%0 Journal Article %J Genome Res %D 2014 %T Natural variation in genome architecture among 205 Drosophila melanogaster Genetic Reference Panel lines. %A Huang, Wen %A Massouras, Andreas %A Inoue, Yutaka %A Peiffer, Jason %A RĂ mia, Miquel %A Tarone, Aaron M %A Turlapati, Lavanya %A Zichner, Thomas %A Zhu, Dianhui %A Lyman, Richard F %A Magwire, Michael M %A Blankenburg, Kerstin %A Carbone, Mary Anna %A Chang, Kyle %A Ellis, Lisa L %A Fernandez, Sonia %A Han, Yi %A Highnam, Gareth %A Hjelmen, Carl E %A Jack, John R %A Javaid, Mehwish %A Jayaseelan, Joy %A Kalra, Divya %A Lee, Sandy %A Lewis, Lora %A Munidasa, Mala %A Ongeri, Fiona %A Patel, Shohba %A Perales, Lora %A Perez, Agapito %A Pu, LingLing %A Rollmann, Stephanie M %A Ruth, Robert %A Saada, Nehad %A Warner, Crystal %A Williams, Aneisa %A Wu, Yuan-Qing %A Yamamoto, Akihiko %A Zhang, Yiqing %A Zhu, Yiming %A Anholt, Robert R H %A Korbel, Jan O %A Mittelman, David %A Muzny, Donna M %A Gibbs, Richard A %A Barbadilla, Antonio %A Johnston, J Spencer %A Stone, Eric A %A Richards, Stephen %A Deplancke, Bart %A Mackay, Trudy F C %K Animals %K Chromatin %K Drosophila melanogaster %K Female %K Genetic Linkage %K Genetic Variation %K Genome Size %K Genome, Insect %K Genome-Wide Association Study %K Genotype %K Genotyping Techniques %K High-Throughput Nucleotide Sequencing %K INDEL Mutation %K Linkage Disequilibrium %K Male %K Molecular Sequence Annotation %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait, Heritable %K Reproducibility of Results %X

The Drosophila melanogaster Genetic Reference Panel (DGRP) is a community resource of 205 sequenced inbred lines, derived to improve our understanding of the effects of naturally occurring genetic variation on molecular and organismal phenotypes. We used an integrated genotyping strategy to identify 4,853,802 single nucleotide polymorphisms (SNPs) and 1,296,080 non-SNP variants. Our molecular population genomic analyses show higher deletion than insertion mutation rates and stronger purifying selection on deletions. Weaker selection on insertions than deletions is consistent with our observed distribution of genome size determined by flow cytometry, which is skewed toward larger genomes. Insertion/deletion and single nucleotide polymorphisms are positively correlated with each other and with local recombination, suggesting that their nonrandom distributions are due to hitchhiking and background selection. Our cytogenetic analysis identified 16 polymorphic inversions in the DGRP. Common inverted and standard karyotypes are genetically divergent and account for most of the variation in relatedness among the DGRP lines. Intriguingly, variation in genome size and many quantitative traits are significantly associated with inversions. Approximately 50% of the DGRP lines are infected with Wolbachia, and four lines have germline insertions of Wolbachia sequences, but effects of Wolbachia infection on quantitative traits are rarely significant. The DGRP complements ongoing efforts to functionally annotate the Drosophila genome. Indeed, 15% of all D. melanogaster genes segregate for potentially damaged proteins in the DGRP, and genome-wide analyses of quantitative traits identify novel candidate genes. The DGRP lines, sequence data, genotypes, quality scores, phenotypes, and analysis and visualization tools are publicly available.

%B Genome Res %V 24 %P 1193-208 %8 2014 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/24714809?dopt=Abstract %R 10.1101/gr.171546.113 %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