%0 Journal Article %J Nat Genet %D 2013 %T Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. %A Baud, Amelie %A Hermsen, Roel %A Guryev, Victor %A Stridh, Pernilla %A Graham, Delyth %A McBride, Martin W %A Foroud, Tatiana %A Calderari, Sophie %A Diez, Margarita %A Ockinger, Johan %A Beyeen, Amennai D %A Gillett, Alan %A Abdelmagid, Nada %A Guerreiro-Cacais, Andre Ortlieb %A Jagodic, Maja %A Tuncel, Jonatan %A Norin, Ulrika %A Beattie, Elisabeth %A Huynh, Ngan %A Miller, William H %A Koller, Daniel L %A Alam, Imranul %A Falak, Samreen %A Osborne-Pellegrin, Mary %A Martinez-Membrives, Esther %A Canete, Toni %A Blazquez, Gloria %A Vicens-Costa, Elia %A Mont-Cardona, Carme %A Diaz-Moran, Sira %A Tobena, Adolf %A Hummel, Oliver %A Zelenika, Diana %A Saar, Kathrin %A Patone, Giannino %A Bauerfeind, Anja %A Bihoreau, Marie-Therese %A Heinig, Matthias %A Lee, Young-Ae %A Rintisch, Carola %A Schulz, Herbert %A Wheeler, David A %A Worley, Kim C %A Muzny, Donna M %A Gibbs, Richard A %A Lathrop, Mark %A Lansu, Nico %A Toonen, Pim %A Ruzius, Frans Paul %A de Bruijn, Ewart %A Hauser, Heidi %A Adams, David J %A Keane, Thomas %A Atanur, Santosh S %A Aitman, Tim J %A Flicek, Paul %A Malinauskas, Tomas %A Jones, E Yvonne %A Ekman, Diana %A Lopez-Aumatell, Regina %A Dominiczak, Anna F %A Johannesson, Martina %A Holmdahl, Rikard %A Olsson, Tomas %A Gauguier, Dominique %A Hübner, Norbert %A Fernandez-Teruel, Alberto %A Cuppen, Edwin %A Mott, Richard %A Flint, Jonathan %K Animals %K Animals, Outbred Strains %K Anxiety %K Chromosome Mapping %K Genetic Variation %K Genotype %K Heart Diseases %K Humans %K Mice %K Mice, Inbred C57BL %K Models, Molecular %K Multiple Sclerosis %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Rats %K Sequence Analysis, DNA %X

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.

%B Nat Genet %V 45 %P 767-75 %8 2013 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/23708188?dopt=Abstract %R 10.1038/ng.2644 %0 Journal Article %J Nature %D 2012 %T Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. %A Biankin, Andrew V %A Waddell, Nicola %A Kassahn, Karin S %A Gingras, Marie-Claude %A Muthuswamy, Lakshmi B %A Johns, Amber L %A Miller, David K %A Wilson, Peter J %A Patch, Ann-Marie %A Wu, Jianmin %A Chang, David K %A Cowley, Mark J %A Gardiner, Brooke B %A Song, Sarah %A Harliwong, Ivon %A Idrisoglu, Senel %A Nourse, Craig %A Nourbakhsh, Ehsan %A Manning, Suzanne %A Wani, Shivangi %A Gongora, Milena %A Pajic, Marina %A Scarlett, Christopher J %A Gill, Anthony J %A Pinho, Andreia V %A Rooman, Ilse %A Anderson, Matthew %A Holmes, Oliver %A Leonard, Conrad %A Taylor, Darrin %A Wood, Scott %A Xu, Qinying %A Nones, Katia %A Fink, J Lynn %A Christ, Angelika %A Bruxner, Tim %A Cloonan, Nicole %A Kolle, Gabriel %A Newell, Felicity %A Pinese, Mark %A Mead, R Scott %A Humphris, Jeremy L %A Kaplan, Warren %A Jones, Marc D %A Colvin, Emily K %A Nagrial, Adnan M %A Humphrey, Emily S %A Chou, Angela %A Chin, Venessa T %A Chantrill, Lorraine A %A Mawson, Amanda %A Samra, Jaswinder S %A Kench, James G %A Lovell, Jessica A %A Daly, Roger J %A Merrett, Neil D %A Toon, Christopher %A Epari, Krishna %A Nguyen, Nam Q %A Barbour, Andrew %A Zeps, Nikolajs %A Kakkar, Nipun %A Zhao, Fengmei %A Wu, Yuan Qing %A Wang, Min %A Muzny, Donna M %A Fisher, William E %A Brunicardi, F Charles %A Hodges, Sally E %A Reid, Jeffrey G %A Drummond, Jennifer %A Chang, Kyle %A Han, Yi %A Lewis, Lora R %A Dinh, Huyen %A Buhay, Christian J %A Beck, Timothy %A Timms, Lee %A Sam, Michelle %A Begley, Kimberly %A Brown, Andrew %A Pai, Deepa %A Panchal, Ami %A Buchner, Nicholas %A De Borja, Richard %A Denroche, Robert E %A Yung, Christina K %A Serra, Stefano %A Onetto, Nicole %A Mukhopadhyay, Debabrata %A Tsao, Ming-Sound %A Shaw, Patricia A %A Petersen, Gloria M %A Gallinger, Steven %A Hruban, Ralph H %A Maitra, Anirban %A Iacobuzio-Donahue, Christine A %A Schulick, Richard D %A Wolfgang, Christopher L %A Morgan, Richard A %A Lawlor, Rita T %A Capelli, Paola %A Corbo, Vincenzo %A Scardoni, Maria %A Tortora, Giampaolo %A Tempero, Margaret A %A Mann, Karen M %A Jenkins, Nancy A %A Perez-Mancera, Pedro A %A Adams, David J %A Largaespada, David A %A Wessels, Lodewyk F A %A Rust, Alistair G %A Stein, Lincoln D %A Tuveson, David A %A Copeland, Neal G %A Musgrove, Elizabeth A %A Scarpa, Aldo %A Eshleman, James R %A Hudson, Thomas J %A Sutherland, Robert L %A Wheeler, David A %A Pearson, John V %A McPherson, John D %A Gibbs, Richard A %A Grimmond, Sean M %K Animals %K Axons %K Carcinoma, Pancreatic Ductal %K Gene Dosage %K Gene Expression Regulation, Neoplastic %K Genome %K Humans %K Kaplan-Meier Estimate %K Mice %K Mutation %K Pancreatic Neoplasms %K Proteins %K Signal Transduction %X

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

%B Nature %V 491 %P 399-405 %8 2012 Nov 15 %G eng %N 7424 %1 https://www.ncbi.nlm.nih.gov/pubmed/23103869?dopt=Abstract %R 10.1038/nature11547