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1.  The Common Marmoset Genome Provides Insight into Primate Biology and Evolution 
Worley, Kim C. | Warren, Wesley C. | Rogers, Jeffrey | Locke, Devin | Muzny, Donna M. | Mardis, Elaine R. | Weinstock, George M. | Tardif, Suzette D. | Aagaard, Kjersti M. | Archidiacono, Nicoletta | Rayan, Nirmala Arul | Batzer, Mark A. | Beal, Kathryn | Brejova, Brona | Capozzi, Oronzo | Capuano, Saverio B. | Casola, Claudio | Chandrabose, Mimi M. | Cree, Andrew | Dao, Marvin Diep | de Jong, Pieter J. | del Rosario, Ricardo Cruz-Herrera | Delehaunty, Kim D. | Dinh, Huyen H. | Eichler, Evan | Fitzgerald, Stephen | Flicek, Paul | Fontenot, Catherine C. | Fowler, R. Gerald | Fronick, Catrina | Fulton, Lucinda A. | Fulton, Robert S. | Gabisi, Ramatu Ayiesha | Gerlach, Daniel | Graves, Tina A. | Gunaratne, Preethi H. | Hahn, Matthew W. | Haig, David | Han, Yi | Harris, R. Alan | Herrero, Javier M. | Hillier, LaDeana W. | Hubley, Robert | Hughes, Jennifer F. | Hume, Jennifer | Jhangiani, Shalini N. | Jorde, Lynn B. | Joshi, Vandita | Karakor, Emre | Konkel, Miriam K. | Kosiol, Carolin | Kovar, Christie L. | Kriventseva, Evgenia V. | Lee, Sandra L. | Lewis, Lora R. | Liu, Yih-shin | Lopez, John | Lopez-Otin, Carlos | Lorente-Galdos, Belen | Mansfield, Keith G. | Marques-Bonet, Tomas | Minx, Patrick | Misceo, Doriana | Moncrieff, J. Scott | Morgan, Margaret B. | Muthuswamy, Raveendran | Nazareth, Lynne V. | Newsham, Irene | Nguyen, Ngoc Bich | Okwuonu, Geoffrey O. | Prabhakar, Shyam | Perales, Lora | Pu, Ling-Ling | Puente, Xose S. | Quesada, Victor | Ranck, Megan C. | Raney, Brian J. | Deiros, David Rio | Rocchi, Mariano | Rodriguez, David | Ross, Corinna | Ruffier, Magali | Ruiz, San Juana | Sajjadian, S. | Santibanez, Jireh | Schrider, Daniel R. | Searle, Steve | Skaletsky, Helen | Soibam, Benjamin | Smit, Arian F. A. | Tennakoon, Jayantha B. | Tomaska, Lubomir | Ullmer, Brygg | Vejnar, Charles E. | Ventura, Mario | Vilella, Albert J. | Vinar, Tomas | Vogel, Jan-Hinnerk | Walker, Jerilyn A. | Wang, Qing | Warner, Crystal M. | Wildman, Derek E. | Witherspoon, David J. | Wright, Rita A. | Wu, Yuanqing | Xiao, Weimin | Xing, Jinchuan | Zdobnov, Evgeny M. | Zhu, Baoli | Gibbs, Richard A. | Wilson, Richard K.
Nature genetics  2014;46(8):850-857.
A first analysis of the genome sequence of the common marmoset (Callithrix jacchus), assembled using traditional Sanger methods and Ensembl annotation, has permitted genomic comparison with apes and that old world monkeys and the identification of specific molecular features a rapid reproductive capacity partly due to may contribute to the unique biology of diminutive The common marmoset has prevalence of this dizygotic primate. twins. Remarkably, these twins share placental circulation and exchange hematopoietic stem cells in utero, resulting in adults that are hematopoietic chimeras.
We observed positive selection or non-synonymous substitutions for genes encoding growth hormone / insulin-like growth factor (growth pathways), respiratory complex I (metabolic pathways), immunobiology, and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibit rapid sequence evolution. This New World monkey genome sequence enables significantly increased power for comparative analyses among available primate genomes and facilitates biomedical research application.
doi:10.1038/ng.3042
PMCID: PMC4138798  PMID: 25038751
2.  Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy 
The New England journal of medicine  2010;362(13):1181-1191.
BACKGROUND
Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot–Marie–Tooth disease.
METHODS
We identified a family with a recessive form of Charcot–Marie–Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members.
RESULTS
We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot–Marie–Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome.
CONCLUSIONS
As shown in this study of a family with Charcot–Marie–Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.
doi:10.1056/NEJMoa0908094
PMCID: PMC4036802  PMID: 20220177
3.  Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders 
Neuron  2013;77(2):235-242.
SUMMARY
To characterize the role of rare complete human knockouts in autism spectrum disorders (ASD), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a two-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudo-autosomal regions on the X-chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together these results provide compelling evidence that rare autosomal and X-chromosome complete gene knockouts are important inherited risk factors for ASD.
doi:10.1016/j.neuron.2012.12.029
PMCID: PMC3613849  PMID: 23352160
4.  Analysis of Rare, Exonic Variation amongst Subjects with Autism Spectrum Disorders and Population Controls 
PLoS Genetics  2013;9(4):e1003443.
We report on results from whole-exome sequencing (WES) of 1,039 subjects diagnosed with autism spectrum disorders (ASD) and 870 controls selected from the NIMH repository to be of similar ancestry to cases. The WES data came from two centers using different methods to produce sequence and to call variants from it. Therefore, an initial goal was to ensure the distribution of rare variation was similar for data from different centers. This proved straightforward by filtering called variants by fraction of missing data, read depth, and balance of alternative to reference reads. Results were evaluated using seven samples sequenced at both centers and by results from the association study. Next we addressed how the data and/or results from the centers should be combined. Gene-based analyses of association was an obvious choice, but should statistics for association be combined across centers (meta-analysis) or should data be combined and then analyzed (mega-analysis)? Because of the nature of many gene-based tests, we showed by theory and simulations that mega-analysis has better power than meta-analysis. Finally, before analyzing the data for association, we explored the impact of population structure on rare variant analysis in these data. Like other recent studies, we found evidence that population structure can confound case-control studies by the clustering of rare variants in ancestry space; yet, unlike some recent studies, for these data we found that principal component-based analyses were sufficient to control for ancestry and produce test statistics with appropriate distributions. After using a variety of gene-based tests and both meta- and mega-analysis, we found no new risk genes for ASD in this sample. Our results suggest that standard gene-based tests will require much larger samples of cases and controls before being effective for gene discovery, even for a disorder like ASD.
Author Summary
This study evaluates association of rare variants and autism spectrum disorders (ASD) in case and control samples sequenced by two centers. Before doing association analyses, we studied how to combine information across studies. We first harmonized the whole-exome sequence (WES) data, across centers, in terms of the distribution of rare variation. Key features included filtering called variants by fraction of missing data, read depth, and balance of alternative to reference reads. After filtering, the vast majority of variants calls from seven samples sequenced at both centers matched. We also evaluated whether one should combine summary statistics from data from each center (meta-analysis) or combine data and analyze it together (mega-analysis). For many gene-based tests, we showed that mega-analysis yields more power. After quality control of data from 1,039 ASD cases and 870 controls and a range of analyses, no gene showed exome-wide evidence of significant association. Our results comport with recent results demonstrating that hundreds of genes affect risk for ASD; they suggest that rare risk variants are scattered across these many genes, and thus larger samples will be required to identify those genes.
doi:10.1371/journal.pgen.1003443
PMCID: PMC3623759  PMID: 23593035
5.  Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes 
Biankin, Andrew V. | Waddell, Nicola | Kassahn, Karin S. | Gingras, Marie-Claude | Muthuswamy, Lakshmi B. | Johns, Amber L. | Miller, David K. | Wilson, Peter J. | Patch, Ann-Marie | Wu, Jianmin | Chang, David K. | Cowley, Mark J. | Gardiner, Brooke B. | Song, Sarah | Harliwong, Ivon | Idrisoglu, Senel | Nourse, Craig | Nourbakhsh, Ehsan | Manning, Suzanne | Wani, Shivangi | Gongora, Milena | Pajic, Marina | Scarlett, Christopher J. | Gill, Anthony J. | Pinho, Andreia V. | Rooman, Ilse | Anderson, Matthew | Holmes, Oliver | Leonard, Conrad | Taylor, Darrin | Wood, Scott | Xu, Qinying | Nones, Katia | Fink, J. Lynn | Christ, Angelika | Bruxner, Tim | Cloonan, Nicole | Kolle, Gabriel | Newell, Felicity | Pinese, Mark | Mead, R. Scott | Humphris, Jeremy L. | Kaplan, Warren | Jones, Marc D. | Colvin, Emily K. | Nagrial, Adnan M. | Humphrey, Emily S. | Chou, Angela | Chin, Venessa T. | Chantrill, Lorraine A. | Mawson, Amanda | Samra, Jaswinder S. | Kench, James G. | Lovell, Jessica A. | Daly, Roger J. | Merrett, Neil D. | Toon, Christopher | Epari, Krishna | Nguyen, Nam Q. | Barbour, Andrew | Zeps, Nikolajs | Kakkar, Nipun | Zhao, Fengmei | Wu, Yuan Qing | Wang, Min | Muzny, Donna M. | Fisher, William E. | Brunicardi, F. Charles | Hodges, Sally E. | Reid, Jeffrey G. | Drummond, Jennifer | Chang, Kyle | Han, Yi | Lewis, Lora R. | Dinh, Huyen | Buhay, Christian J. | Beck, Timothy | Timms, Lee | Sam, Michelle | Begley, Kimberly | Brown, Andrew | Pai, Deepa | Panchal, Ami | Buchner, Nicholas | De Borja, Richard | Denroche, Robert E. | Yung, Christina K. | Serra, Stefano | Onetto, Nicole | Mukhopadhyay, Debabrata | Tsao, Ming-Sound | Shaw, Patricia A. | Petersen, Gloria M. | Gallinger, Steven | Hruban, Ralph H. | Maitra, Anirban | Iacobuzio-Donahue, Christine A. | Schulick, Richard D. | Wolfgang, Christopher L. | Morgan, Richard A. | Lawlor, Rita T. | Capelli, Paola | Corbo, Vincenzo | Scardoni, Maria | Tortora, Giampaolo | Tempero, Margaret A. | Mann, Karen M. | Jenkins, Nancy A. | Perez-Mancera, Pedro A. | Adams, David J. | Largaespada, David A. | Wessels, Lodewyk F. A. | Rust, Alistair G. | Stein, Lincoln D. | Tuveson, David A. | Copeland, Neal G. | Musgrove, Elizabeth A. | Scarpa, Aldo | Eshleman, James R. | Hudson, Thomas J. | Sutherland, Robert L. | Wheeler, David A. | Pearson, John V. | McPherson, John D. | Gibbs, Richard A. | Grimmond, Sean M.
Nature  2012;491(7424):399-405.
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.
doi:10.1038/nature11547
PMCID: PMC3530898  PMID: 23103869
6.  Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development 
Renfree, Marilyn B | Papenfuss, Anthony T | Deakin, Janine E | Lindsay, James | Heider, Thomas | Belov, Katherine | Rens, Willem | Waters, Paul D | Pharo, Elizabeth A | Shaw, Geoff | Wong, Emily SW | Lefèvre, Christophe M | Nicholas, Kevin R | Kuroki, Yoko | Wakefield, Matthew J | Zenger, Kyall R | Wang, Chenwei | Ferguson-Smith, Malcolm | Nicholas, Frank W | Hickford, Danielle | Yu, Hongshi | Short, Kirsty R | Siddle, Hannah V | Frankenberg, Stephen R | Chew, Keng Yih | Menzies, Brandon R | Stringer, Jessica M | Suzuki, Shunsuke | Hore, Timothy A | Delbridge, Margaret L | Mohammadi, Amir | Schneider, Nanette Y | Hu, Yanqiu | O'Hara, William | Al Nadaf, Shafagh | Wu, Chen | Feng, Zhi-Ping | Cocks, Benjamin G | Wang, Jianghui | Flicek, Paul | Searle, Stephen MJ | Fairley, Susan | Beal, Kathryn | Herrero, Javier | Carone, Dawn M | Suzuki, Yutaka | Sugano, Sumio | Toyoda, Atsushi | Sakaki, Yoshiyuki | Kondo, Shinji | Nishida, Yuichiro | Tatsumoto, Shoji | Mandiou, Ion | Hsu, Arthur | McColl, Kaighin A | Lansdell, Benjamin | Weinstock, George | Kuczek, Elizabeth | McGrath, Annette | Wilson, Peter | Men, Artem | Hazar-Rethinam, Mehlika | Hall, Allison | Davis, John | Wood, David | Williams, Sarah | Sundaravadanam, Yogi | Muzny, Donna M | Jhangiani, Shalini N | Lewis, Lora R | Morgan, Margaret B | Okwuonu, Geoffrey O | Ruiz, San Juana | Santibanez, Jireh | Nazareth, Lynne | Cree, Andrew | Fowler, Gerald | Kovar, Christie L | Dinh, Huyen H | Joshi, Vandita | Jing, Chyn | Lara, Fremiet | Thornton, Rebecca | Chen, Lei | Deng, Jixin | Liu, Yue | Shen, Joshua Y | Song, Xing-Zhi | Edson, Janette | Troon, Carmen | Thomas, Daniel | Stephens, Amber | Yapa, Lankesha | Levchenko, Tanya | Gibbs, Richard A | Cooper, Desmond W | Speed, Terence P | Fujiyama, Asao | M Graves, Jennifer A | O'Neill, Rachel J | Pask, Andrew J | Forrest, Susan M | Worley, Kim C
Genome Biology  2011;12(8):R81.
Background
We present the genome sequence of the tammar wallaby, Macropus eugenii, which is a member of the kangaroo family and the first representative of the iconic hopping mammals that symbolize Australia to be sequenced. The tammar has many unusual biological characteristics, including the longest period of embryonic diapause of any mammal, extremely synchronized seasonal breeding and prolonged and sophisticated lactation within a well-defined pouch. Like other marsupials, it gives birth to highly altricial young, and has a small number of very large chromosomes, making it a valuable model for genomics, reproduction and development.
Results
The genome has been sequenced to 2 × coverage using Sanger sequencing, enhanced with additional next generation sequencing and the integration of extensive physical and linkage maps to build the genome assembly. We also sequenced the tammar transcriptome across many tissues and developmental time points. Our analyses of these data shed light on mammalian reproduction, development and genome evolution: there is innovation in reproductive and lactational genes, rapid evolution of germ cell genes, and incomplete, locus-specific X inactivation. We also observe novel retrotransposons and a highly rearranged major histocompatibility complex, with many class I genes located outside the complex. Novel microRNAs in the tammar HOX clusters uncover new potential mammalian HOX regulatory elements.
Conclusions
Analyses of these resources enhance our understanding of marsupial gene evolution, identify marsupial-specific conserved non-coding elements and critical genes across a range of biological systems, including reproduction, development and immunity, and provide new insight into marsupial and mammalian biology and genome evolution.
doi:10.1186/gb-2011-12-8-r81
PMCID: PMC3277949  PMID: 21854559
7.  Comparative and demographic analysis of orangutan genomes 
Locke, Devin P. | Hillier, LaDeana W. | Warren, Wesley C. | Worley, Kim C. | Nazareth, Lynne V. | Muzny, Donna M. | Yang, Shiaw-Pyng | Wang, Zhengyuan | Chinwalla, Asif T. | Minx, Pat | Mitreva, Makedonka | Cook, Lisa | Delehaunty, Kim D. | Fronick, Catrina | Schmidt, Heather | Fulton, Lucinda A. | Fulton, Robert S. | Nelson, Joanne O. | Magrini, Vincent | Pohl, Craig | Graves, Tina A. | Markovic, Chris | Cree, Andy | Dinh, Huyen H. | Hume, Jennifer | Kovar, Christie L. | Fowler, Gerald R. | Lunter, Gerton | Meader, Stephen | Heger, Andreas | Ponting, Chris P. | Marques-Bonet, Tomas | Alkan, Can | Chen, Lin | Cheng, Ze | Kidd, Jeffrey M. | Eichler, Evan E. | White, Simon | Searle, Stephen | Vilella, Albert J. | Chen, Yuan | Flicek, Paul | Ma, Jian | Raney, Brian | Suh, Bernard | Burhans, Richard | Herrero, Javier | Haussler, David | Faria, Rui | Fernando, Olga | Darré, Fleur | Farré, Domènec | Gazave, Elodie | Oliva, Meritxell | Navarro, Arcadi | Roberto, Roberta | Capozzi, Oronzo | Archidiacono, Nicoletta | Valle, Giuliano Della | Purgato, Stefania | Rocchi, Mariano | Konkel, Miriam K. | Walker, Jerilyn A. | Ullmer, Brygg | Batzer, Mark A. | Smit, Arian F. A. | Hubley, Robert | Casola, Claudio | Schrider, Daniel R. | Hahn, Matthew W. | Quesada, Victor | Puente, Xose S. | Ordoñez, Gonzalo R. | López-Otín, Carlos | Vinar, Tomas | Brejova, Brona | Ratan, Aakrosh | Harris, Robert S. | Miller, Webb | Kosiol, Carolin | Lawson, Heather A. | Taliwal, Vikas | Martins, André L. | Siepel, Adam | RoyChoudhury, Arindam | Ma, Xin | Degenhardt, Jeremiah | Bustamante, Carlos D. | Gutenkunst, Ryan N. | Mailund, Thomas | Dutheil, Julien Y. | Hobolth, Asger | Schierup, Mikkel H. | Chemnick, Leona | Ryder, Oliver A. | Yoshinaga, Yuko | de Jong, Pieter J. | Weinstock, George M. | Rogers, Jeffrey | Mardis, Elaine R. | Gibbs, Richard A. | Wilson, Richard K.
Nature  2011;469(7331):529-533.
“Orangutan” is derived from the Malay term “man of the forest” and aptly describes the Southeast Asian great apes native to Sumatra and Borneo. The orangutan species, Pongo abelii (Sumatran) and Pongo pygmaeus (Bornean), are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution. Here we present a Sumatran orangutan draft genome assembly and short read sequence data from five Sumatran and five Bornean orangutan genomes. Our analyses reveal that, compared to other primates, the orangutan genome has many unique features. Structural evolution of the orangutan genome has proceeded much more slowly than other great apes, evidenced by fewer rearrangements, less segmental duplication, a lower rate of gene family turnover and surprisingly quiescent Alu repeats, which have played a major role in restructuring other primate genomes. We also describe the first primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orangutan genome structure. Orangutans have extremely low energy usage for a eutherian mammal1, far lower than their hominid relatives. Adding their genome to the repertoire of sequenced primates illuminates new signals of positive selection in several pathways including glycolipid metabolism. From the population perspective, both Pongo species are deeply diverse; however, Sumatran individuals possess greater diversity than their Bornean counterparts, and more species-specific variation. Our estimate of Bornean/Sumatran speciation time, 400k years ago (ya), is more recent than most previous studies and underscores the complexity of the orangutan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (Ne) expanded exponentially relative to the ancestral Ne after the split, while Bornean Ne declined over the same period. Overall, the resources and analyses presented here offer new opportunities in evolutionary genomics, insights into hominid biology, and an extensive database of variation for conservation efforts.
doi:10.1038/nature09687
PMCID: PMC3060778  PMID: 21270892
8.  The Chaperone-Like Protein HYPK Acts Together with NatA in Cotranslational N-Terminal Acetylation and Prevention of Huntingtin Aggregation▿ †  
Molecular and Cellular Biology  2010;30(8):1898-1909.
The human NatA protein Nα-terminal-acetyltransferase complex is responsible for cotranslational N-terminal acetylation of proteins with Ser, Ala, Thr, Gly, and Val N termini. The NatA complex is composed of the catalytic subunit hNaa10p (hArd1) and the auxiliary subunit hNaa15p (hNat1/NATH). Using immunoprecipitation coupled with mass spectrometry, we identified endogenous HYPK, a Huntingtin (Htt)-interacting protein, as a novel stable interactor of NatA. HYPK has chaperone-like properties preventing Htt aggregation. HYPK, hNaa10p, and hNaa15p were associated with polysome fractions, indicating a function of HYPK associated with the NatA complex during protein translation. Knockdown of both hNAA10 and hNAA15 decreased HYPK protein levels, possibly indicating that NatA is required for the stability of HYPK. The biological importance of HYPK was evident from HYPK-knockdown HeLa cells displaying apoptosis and cell cycle arrest in the G0/G1 phase. Knockdown of HYPK or hNAA10 resulted in increased aggregation of an Htt-enhanced green fluorescent protein (Htt-EGFP) fusion with expanded polyglutamine stretches, suggesting that both HYPK and NatA prevent Htt aggregation. Furthermore, we demonstrated that HYPK is required for N-terminal acetylation of the known in vivo NatA substrate protein PCNP. Taken together, the data indicate that the physical interaction between HYPK and NatA seems to be of functional importance both for Htt aggregation and for N-terminal acetylation.
doi:10.1128/MCB.01199-09
PMCID: PMC2849469  PMID: 20154145
9.  The DNA sequence of the human X chromosome 
Ross, Mark T. | Grafham, Darren V. | Coffey, Alison J. | Scherer, Steven | McLay, Kirsten | Muzny, Donna | Platzer, Matthias | Howell, Gareth R. | Burrows, Christine | Bird, Christine P. | Frankish, Adam | Lovell, Frances L. | Howe, Kevin L. | Ashurst, Jennifer L. | Fulton, Robert S. | Sudbrak, Ralf | Wen, Gaiping | Jones, Matthew C. | Hurles, Matthew E. | Andrews, T. Daniel | Scott, Carol E. | Searle, Stephen | Ramser, Juliane | Whittaker, Adam | Deadman, Rebecca | Carter, Nigel P. | Hunt, Sarah E. | Chen, Rui | Cree, Andrew | Gunaratne, Preethi | Havlak, Paul | Hodgson, Anne | Metzker, Michael L. | Richards, Stephen | Scott, Graham | Steffen, David | Sodergren, Erica | Wheeler, David A. | Worley, Kim C. | Ainscough, Rachael | Ambrose, Kerrie D. | Ansari-Lari, M. Ali | Aradhya, Swaroop | Ashwell, Robert I. S. | Babbage, Anne K. | Bagguley, Claire L. | Ballabio, Andrea | Banerjee, Ruby | Barker, Gary E. | Barlow, Karen F. | Barrett, Ian P. | Bates, Karen N. | Beare, David M. | Beasley, Helen | Beasley, Oliver | Beck, Alfred | Bethel, Graeme | Blechschmidt, Karin | Brady, Nicola | Bray-Allen, Sarah | Bridgeman, Anne M. | Brown, Andrew J. | Brown, Mary J. | Bonnin, David | Bruford, Elspeth A. | Buhay, Christian | Burch, Paula | Burford, Deborah | Burgess, Joanne | Burrill, Wayne | Burton, John | Bye, Jackie M. | Carder, Carol | Carrel, Laura | Chako, Joseph | Chapman, Joanne C. | Chavez, Dean | Chen, Ellson | Chen, Guan | Chen, Yuan | Chen, Zhijian | Chinault, Craig | Ciccodicola, Alfredo | Clark, Sue Y. | Clarke, Graham | Clee, Chris M. | Clegg, Sheila | Clerc-Blankenburg, Kerstin | Clifford, Karen | Cobley, Vicky | Cole, Charlotte G. | Conquer, Jen S. | Corby, Nicole | Connor, Richard E. | David, Robert | Davies, Joy | Davis, Clay | Davis, John | Delgado, Oliver | DeShazo, Denise | Dhami, Pawandeep | Ding, Yan | Dinh, Huyen | Dodsworth, Steve | Draper, Heather | Dugan-Rocha, Shannon | Dunham, Andrew | Dunn, Matthew | Durbin, K. James | Dutta, Ireena | Eades, Tamsin | Ellwood, Matthew | Emery-Cohen, Alexandra | Errington, Helen | Evans, Kathryn L. | Faulkner, Louisa | Francis, Fiona | Frankland, John | Fraser, Audrey E. | Galgoczy, Petra | Gilbert, James | Gill, Rachel | Glöckner, Gernot | Gregory, Simon G. | Gribble, Susan | Griffiths, Coline | Grocock, Russell | Gu, Yanghong | Gwilliam, Rhian | Hamilton, Cerissa | Hart, Elizabeth A. | Hawes, Alicia | Heath, Paul D. | Heitmann, Katja | Hennig, Steffen | Hernandez, Judith | Hinzmann, Bernd | Ho, Sarah | Hoffs, Michael | Howden, Phillip J. | Huckle, Elizabeth J. | Hume, Jennifer | Hunt, Paul J. | Hunt, Adrienne R. | Isherwood, Judith | Jacob, Leni | Johnson, David | Jones, Sally | de Jong, Pieter J. | Joseph, Shirin S. | Keenan, Stephen | Kelly, Susan | Kershaw, Joanne K. | Khan, Ziad | Kioschis, Petra | Klages, Sven | Knights, Andrew J. | Kosiura, Anna | Kovar-Smith, Christie | Laird, Gavin K. | Langford, Cordelia | Lawlor, Stephanie | Leversha, Margaret | Lewis, Lora | Liu, Wen | Lloyd, Christine | Lloyd, David M. | Loulseged, Hermela | Loveland, Jane E. | Lovell, Jamieson D. | Lozado, Ryan | Lu, Jing | Lyne, Rachael | Ma, Jie | Maheshwari, Manjula | Matthews, Lucy H. | McDowall, Jennifer | McLaren, Stuart | McMurray, Amanda | Meidl, Patrick | Meitinger, Thomas | Milne, Sarah | Miner, George | Mistry, Shailesh L. | Morgan, Margaret | Morris, Sidney | Müller, Ines | Mullikin, James C. | Nguyen, Ngoc | Nordsiek, Gabriele | Nyakatura, Gerald | O’Dell, Christopher N. | Okwuonu, Geoffery | Palmer, Sophie | Pandian, Richard | Parker, David | Parrish, Julia | Pasternak, Shiran | Patel, Dina | Pearce, Alex V. | Pearson, Danita M. | Pelan, Sarah E. | Perez, Lesette | Porter, Keith M. | Ramsey, Yvonne | Reichwald, Kathrin | Rhodes, Susan | Ridler, Kerry A. | Schlessinger, David | Schueler, Mary G. | Sehra, Harminder K. | Shaw-Smith, Charles | Shen, Hua | Sheridan, Elizabeth M. | Shownkeen, Ratna | Skuce, Carl D. | Smith, Michelle L. | Sotheran, Elizabeth C. | Steingruber, Helen E. | Steward, Charles A. | Storey, Roy | Swann, R. Mark | Swarbreck, David | Tabor, Paul E. | Taudien, Stefan | Taylor, Tineace | Teague, Brian | Thomas, Karen | Thorpe, Andrea | Timms, Kirsten | Tracey, Alan | Trevanion, Steve | Tromans, Anthony C. | d’Urso, Michele | Verduzco, Daniel | Villasana, Donna | Waldron, Lenee | Wall, Melanie | Wang, Qiaoyan | Warren, James | Warry, Georgina L. | Wei, Xuehong | West, Anthony | Whitehead, Siobhan L. | Whiteley, Mathew N. | Wilkinson, Jane E. | Willey, David L. | Williams, Gabrielle | Williams, Leanne | Williamson, Angela | Williamson, Helen | Wilming, Laurens | Woodmansey, Rebecca L. | Wray, Paul W. | Yen, Jennifer | Zhang, Jingkun | Zhou, Jianling | Zoghbi, Huda | Zorilla, Sara | Buck, David | Reinhardt, Richard | Poustka, Annemarie | Rosenthal, André | Lehrach, Hans | Meindl, Alfons | Minx, Patrick J. | Hillier, LaDeana W. | Willard, Huntington F. | Wilson, Richard K. | Waterston, Robert H. | Rice, Catherine M. | Vaudin, Mark | Coulson, Alan | Nelson, David L. | Weinstock, George | Sulston, John E. | Durbin, Richard | Hubbard, Tim | Gibbs, Richard A. | Beck, Stephan | Rogers, Jane | Bentley, David R.
Nature  2005;434(7031):325-337.
The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.
doi:10.1038/nature03440
PMCID: PMC2665286  PMID: 15772651
10.  Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation 
The Journal of Experimental Medicine  2007;204(11):2603-2614.
The interleukin (IL)-1 family members IL-1α, -1β, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5−/− pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders.
doi:10.1084/jem.20070157
PMCID: PMC2118475  PMID: 17908936
11.  Subtle genetic changes enhance virulence of methicillin resistant and sensitive Staphylococcus aureus 
BMC Microbiology  2007;7:99.
Background
Community acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) increasingly causes disease worldwide. USA300 has emerged as the predominant clone causing superficial and invasive infections in children and adults in the USA. Epidemiological studies suggest that USA300 is more virulent than other CA-MRSA. The genetic determinants that render virulence and dominance to USA300 remain unclear.
Results
We sequenced the genomes of two pediatric USA300 isolates: one CA-MRSA and one CA-methicillin susceptible (MSSA), isolated at Texas Children's Hospital in Houston. DNA sequencing was performed by Sanger dideoxy whole genome shotgun (WGS) and 454 Life Sciences pyrosequencing strategies. The sequence of the USA300 MRSA strain was rigorously annotated. In USA300-MRSA 2658 chromosomal open reading frames were predicted and 3.1 and 27 kilobase (kb) plasmids were identified. USA300-MSSA contained a 20 kb plasmid with some homology to the 27 kb plasmid found in USA300-MRSA. Two regions found in US300-MRSA were absent in USA300-MSSA. One of these carried the arginine deiminase operon that appears to have been acquired from S. epidermidis. The USA300 sequence was aligned with other sequenced S. aureus genomes and regions unique to USA300 MRSA were identified.
Conclusion
USA300-MRSA is highly similar to other MRSA strains based on whole genome alignments and gene content, indicating that the differences in pathogenesis are due to subtle changes rather than to large-scale acquisition of virulence factor genes. The USA300 Houston isolate differs from another sequenced USA300 strain isolate, derived from a patient in San Francisco, in plasmid content and a number of sequence polymorphisms. Such differences will provide new insights into the evolution of pathogens.
doi:10.1186/1471-2180-7-99
PMCID: PMC2222628  PMID: 17986343
12.  Paradoxical DNA Repair and Peroxide Resistance Gene Conservation in Bacillus pumilus SAFR-032 
PLoS ONE  2007;2(9):e928.
Background
Bacillus spores are notoriously resistant to unfavorable conditions such as UV radiation, γ-radiation, H2O2, desiccation, chemical disinfection, or starvation. Bacillus pumilus SAFR-032 survives standard decontamination procedures of the Jet Propulsion Lab spacecraft assembly facility, and both spores and vegetative cells of this strain exhibit elevated resistance to UV radiation and H2O2 compared to other Bacillus species.
Principal Findings
The genome of B. pumilus SAFR-032 was sequenced and annotated. Lists of genes relevant to DNA repair and the oxidative stress response were generated and compared to B. subtilis and B. licheniformis. Differences in conservation of genes, gene order, and protein sequences are highlighted because they potentially explain the extreme resistance phenotype of B. pumilus. The B. pumilus genome includes genes not found in B. subtilis or B. licheniformis and conserved genes with sequence divergence, but paradoxically lacks several genes that function in UV or H2O2 resistance in other Bacillus species.
Significance
This study identifies several candidate genes for further research into UV and H2O2 resistance. These findings will help explain the resistance of B. pumilus and are applicable to understanding sterilization survival strategies of microbes.
doi:10.1371/journal.pone.0000928
PMCID: PMC1976550  PMID: 17895969
13.  RANK Overexpression in Transgenic Mice with Mouse Mammary Tumor Virus Promoter-Controlled RANK Increases Proliferation and Impairs Alveolar Differentiation in the Mammary Epithelia and Disrupts Lumen Formation in Cultured Epithelial Acini▿ †  
Molecular and Cellular Biology  2006;27(4):1442-1454.
RANK and RANKL, the key regulators of osteoclast differentiation and activation, also play an important role in the control of proliferation and differentiation of mammary epithelial cells during pregnancy. Here, we show that RANK protein expression is strictly regulated in a spatial and temporal manner during mammary gland development. RANK overexpression under the control of the mouse mammary tumor virus (MMTV) promoter in a transgenic mouse model results in increased mammary epithelial cell proliferation during pregnancy, impaired differentiation of lobulo-alveolar structures, decreased expression of the milk proteins β-casein and whey acidic protein, and deficient lactation. We also show that treatment of three-dimensional in vitro cultures of primary mammary cells from MMTV-RANK mice with RANKL results in increased proliferation and decreased apoptosis in the luminal area, resulting in bigger acini with filled lumens. Taken together, these results suggest that signaling through RANK not only promotes proliferation but also inhibits the terminal differentiation of mammary epithelial cells. Moreover, the increased proliferation and survival observed in a three-dimensional culture system suggests a role for aberrant RANK signaling during breast tumorigenesis.
doi:10.1128/MCB.01298-06
PMCID: PMC1800710  PMID: 17145767
14.  Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development 
Renfree, Marilyn B | Papenfuss, Anthony T | Deakin, Janine E | Lindsay, James | Heider, Thomas | Belov, Katherine | Rens, Willem | Waters, Paul D | Pharo, Elizabeth A | Shaw, Geoff | Wong, Emily SW | Lefèvre, Christophe M | Nicholas, Kevin R | Kuroki, Yoko | Wakefield, Matthew J | Zenger, Kyall R | Wang, Chenwei | Ferguson-Smith, Malcolm | Nicholas, Frank W | Hickford, Danielle | Yu, Hongshi | Short, Kirsty R | Siddle, Hannah V | Frankenberg, Stephen R | Chew, Keng Y | Menzies, Brandon R | Stringer, Jessica M | Suzuki, Shunsuke | Hore, Timothy A | Delbridge, Margaret L | Patel, Hardip | Mohammadi, Amir | Schneider, Nanette Y | Hu, Yanqiu | O'Hara, William | Al Nadaf, Shafagh | Wu, Chen | Feng, Zhi-Ping | Cocks, Benjamin G | Wang, Jianghui | Flicek, Paul | Searle, Stephen MJ | Fairley, Susan | Beal, Kathryn | Herrero, Javier | Carone, Dawn M | Suzuki, Yutaka | Sugano, Sumio | Toyoda, Atsushi | Sakaki, Yoshiyuki | Kondo, Shinji | Nishida, Yuichiro | Tatsumoto, Shoji | Mandiou, Ion | Hsu, Arthur | McColl, Kaighin A | Lansdell, Benjamin | Weinstock, George | Kuczek, Elizabeth | McGrath, Annette | Wilson, Peter | Men, Artem | Hazar-Rethinam, Mehlika | Hall, Allison | Davis, John | Wood, David | Williams, Sarah | Sundaravadanam, Yogi | Muzny, Donna M | Jhangiani, Shalini N | Lewis, Lora R | Morgan, Margaret B | Okwuonu, Geoffrey O | Ruiz, San J | Santibanez, Jireh | Nazareth, Lynne | Cree, Andrew | Fowler, Gerald | Kovar, Christie L | Dinh, Huyen H | Joshi, Vandita | Jing, Chyn | Lara, Fremiet | Thornton, Rebecca | Chen, Lei | Deng, Jixin | Liu, Yue | Shen, Joshua Y | Song, Xing-Zhi | Edson, Janette | Troon, Carmen | Thomas, Daniel | Stephens, Amber | Yapa, Lankesha | Levchenko, Tanya | Gibbs, Richard A | Cooper, Desmond W | Speed, Terence P | Fujiyama, Asao | M Graves, Jennifer A | O'Neill, Rachel J | Pask, Andrew J | Forrest, Susan M | Worley, Kim C
Genome Biology  2011;12(12):414.
doi:10.1186/gb-2011-12-12-414
PMCID: PMC3334613

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