. Gibbs O58 Rhesus macaques exhibit more non-synonymous variation but greater impact of purifying selection than humans R. A. Harris, M. Raveenedran, C. Xue, M. Dahdouli, L. Cox, G. Fan, B. Ferguson, J. Hovarth, Z. Johnson, S. Kanthaswamy, M. Kubisch, M. Platt, D. Smith, E. Vallender, R. Wiseman, X. Liu, J. Below, D. Muzny, R. Gibbs, F. Yu, J. Rogers O59 Assessing RNA structure disruption induced by single-nucleotide variation J. Lin, Y. Zhang, Z. Ouyang P1 A meta-analysis of genome-wide association studies of mitochondrial dna copy number A. Moore, Z. Wang, J. Hofmann, M. Purdue, R. Stolzenberg-Solomon, S. Weinstein, D. Albanes, C.-S. Liu, W.-L. Cheng, T.-T. Lin, Q. Lan, N. Rothman, S. Berndt P2 Missense polymorphic genetic combinations underlying down syndrome susceptibility E. S. Chen P4 The evaluation of alteration of ELAM-1 expression in the endometriosis patients H. Bahrami, A. Khoshzaban, S. Heidari Keshal P5 Obesity and the incidence of apolipoprotein E polymorphisms in an assorted population from Saudi Arabia population K. K. R. Alharbi P6 Genome-associated personalized antithrombotical therapy for patients with high risk of thrombosis and bleeding M. Zhalbinova, A. Akilzhanova, S. Rakhimova, M. Bekbosynova, S. Myrzakhmetova P7 Frequency of Xmn1 polymorphism among sickle cell carrier cases in UAE population M. Matar P8 Differentiating inflammatory bowel diseases by using genomic data: dimension of the problem and network organization N. Mili, R. Molinari, Y. Ma, S. Guerrier P9 Vulnerability of genetic variants to the risk of autism among Saudi children N. Elhawary, M. Tayeb, N. Bogari, N. Qotb P10 Chromatin profiles from ex vivo purified dopaminergic neurons establish a promising model to support studies of neurological function and dysfunction S. A. McClymont, P. W. Hook, L. A. Goff, A. McCallion P11 Utilization of a sensitized chemical mutagenesis screen to identify genetic modifiers of retinal dysplasia in homozygous Nr2e3rd7 mice Y. Kong, J. R. Charette, W. L. Hicks, J. K. Naggert, L. Zhao, P. M. Nishina P12 Ion torrent next generation sequencing of recessive polycystic kidney disease in Saudi patients B. M. Edrees, M. Athar, F. A. Al-Allaf, M. M. Taher, W. Khan, A. Bouazzaoui, N. A. Harbi, R. Safar, H. Al-Edressi, A. Anazi, N. Altayeb, M. A. Ahmed, K. Alansary, Z. Abduljaleel P13 Digital expression profiling of Purkinje neurons and dendrites in different subcellular compartments A. Kratz, P. Beguin, S. Poulain, M. Kaneko, C. Takahiko, A. Matsunaga, S. Kato, A. M. Suzuki, N. Bertin, T. Lassmann, R. Vigot, P. Carninci, C. Plessy, T. Launey P14 The evolution of imperfection and imperfection of evolution: the functional and functionless fractions of the human genome D. Graur P16 Species-independent identification of known and novel recurrent genomic entities in multiple cancer patients J. Friis-Nielsen, J. M. Izarzugaza, S. Brunak P18 Discovery of active gene modules which are densely conserved across multiple cancer types reveal their prognostic power and mutually exclusive mutation patterns B. S. Soibam P19 Whole exome sequencing of dysplastic leukoplakia tissue indicates sequential accumulation of somatic mutations from oral precancer to cancer D. Das, N. Biswas, S. Das, S. Sarkar, A. Maitra, C. Panda, P. Majumder P21 Epigenetic mechanisms of carcinogensis by hereditary breast cancer genes J. J. Gruber, N. Jaeger, M. Snyder P22 RNA direct: a novel RNA enrichment strategy applied to transcripts associated with solid tumors K. Patel, S. Bowman, T. Davis, D. Kraushaar, A. Emerman, S. Russello, N. Henig, C. Hendrickson P23 RNA sequencing identifies gene mutations for neuroblastoma K. Zhang P24 Participation of SFRP1 in the modulation of TMPRSS2-ERG fusion gene in prostate cancer cell lines M. Rodriguez-Dorantes, C. D. Cruz-Hernandez, C. D. P. Garcia-Tobilla, S. Solorzano-Rosales P25 Targeted Methylation Sequencing of Prostate Cancer N. Jäger, J. Chen, R. Haile, M. Hitchins, J. D. Brooks, M. Snyder P26 Mutant TPMT alleles in children with acute lymphoblastic leukemia from México City and Yucatán, Mexico S. Jiménez-Morales, M. Ramírez, J. Nuñez, V. Bekker, Y. Leal, E. Jiménez, A. Medina, A. Hidalgo, J. Mejía P28 Genetic modifiers of Alström syndrome J. Naggert, G. B. Collin, K. DeMauro, R. Hanusek, P. M. Nishina P31 Association of genomic variants with the occurrence of angiotensin-converting-enzyme inhibitor (ACEI)-induced coughing among Filipinos E. M. Cutiongco De La Paz, R. Sy, J. Nevado, P. Reganit, L. Santos, J. D. Magno, F. E. Punzalan , D. Ona , E. Llanes, R. L. Santos-Cortes , R. Tiongco, J. Aherrera, L. Abrahan, P. Pagauitan-Alan; Philippine Cardiogenomics Study Group P32 The use of “humanized” mouse models to validate disease association of a de novo GARS variant and to test a novel gene therapy strategy for Charcot-Marie-Tooth disease type 2D K. H. Morelli, J. S. Domire, N. Pyne, S. Harper, R. Burgess P34 Molecular regulation of chondrogenic human induced pluripotent stem cells M. A. Gari, A. Dallol, H. Alsehli, A. Gari, M. Gari, A. Abuzenadah P35 Molecular profiling of hematologic malignancies: implementation of a variant assessment algorithm for next generation sequencing data analysis and clinical reporting M. Thomas, M. Sukhai, S. Garg, M. Misyura, T. Zhang, A. Schuh, T. Stockley, S. Kamel-Reid P36 Accessing genomic evidence for clinical variants at NCBI S. Sherry, C. Xiao, D. Slotta, K. Rodarmer, M. Feolo, M. Kimelman, G. Godynskiy, C. O’Sullivan, E. Yaschenko P37 NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA C. Xiao, E. Yaschenko, S. Sherry P38 Computational assessment of drug induced hepatotoxicity through gene expression profiling C. Rangel-Escareño, H. Rueda-Zarate P40 Flowr: robust and efficient pipelines using a simple language-agnostic approach;ultraseq; fast modular pipeline for somatic variation calling using flowr S. Seth, S. Amin, X. Song, X. Mao, H. Sun, R. G. Verhaak, A. Futreal, J. Zhang P41 Applying “Big data” technologies to the rapid analysis of heterogenous large cohort data S. J. Whiite, T. Chiang, A. English, J. Farek, Z. Kahn, W. Salerno, N. Veeraraghavan, E. Boerwinkle, R. Gibbs P42 FANTOM5 web resource for the large-scale genome-wide transcription start site activity profiles of wide-range of mammalian cells T. Kasukawa, M. Lizio, J. Harshbarger, S. Hisashi, J. Severin, A. Imad, S. Sahin, T. C. Freeman, K. Baillie, A. Sandelin, P. Carninci, A. R. R. Forrest, H. Kawaji, The FANTOM Consortium P43 Rapid and scalable typing of structural variants for disease cohorts W. Salerno, A. English, S. N. Shekar, A. Mangubat, J. Bruestle, E. Boerwinkle, R. A. Gibbs P44 Polymorphism of glutathione S-transferases and sulphotransferases genes in an Arab population A. H. Salem, M. Ali, A. Ibrahim, M. Ibrahim P46 Genetic divergence of CYP3A5*3 pharmacogenomic marker for native and admixed Mexican populations J. C. Fernandez-Lopez, V. Bonifaz-Peña, C. Rangel-Escareño, A. Hidalgo-Miranda, A. V. Contreras P47 Whole exome sequence meta-analysis of 13 white blood cell, red blood cell, and platelet traits L. Polfus, CHARGE and NHLBI Exome Sequence Project Working Groups P48 Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study S. Davis, R. Xu, S. Gebeab, P Riestra, A Gaye, R. Khan, J. Wilson, A. Bidulescu P49 Common variants in casr gene are associated with serum calcium levels in koreans S. H. Jung, N. Vinayagamoorthy, S. H. Yim, Y. J. Chung P50 Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with multiple exponential functions Y. Zhou, S. Xu P51 A Bayesian framework for generalized linear mixed models in genome-wide association studies X. Wang, V. Philip, G. Carter P52 Targeted sequencing approach for the identification of the genetic causes of hereditary hearing impairment A. A. Abuzenadah, M. Gari, R. Turki, A. Dallol P53 Identification of enhancer sequences by ATAC-seq open chromatin profiling A. Uyar, A. Kaygun, S. Zaman, E. Marquez, J. George, D. Ucar P54 Direct enrichment for the rapid preparation of targeted NGS libraries C. L. Hendrickson, A. Emerman, D. Kraushaar, S. Bowman, N. Henig, T. Davis, S. Russello, K. Patel P56 Performance of the Agilent D5000 and High Sensitivity D5000 ScreenTape assays for the Agilent 4200 Tapestation System R. Nitsche, L. Prieto-Lafuente P57 ClinVar: a multi-source archive for variant interpretation M. Landrum, J. Lee, W. Rubinstein, D. Maglott P59 Association of functional variants and protein physical interactions of human MUTY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome Z. Abduljaleel, W. Khan, F. A. Al-Allaf, M. Athar , M. M. Taher, N. Shahzad P60 Modification of the microbiom constitution in the gut using chicken IgY antibodies resulted in a reduction of acute graft-versus-host disease after experimental bone marrow transplantation A. Bouazzaoui, E. Huber, A. Dan, F. A. Al-Allaf, W. Herr, G. Sprotte, J. Köstler, A. Hiergeist, A. Gessner, R. Andreesen, E. Holler P61 Compound heterozygous mutation in the LDLR gene in Saudi patients suffering severe hypercholesterolemia F. Al-Allaf, A. Alashwal, Z. Abduljaleel, M. Taher, A. Bouazzaoui, H. Abalkhail, A. Al-Allaf, R. Bamardadh, M. Atha

Epidemiology of major infectious diseases in indigenous and ethnic minority peoples of the Asia Pacific region

This study found a high prevalence of HIV, tuberculosis (TB), malaria, and soil-transmitted helminth (STH) infection within indigenous and ethnic minority populations of the Asia Pacific region. These populations had a higher risk of HIV, malaria, and STH infection than comparative reference majority populations and were also disadvantaged across TB diagnosis and treatment metrics. Vulnerable populations must be considered if the Sustainable Development Agenda goal of ending these pandemics by 2030 is to be achieved

Cardiovascular risk in high altitude people of Nepal

Background Permanently living at high altitude (HA) directly affects the cardiovascular system because of lower arterial blood oxygen content compared to sea-level and other associated physiological changes. It is uncertain if there are clear-cut benefits or risks to cardiovascular health from living at HA and whether these benefits or risks, if they exist, vary in different populations. In Nepal, a comprehensive cardiovascular risk assessment of a sample of individuals representing a HA population has not previously been performed. The main aims of this project were to estimate, in residents at HA, the prevalence of coronary heart disease (CHD) and cerebrovascular disease; to estimate the distribution of key cardiovascular risk factors; and to estimate any possible relationships between CHD or blood pressure with altitude. Methods The study design was a cross-sectional survey. The sampling technique was cluster sampling of study areas on the basis of altitude level, population density and logistical support to undertake the study, but the participants within the study areas were randomly selected. The sample consisted of 521 residents aged 30 years or over from the Nepal districts of Mustang and Humla, permanently living at altitudes of 2800 metre (m), 2890 m, 3270 m, or 3620 m. Data was collected by administering the WHO STEPS interview questionnaire for non-communicable disease risk factors, a questionnaire for verifying stroke-free status (QVSFS), bio-physical measurements (blood pressure, height, weight, waist, hip), biochemical measurements (lipid profile and glycated haemoglobin), and a resting 12 lead electrocardiogram (ECG). The prevalence of CHD was defined as the presence of pathological Q waves in the ECG or self-report of personal history of CHD (previous event of myocardial infarction (MI) or chest pain from heart disease (angina)). ECG recordings were categorized as definitely abnormal (e.g. showing evidence of previous MI, borderline (e.g. non-specific T-wave inversion) or normal after review by a cardiologist using standard widely accepted criteria. Blood pressure (systolic/diastolic) was classified as normal (<120/80 mmHg), pre-hypertension (HT) (120–39/80–89 mmHg), HT (≥140/90 mmHg), Stage I HT (140–159/90–99 mmHg), and Stage II HT (≥160/100 mmHg). Analysis of variance (ANOVA) and analysis of covariance (ANCOVA) models were used for the relationship between systolic blood pressure (SBP), diastolic blood pressure (DBP) and altitude. Logistic regression was used to estimate the association between an abnormal (or borderline abnormal) ECG and altitude in univariate and multivariate models. Results None of the participants showed definite electrocardiographic evidence of CHD. Overall, 5.6% of the participants gave a self-reported history of CHD. Altogether 19.6% of the participants had an abnormal (or borderline abnormal) ECG. The main categories of abnormality were right axis deviation (5.4%) and left ventricular hypertrophy by voltage criteria (3.5%). Observed ECG abnormalities differed between ethnic populations: suggestive of left sided cardiac abnormalities in the Mustang district with a majority population of Tibetans; and right sided abnormalities in the Humla district with a majority population of Khas-Arya. There was a moderate association between the probability of abnormal (or borderline abnormal) ECG and altitude, adjusted for potential confounding variables, with an odds ratio for a greater probability of an abnormal ECG (95% CI) of 2.83 (1.07 to 7.45), P=0.03 per 1000 m elevation of altitude. A history of stroke or of symptoms of stroke (by positive self-report of at least one criterion of the QVSFS) was identified in 6.7% of the participants. A multivariate model adjusting for potential confounding variables showed that there was moderate evidence of an association between SBP and altitude; mean SBP (95% CI) increase by 11.3 mmHg (-0.1 to 22.7), P=0.05 for every 1000 m elevation. The distribution and prevalence of key cardiovascular disease-related risk factors did not differ by altitude level. Rather, they differed by ethnicity, residential settings (urban or rural) and cultural practices. The prevalence of HT or being on treatment for HT was higher in the Mustang district with dominant Tibetan-related populations (between 41% and 54.5%) than in the Humla district, with dominant Khas-Arya (29.1%). Only 3.3% to 10.3% participants in Mustang self-reported being current smokers, whereas this rate was 38.6% in Humla. The prevalence of current drinker was high at all altitude levels ranging from 45.4% (3620 m) to 63.9% (3270 m). The prevalence of abnormal lipid components, diabetes or being on treatment for diabetes, and overweight or obesity, were all higher in urban (2800 m and 3620 m) compared to rural (3270 m and 2890 m) residential settings. Conclusion The HA populations sampled in this study had a lower prevalence of CHD and a higher prevalence of stroke than that of relevant comparator low altitude populations. None of the participants had ECG evidence of past CHD. Cardiovascular risk profiles of HA populations may depend on altitude, ethnicity, cultural lifestyle practices, and residential setting (urban or rural). Altitude per se could be an important additional risk factor because of its association with SBP and abnormal (or borderline abnormal) ECG. Different ancestry-related physiological responses to the low oxygen environment at HA may affect cardiovascular health consistent with the evidence of different patterns of ECG abnormality. The findings of the present study suggest that ethnicity and associated lifestyle or cultural practices (such as salt and alcohol intake, smoking habit) and residential settings (mainly differences in physical activity and fruit and vegetable consumption in urban and rural participants), are also likely to be important determinants of cardiovascular health for HA residents

An Informatics Roadmap Toward a FAIR Understanding of Mitochondrial Biology and Rare Mitochondrial Disease

Mitochondrial biology is integral to our fundamental understanding of human health and many diseases. They exist in every human cell type except for red blood cells and have critical functions in metabolism, oxidative phosphorylation, oxidation-reduction, and as signaling hubs responsible for mediating protective mechanisms. Rare mitochondrial diseases (RMDs) are devastating and complex, affect multiple organ systems, and disproportionately impact young children. Despite copious existing knowledge and increased public interest, the knowledge is fragmented and difficult to access. Clinical case reports (CCRs) on RMDs contain valuable clinical insights, but they are scarce and lack the metadata necessary to facilitate their discovery among the two million CCRs on PubMed. The unstructured text data of CCRs is also ill-suited to computational approaches, limiting our ability to derive the knowledge contained within.To address these issues, I assembled all available informatics tools and resources with mitochondrial components and used them to contribute to Gene Wiki pages that enable easy access to mitochondrial knowledge for researchers, students, clinicians, and patients. Through these efforts, I made mitochondrial gene, protein, and disease knowledge widely accessible with contributions of over 4MB of content across 541 Gene Wiki pages. Concurrently, I used Gene Wiki as an educational platform to train over 50 students in the biosciences and pre-medical studies in mitochondrial biology and disease, as well as instilling effective research and writing methods in biomedicine.To impose structure on CCRs and render them FAIR (Findable, Accessible, Interoperable, Reusable), I developed and applied a standardized metadata template to RMD CCRs and codified patient symptomology with the International Statistical Classification of Disease and Related Health Problems (ICD) system. I created the open-source, cloud-based MitoCases RMD Knowledge Platform (http://mitocases.org/) to house data on 384 RMD CCRs, including 4,561 instances of 952 unique ICD codes. Supplementing CCRs with structured metadata amplifies machine-readable information content and provides a distinct improvement in searching for CCRs as compared to indexing by title and abstract. Finally, I employed these resources to conduct a thorough review of Barth syndrome and characterized the diversity of presentations, range of genetic etiologies, and treatment paradigms

The Future of Medicine: Frontiers in Integrative Health and Medicine

Contemporary healthcare trends indicate that many chronic and communicable diseases are related to lifestyle, stress, personal choices and systemic factors. In response to the shortfalls of modern medicine regarding the prevention of these diseases and the promotion of whole-person health, providers and consumers worldwide are exploring integrative, natural and complementary approaches to prevention, treatment and health promotion. These trends harbor the future of medicine. The issues of clinician burnout, high rates of adverse effects, high cost, and lack of rigorous methods to promote individual and collective immunity are addressed by leading physicians and scientists from around the world. The original research and reviews in this volume investigate efficacy, molecular mechanisms and hypotheses that suggest that traditional systems of medicine and health, e.g., Ayurveda, yoga, traditional Chinese medicine, and mind–body–lifestyle medicine, may offer preventive and cost-effective solutions to contemporary health care challenges. Integrating innovative health approaches with conventional medicine offers a whole system of medicine that encompasses the individual, family, community and environment—from single person to planetary health

Wholistic Healing: The Physician Perspective of the Tibetan Medical Philosophy

In Western medicine, anatomy is divided into multiple disciplines with specialists focused on their specialization, thereby limiting the whole system medical approach within the diagnosis, practice, and treatment of illness. The purpose of this qualitative study with an emergent design was to explore how physicians of Tibetan medicine viewed treating the whole person through the lens of Sowa Rigpa. Inquiry and analytical thinking were viewed through the lens of Otto and Knight’s principles of wholistic healing, Wilber’s integral model, and the philosophy of Merleau-Ponty. Phase I consisted of key informant interviews with four participants that were recent graduates of Tibetan medicine or scholars knowledgeable in Tibetan medicine. Phase II consisted of interviews with seven Tibetan medicine doctors. Inductive coding and thematic analysis showed nine themes associated with whole person care and wholistic healing: an applied philosophy of wholism, the anatomy and physiology of wholism, the pathology of disease, health and wellness, disease prevention, patient assessment and diagnosis, treatment and healing, self–awareness and healing, and the doctor and doctor–patient relationship. The findings may provide positive social change through insight for allopathic physicians and scholars on how to address the complex factors associated with healing and curing from a whole person perspective while also promoting engaged collaboration among cultures and medical disciplines

The genetic background of five canine models of rare human disease

This thesis addresses the genetic background of five spontaneous canine models of rare human disease. By utilizing genome-wide mapping methods, next-generation sequencing analyses and variant validation combined with detailed clinical and post-mortem examinations, we characterized new canine models, identified novel disease-associated variants and dissected their effects on health and morphology. In Study I, next-generation sequencing analysis in a Central Asian Shepherd dog affected by epidermolysis bullosa revealed a nonsense variant in COL7A1. Validation of the variant in 190 dogs confirmed the disease type as recessive dystrophic epidermolysis bullosa. Immunohistochemical stainings in skin samples illustrated the lack of full-length type VII collagen protein in the affected dog. In Study II, genome-wide association analysis combined with next-generation sequence analysis identified a locus and candidate variant associated with recessive pituitary dwarfism in Karelian Bear Dogs. A splice site variant in POU1F1 was confirmed with validation in over 8000 dogs. Computational predictions indicated weakening of the splice acceptor site at the affected intron-exon junction. In Study III, homozygosity mapping combined with next-generation sequence analysis identified candidate regions and variants associated with recessive congenital hearing loss in Rottweilers. A missense variant in LOXHD1 was confirmed with validation in over 800 000 dogs, revealing a link between the variant and Rottweiler breed background. In Study IV, variant screening combined with clinical examinations and statistical analyses revealed novel morphological consequences of a previously described variant in DVL2. The findings showed that the variant is involved in variable caudal vertebral anomalies and contributes to a brachycephalic phenotype. Varying allele frequencies were identified across populations, indicating the differential impact of the variant on the genetic health of dog breeds. In Study V, clinical and post-mortem examinations revealed malignant polymorphic ventricular arrhythmia and sudden cardiac death in young Leonberger dogs. The high prevalence of the disorder in litters and families strongly indicated a genetic aetiology. However, genome-wide association analyses failed to reveal associated loci, likely due to genetic or phenotypic heterogeneity. Future studies aim to overcome these obstacles with expanded cohorts and improved clinical and molecular phenotypes. Our findings have multiple scientific and practical implications. The discoveries facilitate diagnostics and treatment by revealing the molecular and pathophysiological mechanisms of the disorders. Affected dogs also provide novel large animal models for preclinical studies, benefitting both human and veterinary medicine. Finally, the development of gene tests support dog owners and breeders in revising breeding programmes to improve the health of dog breeds.Tässä väitöskirjatyössä selvitettiin viiden koirilla esiintyvän perinnöllisen sairauden taustaa. Tutkimuksissa käytettiin genominlaajuista assosiaatioanalyysiä, seuraavan sukupolven sekvensointianalyysiä ja geneettisten varianttien validaatiota yhdessä yksityiskohtaisten kliinisten ja patologisten tutkimusten kanssa. Työn tuloksena kuvattiin uusia koirilla esiintyviä sairauksia ja tunnistettiin sairauksia aiheuttavia geenimuunnoksia ja niiden vaikutuksia koirien terveyteen ja ruumiinrakenteeseen. Osatyössä I tunnistettiin seuraavan sukupolven sekvensointianalyysillä keskiaasiankoirien epidermolysis bullosa -ihosairauteen liittyvä ehdokasgeenivirhe COL7A1-geenissä. Geenivirheen yhteys sairauteen varmennettiin 190 koiran perimässä, ja sairauden alatyypiksi tarkennettiin resessiivinen dystrofinen epidermolysis bullosa. Immunohistokemialliset värjäykset ihonäytteissä paljastivat täyspitkän kollageeni VII -proteiinin puutoksen sairastuneen koiran ihossa. Osatyössä II tunnistettiin genominlaajuista assosiaatioanalyysiä ja seuraavan sukupolven sekvensointianalyysiä käyttäen karjalankarhukoirien aivolisäkeperäiseen lyhytkasvuisuuteen liittyvä perimän alue ja ehdokasgeenivirhe. POU1F1-geenin silmukointialueella sijaitsevan geenivirheen yhteys sairauteen varmennettiin yli 8000 koiran perimässä. Laskennallinen ennuste viittasi geenivirheen sisältävän introni-eksoni -liitoksen silmukointialueen heikentymiseen. Osatyössä III tunnistettiin homotsygotiakartoitusta ja seuraavan sukupolven sekvensointianalyysiä käyttäen rottweilerien synnynnäiseen kuurouteen liittyviä perimän ehdokasalueita ja -geenivirheitä. LOXHD1-geenissä sijaitsevan geenivirheen yhteys sairauteen varmennettiin yli 800 000 koiran perimässä. Varmennus paljasti myös geenivirheen esiintyvän lähes yksinomaan rottweiler-taustaisissa koirissa. Osatyössä IV tarkennettiin varianttiseulontaa, kliinisiä tutkimuksia ja tilastoanalyysejä käyttäen aiemmin kuvatun DVL2-geenivirheen vaikutuksia koirien ruumiinrakenteeseen. Tulokset osoittivat geenivirheen yhteyden erilaisiin kaudaalinikamien epämuodostumiin ja kuonon pituuden lyhenemiseen. Vaihteleva frekvenssi osoitti geenivirheeseen liittyvien terveysongelmien kuorman eroavan rotujen välillä. Osatyössä V tunnistettiin kliinisiä ja patologisia tutkimuksia käyttäen pahanlaatuisia kammiorytmihäiriöitä ja äkillisiä sydänperäisiä kuolemia nuorissa leonberginkoirissa. Sairauden korkea esiintyvyys pentueittain ja suvuittain viittasi perinnölliseen taustaan, mutta genominlaajuista analyysiä käyttäen ei tunnistettu ehdokasalueita perimästä. Tämä johtui todennäköisesti geneettisestä tai fenotyyppisestä heterogeniasta, mikä pyritään tulevissa analyyseissä huomioimaan suuremmalla otoskoolla ja tarkemmilla kliinisillä ja molekyylitason tutkimuksilla. Väitöstyön tuloksilla on useita tieteellisiä ja käytännön vaikutuksia. Löydökset edistävät diagnostiikkaa ja hoidon kehittämistä paljastamalla sairauksien taustalla olevat molekyylitason patofysiologiset mekanismit. Sairastuneet koirat voivat toimia mallieläiminä prekliinisissä tutkimuksissa, mikä hyödyttää sekä ihmis- että eläinlääketiedettä. Löydöksiin perustuvat geenitestit tukevat lisäksi koiranomistajia ja -kasvattajia jalostussuunnitelmien kehittämisessä terveempään suuntaan