Publications by authors named "Ze Cheng"

38 Publications

Global translation inhibition yields condition-dependent de-repression of ribosome biogenesis mRNAs.

Nucleic Acids Res 2019 06;47(10):5061-5073

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.

Ribosome biogenesis (RiBi) is an extremely energy intensive process that is critical for gene expression. It is thus highly regulated, including through the tightly coordinated expression of over 200 RiBi genes by positive and negative transcriptional regulators. We investigated RiBi regulation as cells initiated meiosis in budding yeast and noted early transcriptional activation of RiBi genes, followed by their apparent translational repression 1 hour (h) after stimulation to enter meiosis. Surprisingly, in the representative genes examined, measured translational repression depended on their promoters rather than mRNA regions. Further investigation revealed that the signature of this regulation in our data depended on pre-treating cells with the translation inhibitor, cycloheximide (CHX). This treatment, at 1 h in meiosis, but not earlier, rapidly resulted in accumulation of RiBi mRNAs that were not translated. This effect was also seen in with CHX pre-treatment of cells grown in media lacking amino acids. For NSR1, this effect depended on the -150 to -101 region of the promoter, as well as the RiBi transcriptional repressors Dot6 and Tod6. Condition-specific RiBi mRNA accumulation was also seen with translation inhibitors that are dissimilar from CHX, suggesting that this phenomenon might represent a feedback response to global translation inhibition.
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http://dx.doi.org/10.1093/nar/gkz231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547411PMC
June 2019

Translation and validation of the Tibetan confusion assessment method for the intensive care unit.

Chin Med J (Engl) 2019 May;132(10):1154-1158

Department of Neurosurgery, Tibet Autonomous Region People's Hospital, Lhasa, Tibet 850000, China.

Background: At present, there is no available delirium translated assessment method for 3.3 million Tibetans. This study aimed to provide a method for delirium assessment for Tibetan patients speaking this language by validating a translation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).

Methods: The study was conducted between July 2018 and November 2018. Patients were screened for delirium by a neurologist using the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). Patients were subsequently screened by two nurses using Tibetan translations of the CAM-ICU. With DSM-IV criterion as the reference standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the validity of the CAM-ICU criterion. Interrater reliability was determined by comparing the CAM-ICU ratings of nurse 1 vs. nurse 2 using the κ coefficient.

Results: Ninety-six patients were assessed independently by two nurses and one neurologist. According to DSM-IV standard, 42 out of 96 (43.8%) patients developed delirium. The sensitivities of Tibetan CAM-ICU were 90.5% for nurse 1 and 92.9% for nurse 2, respectively. Their specificities were 85.2% and 90.7%, respectively. The PPV were 82.6% for nurse 1 and 88.6% for nurse 2. Their NPV were 92.0% and 94.2%, respectively. The Tibetan CAM-ICU was done with good interrater reliability between nurse 1 and nurse 2 (κ = 0.91, P < 0.001).

Conclusion: The Tibetan CAM-ICU shows good validity and might be incorporated into clinical practice in Tibetan Intensive Care Units. CLINICAL TRAIL REGISTRY:: www.chictr.org.cn (No. ChiCTR1800018231).
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http://dx.doi.org/10.1097/CM9.0000000000000168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511416PMC
May 2019

Small and Large Ribosomal Subunit Deficiencies Lead to Distinct Gene Expression Signatures that Reflect Cellular Growth Rate.

Mol Cell 2019 01 29;73(1):36-47.e10. Epub 2018 Nov 29.

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

Levels of the ribosome, the conserved molecular machine that mediates translation, are tightly linked to cellular growth rate. In humans, ribosomopathies are diseases associated with cell-type-specific pathologies and reduced ribosomal protein (RP) levels. Because gene expression defects resulting from ribosome deficiency have not yet been experimentally defined, we systematically probed mRNA, translation, and protein signatures that were either unlinked from or linked to cellular growth rate in RP-deficient yeast cells. Ribosome deficiency was associated with altered translation of gene subclasses, and profound general secondary effects of RP loss on the spectrum of cellular mRNAs were seen. Among these effects, growth-defective 60S mutants increased synthesis of proteins involved in proteasome-mediated degradation, whereas 40S mutants accumulated mature 60S subunits and increased translation of ribosome biogenesis genes. These distinct signatures of protein synthesis suggest intriguing and currently mysterious differences in the cellular consequences of deficiency for small and large ribosomal subunits.
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http://dx.doi.org/10.1016/j.molcel.2018.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382079PMC
January 2019

Pervasive, Coordinated Protein-Level Changes Driven by Transcript Isoform Switching during Meiosis.

Cell 2018 02;172(5):910-923.e16

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address:

To better understand the gene regulatory mechanisms that program developmental processes, we carried out simultaneous genome-wide measurements of mRNA, translation, and protein through meiotic differentiation in budding yeast. Surprisingly, we observed that the levels of several hundred mRNAs are anti-correlated with their corresponding protein products. We show that rather than arising from canonical forms of gene regulatory control, the regulation of at least 380 such cases, or over 8% of all measured genes, involves temporally regulated switching between production of a canonical, translatable transcript and a 5' extended isoform that is not efficiently translated into protein. By this pervasive mechanism for the modulation of protein levels through a natural developmental program, a single transcription factor can coordinately activate and repress protein synthesis for distinct sets of genes. The distinction is not based on whether or not an mRNA is induced but rather on the type of transcript produced.
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http://dx.doi.org/10.1016/j.cell.2018.01.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826577PMC
February 2018

The auxin-inducible degradation (AID) system enables versatile conditional protein depletion in C. elegans.

Development 2015 Dec 9;142(24):4374-84. Epub 2015 Nov 9.

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3220, USA Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA Life Sciences Division, Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA California Institute for Quantitative Biosciences, Berkeley, CA 94720, USA

Experimental manipulation of protein abundance in living cells or organisms is an essential strategy for investigation of biological regulatory mechanisms. Whereas powerful techniques for protein expression have been developed in Caenorhabditis elegans, existing tools for conditional disruption of protein function are far more limited. To address this, we have adapted the auxin-inducible degradation (AID) system discovered in plants to enable conditional protein depletion in C. elegans. We report that expression of a modified Arabidopsis TIR1 F-box protein mediates robust auxin-dependent depletion of degron-tagged targets. We document the effectiveness of this system for depletion of nuclear and cytoplasmic proteins in diverse somatic and germline tissues throughout development. Target proteins were depleted in as little as 20-30 min, and their expression could be re-established upon auxin removal. We have engineered strains expressing TIR1 under the control of various promoter and 3' UTR sequences to drive tissue-specific or temporally regulated expression. The degron tag can be efficiently introduced by CRISPR/Cas9-based genome editing. We have harnessed this system to explore the roles of dynamically expressed nuclear hormone receptors in molting, and to analyze meiosis-specific roles for proteins required for germ line proliferation. Together, our results demonstrate that the AID system provides a powerful new tool for spatiotemporal regulation and analysis of protein function in a metazoan model organism.
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http://dx.doi.org/10.1242/dev.129635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689222PMC
December 2015

Enhanced Electrocatalytic Activity by RGO/MWCNTs/NiO Counter Electrode for Dye-sensitized Solar Cells.

Nanomicro Lett 2015 17;7(3):298-306. Epub 2015 May 17.

1Center for Nanoscale Characterization & Devices, Wuhan National Laboratory for Optoelectronics, School of Physics, Huazhong University of Science and Technology, Wuhan, 430074 People's Republic of China.

We applied the reduced graphene oxide/multi-walled carbon nanotubes/nickel oxide (RGO/MWCNTs/NiO) nanocomposite as the counter electrode (CE) in dye-sensitized solar cells (DSSCs) on fluorine-doped tin oxide substrates by blade doctor method. Power conversion efficiency (PCE) of 8.13 % was achieved for this DSSCs device, which is higher than that of DSSCs devices using NiO, RGO, and RGO/NiO-CE (PCE = 2.71 %, PCE = 6.77 % and PCE = 7.63 %). Also, the fill factor of the DSSCs devices using the RGO/MWCNTs/NiO-CE was better than that of other CEs. The electron transfer measurement of cyclic voltammetry and electrochemical impedance spectroscopy showed that RGO/MWCNTs/NiO film could provide fast electron transfer between the CE and the electrolyte, and high electrocatalytic activity for the reduction of triiodide in a CE based on RGO/MWCNTs/NiO in a DSSC.
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http://dx.doi.org/10.1007/s40820-015-0043-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223904PMC
May 2015

Conditional targeted genome editing using somatically expressed TALENs in C. elegans.

Nat Biotechnol 2013 Oct 18;31(10):934-7. Epub 2013 Aug 18.

1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, China. [2] School of Life Sciences, Peking University, Beijing, China. [3].

We have developed a method for the generation of conditional knockouts in Caenorhabditis elegans by expressing transcription activator-like effector nucleases (TALENs) in somatic cells. Using germline transformation with plasmids encoding TALENs under the control of an inducible or tissue-specific promoter, we observed effective gene modifications and resulting phenotypes in specific developmental stages and tissues. We further used this method to bypass the embryonic requirement of cor-1, which encodes the homolog of human severe combined immunodeficiency (SCID) protein coronin, and we determined its essential role in cell migration in larval Q-cell lineages. Our results show that TALENs expressed in the somatic cells of model organisms provide a versatile tool for functional genomics.
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http://dx.doi.org/10.1038/nbt.2674DOI Listing
October 2013

Developmental stage-dependent transcriptional regulatory pathways control neuroblast lineage progression.

Development 2013 Sep 14;140(18):3838-47. Epub 2013 Aug 14.

National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.

Neuroblasts generate neurons with different functions by asymmetric cell division, cell cycle exit and differentiation. The underlying transcriptional regulatory pathways remain elusive. Here, we performed genetic screens in C. elegans and identified three evolutionarily conserved transcription factors (TFs) essential for Q neuroblast lineage progression. Through live cell imaging and genetic analysis, we showed that the storkhead TF HAM-1 regulates spindle positioning and myosin polarization during asymmetric cell division and that the PAR-1-like kinase PIG-1 is a transcriptional regulatory target of HAM-1. The TEAD TF EGL-44, in a physical association with the zinc-finger TF EGL-46, instructs cell cycle exit after the terminal division. Finally, the Sox domain TF EGL-13 is necessary and sufficient to establish the correct neuronal fate. Genetic analysis further demonstrated that HAM-1, EGL-44/EGL-46 and EGL-13 form three transcriptional regulatory pathways. We have thus identified TFs that function at distinct developmental stages to ensure appropriate neuroblast lineage progression and suggest that their vertebrate homologs might similarly regulate neural development.
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http://dx.doi.org/10.1242/dev.098723DOI Listing
September 2013

Development of a new LC-MS/MS based enzyme activity assay for recombinant urate oxidase in plasma and its application to pharmacokinetics in human.

J Pharm Biomed Anal 2013 Jul-Aug;81-82:8-12. Epub 2013 Mar 29.

Research Institute of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Central South University, 410013 Changsha, Hunan, PR China.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of recombinant urate oxidase in human plasma. This assay was based on the determination of enzyme reaction product, (15)N-allantoin, and phenacetin was used as an internal standard (IS). Separation was achieved on a C18 column by the mobile phase of 30% water (containing 0.5% formic acid) and 70% methanol. Quantification was done using multiple reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z 161 → m/z 118 for (15)N-allantoin and m/z 180 → m/z 110.1 for IS at positive ionization mode. The calibration curve was established over the range of 2.077-42.06 U/l and the correlation coefficient was larger than 0.99. The intra-day and inter-day relative standard deviations were less than 10.6%. Accuracy determined at three concentrations ranged between 98.6% and 109.2%. This method was successfully applied to a pharmacokinetic study of intravenous recombinant urate oxidase produced from Escherichia coli in Chinese healthy volunteers.
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http://dx.doi.org/10.1016/j.jpba.2013.03.015DOI Listing
December 2013

Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.

Am J Hum Genet 2013 Feb 31;92(2):221-37. Epub 2013 Jan 31.

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.

Rare copy-number variants (CNVs) have been implicated in autism and intellectual disability. These variants are large and affect many genes but lack clear specificity toward autism as opposed to developmental-delay phenotypes. We exploited the repeat architecture of the genome to target segmental duplication-mediated rearrangement hotspots (n = 120, median size 1.78 Mbp, range 240 kbp to 13 Mbp) and smaller hotspots flanked by repetitive sequence (n = 1,247, median size 79 kbp, range 3-96 kbp) in 2,588 autistic individuals from simplex and multiplex families and in 580 controls. Our analysis identified several recurrent large hotspot events, including association with 1q21 duplications, which are more likely to be identified in individuals with autism than in those with developmental delay (p = 0.01; OR = 2.7). Within larger hotspots, we also identified smaller atypical CNVs that implicated CHD1L and ACACA for the 1q21 and 17q12 deletions, respectively. Our analysis, however, suggested no overall increase in the burden of smaller hotspots in autistic individuals as compared to controls. By focusing on gene-disruptive events, we identified recurrent CNVs, including DPP10, PLCB1, TRPM1, NRXN1, FHIT, and HYDIN, that are enriched in autism. We found that as the size of deletions increases, nonverbal IQ significantly decreases, but there is no impact on autism severity; and as the size of duplications increases, autism severity significantly increases but nonverbal IQ is not affected. The absence of an increased burden of smaller CNVs in individuals with autism and the failure of most large hotspots to refine to single genes is consistent with a model where imbalance of multiple genes contributes to a disease state.
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http://dx.doi.org/10.1016/j.ajhg.2012.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567267PMC
February 2013

Apoptotic regulators promote cytokinetic midbody degradation in C. elegans.

J Cell Biol 2012 Dec 17;199(7):1047-55. Epub 2012 Dec 17.

National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.

Cell death genes are essential for apoptosis and other cellular events, but their nonapoptotic functions are not well understood. The midbody is an important cytokinetic structure required for daughter cell abscission, but its fate after cell division remains elusive in metazoans. In this paper, we show through live-imaging analysis that midbodies generated by Q cell divisions in Caenorhabditis elegans were released to the extracellular space after abscission and subsequently internalized and degraded by the phagocyte that digests apoptotic Q cell corpses. We further show that midbody degradation is defective in apoptotic cell engulfment mutants. Externalized phosphatidylserine (PS), an engulfment signal for corpse phagocytosis, exists on the outer surface of the midbody, and inhibiting PS signaling delayed midbody clearance. Thus, our findings uncover a novel function of cell death genes in midbody internalization and degradation after cell division.
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http://dx.doi.org/10.1083/jcb.201209050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529525PMC
December 2012

Thermodynamic properties of a Kerr nonlinear blackbody.

Authors:
Ze Cheng

Phys Rev E Stat Nonlin Soft Matter Phys 2012 Nov 5;86(5 Pt 1):051102. Epub 2012 Nov 5.

School of Physics, Huazhong University of Science and Technology, Wuhan 430074, People's Republic of China.

Within the framework of quantum field theory, we present the superfluid state of photons in a blackbody whose interior is filled by a Kerr nonlinear crystal. The thermodynamic properties of a Kerr nonlinear blackbody are investigated. At the transition temperature, the Gibbs free energy of the two phases is continuous but the entropy density of the two phases is discontinuous. Hence, there is a jump in the entropy density and this leads to a latent heat density. The photon system undergoes a first-order phase transition from the normal to the superfluid state. The transition temperature is characteristic of a concrete crystal. The entropy density and specific heat capacity are monotonically increasing functions of the temperature but are monotonically decreasing functions of the Kerr nonlinear coefficient.
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http://dx.doi.org/10.1103/PhysRevE.86.051102DOI Listing
November 2012

Comparative and demographic analysis of orang-utan genomes.

Authors:
Devin P Locke LaDeana W Hillier Wesley C Warren Kim C Worley Lynne V Nazareth Donna M Muzny Shiaw-Pyng Yang Zhengyuan Wang Asif T Chinwalla Pat Minx Makedonka Mitreva Lisa Cook Kim D Delehaunty Catrina Fronick Heather Schmidt Lucinda A Fulton Robert S Fulton Joanne O Nelson Vincent Magrini Craig Pohl Tina A Graves Chris Markovic Andy Cree Huyen H Dinh Jennifer Hume Christie L Kovar Gerald R Fowler Gerton Lunter Stephen Meader Andreas Heger Chris P Ponting Tomas Marques-Bonet Can Alkan Lin Chen Ze Cheng Jeffrey M Kidd Evan E Eichler Simon White Stephen Searle Albert J Vilella Yuan Chen Paul Flicek Jian Ma Brian Raney Bernard Suh Richard Burhans Javier Herrero David Haussler Rui Faria Olga Fernando Fleur Darré Domènec Farré Elodie Gazave Meritxell Oliva Arcadi Navarro Roberta Roberto Oronzo Capozzi Nicoletta Archidiacono Giuliano Della Valle Stefania Purgato Mariano Rocchi Miriam K Konkel Jerilyn A Walker Brygg Ullmer Mark A Batzer Arian F A Smit Robert Hubley Claudio Casola Daniel R Schrider Matthew W Hahn Victor Quesada Xose S Puente Gonzalo R Ordoñez Carlos López-Otín Tomas Vinar Brona Brejova Aakrosh Ratan Robert S Harris Webb Miller Carolin Kosiol Heather A Lawson Vikas Taliwal André L Martins Adam Siepel Arindam Roychoudhury Xin Ma Jeremiah Degenhardt Carlos D Bustamante Ryan N Gutenkunst Thomas Mailund Julien Y Dutheil Asger Hobolth Mikkel H Schierup Oliver A Ryder Yuko Yoshinaga Pieter J de Jong George M Weinstock Jeffrey Rogers Elaine R Mardis Richard A Gibbs Richard K Wilson

Nature 2011 Jan;469(7331):529-33

The Genome Center at Washington University, Washington University School of Medicine, 4444 Forest Park Avenue, Saint Louis, Missouri 63108, USA.

'Orang-utan' is derived from a Malay term meaning 'man of the forest' and aptly describes the southeast Asian great apes native to Sumatra and Borneo. The orang-utan 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 orang-utan draft genome assembly and short read sequence data from five Sumatran and five Bornean orang-utan genomes. Our analyses reveal that, compared to other primates, the orang-utan genome has many unique features. Structural evolution of the orang-utan 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 a primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orang-utan genome structure. Orang-utans have extremely low energy usage for a eutherian mammal, 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, 400,000 years ago, is more recent than most previous studies and underscores the complexity of the orang-utan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (N(e)) expanded exponentially relative to the ancestral N(e) after the split, while Bornean N(e) 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.
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http://dx.doi.org/10.1038/nature09687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060778PMC
January 2011

The genome of a songbird.

Nature 2010 Apr;464(7289):757-62

The Genome Center, Washington University School of Medicine, Campus Box 8501, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA.

The zebra finch is an important model organism in several fields with unique relevance to human neuroscience. Like other songbirds, the zebra finch communicates through learned vocalizations, an ability otherwise documented only in humans and a few other animals and lacking in the chicken-the only bird with a sequenced genome until now. Here we present a structural, functional and comparative analysis of the genome sequence of the zebra finch (Taeniopygia guttata), which is a songbird belonging to the large avian order Passeriformes. We find that the overall structures of the genomes are similar in zebra finch and chicken, but they differ in many intrachromosomal rearrangements, lineage-specific gene family expansions, the number of long-terminal-repeat-based retrotransposons, and mechanisms of sex chromosome dosage compensation. We show that song behaviour engages gene regulatory networks in the zebra finch brain, altering the expression of long non-coding RNAs, microRNAs, transcription factors and their targets. We also show evidence for rapid molecular evolution in the songbird lineage of genes that are regulated during song experience. These results indicate an active involvement of the genome in neural processes underlying vocal communication and identify potential genetic substrates for the evolution and regulation of this behaviour.
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http://dx.doi.org/10.1038/nature08819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187626PMC
April 2010

Analysis of recent segmental duplications in the bovine genome.

BMC Genomics 2009 Dec 1;10:571. Epub 2009 Dec 1.

USDA, ARS, ANRI, Bovine Functional Genomics Laboratory, Beltsville, Maryland 20705, USA.

Background: Duplicated sequences are an important source of gene innovation and structural variation within mammalian genomes. We performed the first systematic and genome-wide analysis of segmental duplications in the modern domesticated cattle (Bos taurus). Using two distinct computational analyses, we estimated that 3.1% (94.4 Mb) of the bovine genome consists of recently duplicated sequences (>or= 1 kb in length, >or= 90% sequence identity). Similar to other mammalian draft assemblies, almost half (47% of 94.4 Mb) of these sequences have not been assigned to cattle chromosomes.

Results: In this study, we provide the first experimental validation large duplications and briefly compared their distribution on two independent bovine genome assemblies using fluorescent in situ hybridization (FISH). Our analyses suggest that the (75-90%) of segmental duplications are organized into local tandem duplication clusters. Along with rodents and carnivores, these results now confidently establish tandem duplications as the most likely mammalian archetypical organization, in contrast to humans and great ape species which show a preponderance of interspersed duplications. A cross-species survey of duplicated genes and gene families indicated that duplication, positive selection and gene conversion have shaped primates, rodents, carnivores and ruminants to different degrees for their speciation and adaptation. We identified that bovine segmental duplications corresponding to genes are significantly enriched for specific biological functions such as immunity, digestion, lactation and reproduction.

Conclusion: Our results suggest that in most mammalian lineages segmental duplications are organized in a tandem configuration. Segmental duplications remain problematic for genome and assembly and we highlight genic regions that require higher quality sequence characterization. This study provides insights into mammalian genome evolution and generates a valuable resource for cattle genomics research.
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http://dx.doi.org/10.1186/1471-2164-10-571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796684PMC
December 2009

Lineage-specific biology revealed by a finished genome assembly of the mouse.

PLoS Biol 2009 May 26;7(5):e1000112. Epub 2009 May 26.

National Center for Biotechnology Information, Bethesda, Maryland, United States of America.

The mouse (Mus musculus) is the premier animal model for understanding human disease and development. Here we show that a comprehensive understanding of mouse biology is only possible with the availability of a finished, high-quality genome assembly. The finished clone-based assembly of the mouse strain C57BL/6J reported here has over 175,000 fewer gaps and over 139 Mb more of novel sequence, compared with the earlier MGSCv3 draft genome assembly. In a comprehensive analysis of this revised genome sequence, we are now able to define 20,210 protein-coding genes, over a thousand more than predicted in the human genome (19,042 genes). In addition, we identified 439 long, non-protein-coding RNAs with evidence for transcribed orthologs in human. We analyzed the complex and repetitive landscape of 267 Mb of sequence that was missing or misassembled in the previously published assembly, and we provide insights into the reasons for its resistance to sequencing and assembly by whole-genome shotgun approaches. Duplicated regions within newly assembled sequence tend to be of more recent ancestry than duplicates in the published draft, correcting our initial understanding of recent evolution on the mouse lineage. These duplicates appear to be largely composed of sequence regions containing transposable elements and duplicated protein-coding genes; of these, some may be fixed in the mouse population, but at least 40% of segmentally duplicated sequences are copy number variable even among laboratory mouse strains. Mouse lineage-specific regions contain 3,767 genes drawn mainly from rapidly-changing gene families associated with reproductive functions. The finished mouse genome assembly, therefore, greatly improves our understanding of rodent-specific biology and allows the delineation of ancestral biological functions that are shared with human from derived functions that are not.
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http://dx.doi.org/10.1371/journal.pbio.1000112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680341PMC
May 2009

The genome sequence of taurine cattle: a window to ruminant biology and evolution.

Authors:
Christine G Elsik Ross L Tellam Kim C Worley Richard A Gibbs Donna M Muzny George M Weinstock David L Adelson Evan E Eichler Laura Elnitski Roderic Guigó Debora L Hamernik Steve M Kappes Harris A Lewin David J Lynn Frank W Nicholas Alexandre Reymond Monique Rijnkels Loren C Skow Evgeny M Zdobnov Lawrence Schook James Womack Tyler Alioto Stylianos E Antonarakis Alex Astashyn Charles E Chapple Hsiu-Chuan Chen Jacqueline Chrast Francisco Câmara Olga Ermolaeva Charlotte N Henrichsen Wratko Hlavina Yuri Kapustin Boris Kiryutin Paul Kitts Felix Kokocinski Melissa Landrum Donna Maglott Kim Pruitt Victor Sapojnikov Stephen M Searle Victor Solovyev Alexandre Souvorov Catherine Ucla Carine Wyss Juan M Anzola Daniel Gerlach Eran Elhaik Dan Graur Justin T Reese Robert C Edgar John C McEwan Gemma M Payne Joy M Raison Thomas Junier Evgenia V Kriventseva Eduardo Eyras Mireya Plass Ravikiran Donthu Denis M Larkin James Reecy Mary Q Yang Lin Chen Ze Cheng Carol G Chitko-McKown George E Liu Lakshmi K Matukumalli Jiuzhou Song Bin Zhu Daniel G Bradley Fiona S L Brinkman Lilian P L Lau Matthew D Whiteside Angela Walker Thomas T Wheeler Theresa Casey J Bruce German Danielle G Lemay Nauman J Maqbool Adrian J Molenaar Seongwon Seo Paul Stothard Cynthia L Baldwin Rebecca Baxter Candice L Brinkmeyer-Langford Wendy C Brown Christopher P Childers Timothy Connelley Shirley A Ellis Krista Fritz Elizabeth J Glass Carolyn T A Herzig Antti Iivanainen Kevin K Lahmers Anna K Bennett C Michael Dickens James G R Gilbert Darren E Hagen Hanni Salih Jan Aerts Alexandre R Caetano Brian Dalrymple Jose Fernando Garcia Clare A Gill Stefan G Hiendleder Erdogan Memili Diane Spurlock John L Williams Lee Alexander Michael J Brownstein Leluo Guan Robert A Holt Steven J M Jones Marco A Marra Richard Moore Stephen S Moore Andy Roberts Masaaki Taniguchi Richard C Waterman Joseph Chacko Mimi M Chandrabose Andy Cree Marvin Diep Dao Huyen H Dinh Ramatu Ayiesha Gabisi Sandra Hines Jennifer Hume Shalini N Jhangiani Vandita Joshi Christie L Kovar Lora R Lewis Yih-Shin Liu John Lopez Margaret B Morgan Ngoc Bich Nguyen Geoffrey O Okwuonu San Juana Ruiz Jireh Santibanez Rita A Wright Christian Buhay Yan Ding Shannon Dugan-Rocha Judith Herdandez Michael Holder Aniko Sabo Amy Egan Jason Goodell Katarzyna Wilczek-Boney Gerald R Fowler Matthew Edward Hitchens Ryan J Lozado Charles Moen David Steffen James T Warren Jingkun Zhang Readman Chiu Jacqueline E Schein K James Durbin Paul Havlak Huaiyang Jiang Yue Liu Xiang Qin Yanru Ren Yufeng Shen Henry Song Stephanie Nicole Bell Clay Davis Angela Jolivet Johnson Sandra Lee Lynne V Nazareth Bella Mayurkumar Patel Ling-Ling Pu Selina Vattathil Rex Lee Williams Stacey Curry Cerissa Hamilton Erica Sodergren David A Wheeler Wes Barris Gary L Bennett André Eggen Ronnie D Green Gregory P Harhay Matthew Hobbs Oliver Jann John W Keele Matthew P Kent Sigbjørn Lien Stephanie D McKay Sean McWilliam Abhirami Ratnakumar Robert D Schnabel Timothy Smith Warren M Snelling Tad S Sonstegard Roger T Stone Yoshikazu Sugimoto Akiko Takasuga Jeremy F Taylor Curtis P Van Tassell Michael D Macneil Antonio R R Abatepaulo Colette A Abbey Virpi Ahola Iassudara G Almeida Ariel F Amadio Elen Anatriello Suria M Bahadue Fernando H Biase Clayton R Boldt Jeffery A Carroll Wanessa A Carvalho Eliane P Cervelatti Elsa Chacko Jennifer E Chapin Ye Cheng Jungwoo Choi Adam J Colley Tatiana A de Campos Marcos De Donato Isabel K F de Miranda Santos Carlo J F de Oliveira Heather Deobald Eve Devinoy Kaitlin E Donohue Peter Dovc Annett Eberlein Carolyn J Fitzsimmons Alessandra M Franzin Gustavo R Garcia Sem Genini Cody J Gladney Jason R Grant Marion L Greaser Jonathan A Green Darryl L Hadsell Hatam A Hakimov Rob Halgren Jennifer L Harrow Elizabeth A Hart Nicola Hastings Marta Hernandez Zhi-Liang Hu Aaron Ingham Terhi Iso-Touru Catherine Jamis Kirsty Jensen Dimos Kapetis Tovah Kerr Sari S Khalil Hasan Khatib Davood Kolbehdari Charu G Kumar Dinesh Kumar Richard Leach Justin C-M Lee Changxi Li Krystin M Logan Roberto Malinverni Elisa Marques William F Martin Natalia F Martins Sandra R Maruyama Raffaele Mazza Kim L McLean Juan F Medrano Barbara T Moreno Daniela D Moré Carl T Muntean Hari P Nandakumar Marcelo F G Nogueira Ingrid Olsaker Sameer D Pant Francesca Panzitta Rosemeire C P Pastor Mario A Poli Nathan Poslusny Satyanarayana Rachagani Shoba Ranganathan Andrej Razpet Penny K Riggs Gonzalo Rincon Nelida Rodriguez-Osorio Sandra L Rodriguez-Zas Natasha E Romero Anne Rosenwald Lillian Sando Sheila M Schmutz Libing Shen Laura Sherman Bruce R Southey Ylva Strandberg Lutzow Jonathan V Sweedler Imke Tammen Bhanu Prakash V L Telugu Jennifer M Urbanski Yuri T Utsunomiya Chris P Verschoor Ashley J Waardenberg Zhiquan Wang Robert Ward Rosemarie Weikard Thomas H Welsh Stephen N White Laurens G Wilming Kris R Wunderlich Jianqi Yang Feng-Qi Zhao

Science 2009 Apr;324(5926):522-8

To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
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http://dx.doi.org/10.1126/science.1169588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943200PMC
April 2009

A burst of segmental duplications in the genome of the African great ape ancestor.

Nature 2009 Feb;457(7231):877-81

Department of Genome Sciences, University of Washington and the Howard Hughes Medical Institute, Seattle, Washington 98195, USA.

It is generally accepted that the extent of phenotypic change between human and great apes is dissonant with the rate of molecular change. Between these two groups, proteins are virtually identical, cytogenetically there are few rearrangements that distinguish ape-human chromosomes, and rates of single-base-pair change and retrotransposon activity have slowed particularly within hominid lineages when compared to rodents or monkeys. Studies of gene family evolution indicate that gene loss and gain are enriched within the primate lineage. Here, we perform a systematic analysis of duplication content of four primate genomes (macaque, orang-utan, chimpanzee and human) in an effort to understand the pattern and rates of genomic duplication during hominid evolution. We find that the ancestral branch leading to human and African great apes shows the most significant increase in duplication activity both in terms of base pairs and in terms of events. This duplication acceleration within the ancestral species is significant when compared to lineage-specific rate estimates even after accounting for copy-number polymorphism and homoplasy. We discover striking examples of recurrent and independent gene-containing duplications within the gorilla and chimpanzee that are absent in the human lineage. Our results suggest that the evolutionary properties of copy-number mutation differ significantly from other forms of genetic mutation and, in contrast to the hominid slowdown of single-base-pair mutations, there has been a genomic burst of duplication activity at this period during human evolution.
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http://dx.doi.org/10.1038/nature07744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751663PMC
February 2009

Evolutionary toggling of the MAPT 17q21.31 inversion region.

Nat Genet 2008 Sep;40(9):1076-83

Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

Using comparative sequencing approaches, we investigated the evolutionary history of the European-enriched 17q21.31 MAPT inversion polymorphism. We present a detailed, BAC-based sequence assembly of the inverted human H2 haplotype and compare it to the sequence structure and genetic variation of the corresponding 1.5-Mb region for the noninverted H1 human haplotype and that of chimpanzee and orangutan. We found that inversion of the MAPT region is similarly polymorphic in other great ape species, and we present evidence that the inversions occurred independently in chimpanzees and humans. In humans, the inversion breakpoints correspond to core duplications with the LRRC37 gene family. Our analysis favors the H2 configuration and sequence haplotype as the likely great ape and human ancestral state, with inversion recurrences during primate evolution. We show that the H2 architecture has evolved more extensive sequence homology, perhaps explaining its tendency to undergo microdeletion associated with mental retardation in European populations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684794PMC
http://dx.doi.org/10.1038/ng.193DOI Listing
September 2008

The genomic architecture of segmental duplications and associated copy number variants in dogs.

Genome Res 2009 Mar 7;19(3):491-9. Epub 2009 Jan 7.

Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

Structural variation is an important and abundant source of genetic and phenotypic variation. Here we describe the first systematic and genome-wide analysis of segmental duplications and associated copy number variants (CNVs) in the modern domesticated dog, Canis familiaris, which exhibits considerable morphological, physiological, and behavioral variation. Through computational analyses of the publicly available canine reference sequence, we estimate that segmental duplications comprise approximately 4.21% of the canine genome. Segmental duplications overlap 841 genes and are significantly enriched for specific biological functions such as immunity and defense and KRAB box transcription factors. We designed high-density tiling arrays spanning all predicted segmental duplications and performed aCGH in a panel of 17 breeds and a gray wolf. In total, we identified 3583 CNVs, approximately 68% of which were found in two or more samples that map to 678 unique regions. CNVs span 429 genes that are involved in a wide variety of biological processes such as olfaction, immunity, and gene regulation. Our results provide insight into mechanisms of canine genome evolution and generate a valuable resource for future evolutionary and phenotypic studies.
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http://dx.doi.org/10.1101/gr.084715.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661811PMC
March 2009

Haplotype sorting using human fosmid clone end-sequence pairs.

Genome Res 2008 Dec 3;18(12):2016-23. Epub 2008 Oct 3.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.

An important goal of human genetics and genomics is to understand the complete spectrum of genetic variation across a specific human haplotype. By combining information from a dense SNP map with fosmid end-sequence pairs (ESPs) aligned to the human genome reference sequence, we have developed a simple method to resolve human haplotypes using a previously developed clone resource. By partitioning ESPs into either haplotype, we have generated a haplotype-specific clone map for eight diploid genomes (four Yoruba African and four non-African samples). On average, 59% of each haploid genome is covered by haplotype-assigned clones with an N50 length of 110 kbp. By comparing this clone-based haplotype map against HapMap phased data sets, we estimate an error rate of 0.71% when trio information is available and 6.6% in its absence. We present these data in the form of an interactive browser that allows clones corresponding to specific haplotypes to be recovered and sequenced within these eight human genomes. As an example, we sequenced 165 fosmid clone inserts to generate 6.8 Mbp of sequenced haplotypes, and demonstrate its utility in uncovering phase-switching errors and for the discovery of novel SNPs especially in Asian and African samples. We discuss the potential application of this resource in understanding the pattern of genetic variation in complex regions of the genome that may not be adequately resolved by next-generation sequencing technology or SNP haplotype imputation.
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http://dx.doi.org/10.1101/gr.081786.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593576PMC
December 2008

The genomic distribution of intraspecific and interspecific sequence divergence of human segmental duplications relative to human/chimpanzee chromosomal rearrangements.

BMC Genomics 2008 Aug 12;9:384. Epub 2008 Aug 12.

Unitat de Biologia Evolutiva Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.

Background: It has been suggested that chromosomal rearrangements harbor the molecular footprint of the biological phenomena which they induce, in the form, for instance, of changes in the sequence divergence rates of linked genes. So far, all the studies of these potential associations have focused on the relationship between structural changes and the rates of evolution of single-copy DNA and have tried to exclude segmental duplications (SDs). This is paradoxical, since SDs are one of the primary forces driving the evolution of structure and function in our genomes and have been linked not only with novel genes acquiring new functions, but also with overall higher DNA sequence divergence and major chromosomal rearrangements.

Results: Here we take the opposite view and focus on SDs. We analyze several of the features of SDs, including the rates of intraspecific divergence between paralogous copies of human SDs and of interspecific divergence between human SDs and chimpanzee DNA. We study how divergence measures relate to chromosomal rearrangements, while considering other factors that affect evolutionary rates in single copy DNA.

Conclusion: We find that interspecific SD divergence behaves similarly to divergence of single-copy DNA. In contrast, old and recent paralogous copies of SDs do present different patterns of intraspecific divergence. Also, we show that some relatively recent SDs accumulate in regions that carry inversions in sister lineages.
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http://dx.doi.org/10.1186/1471-2164-9-384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542386PMC
August 2008

Mouse segmental duplication and copy number variation.

Nat Genet 2008 Jul 22;40(7):909-14. Epub 2008 May 22.

Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, USA.

Detailed analyses of the clone-based genome assembly reveal that the recent duplication content of mouse (4.94%) is now comparable to that of human (5.5%), in contrast to previous estimates from the whole-genome shotgun sequence assembly. However, the architecture of mouse and human genomes differs markedly: most mouse duplications are organized into discrete clusters of tandem duplications that show depletion of genes and transcripts and enrichment of long interspersed nuclear element (LINE) and long terminal repeat (LTR) retroposons. We assessed copy number variation of the C57BL/6J duplicated regions within 15 mouse strains previously used for genetic association studies, sequencing and the Mouse Phenome Project. We determined that over 60% of these base pairs are polymorphic among the strains (on average, there was 20 Mb of copy-number-variable DNA between different mouse strains). Our data suggest that different mouse strains show comparable, if not greater, copy number polymorphism when compared to human; however, such variation is more locally restricted. We show large and complex patterns of interstrain copy number variation restricted to large gene families associated with spermatogenesis, pregnancy, viviparity, pheromone signaling and immune response.
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http://dx.doi.org/10.1038/ng.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574762PMC
July 2008

Genome analysis of the platypus reveals unique signatures of evolution.

Authors:
Wesley C Warren LaDeana W Hillier Jennifer A Marshall Graves Ewan Birney Chris P Ponting Frank Grützner Katherine Belov Webb Miller Laura Clarke Asif T Chinwalla Shiaw-Pyng Yang Andreas Heger Devin P Locke Pat Miethke Paul D Waters Frédéric Veyrunes Lucinda Fulton Bob Fulton Tina Graves John Wallis Xose S Puente Carlos López-Otín Gonzalo R Ordóñez Evan E Eichler Lin Chen Ze Cheng Janine E Deakin Amber Alsop Katherine Thompson Patrick Kirby Anthony T Papenfuss Matthew J Wakefield Tsviya Olender Doron Lancet Gavin A Huttley Arian F A Smit Andrew Pask Peter Temple-Smith Mark A Batzer Jerilyn A Walker Miriam K Konkel Robert S Harris Camilla M Whittington Emily S W Wong Neil J Gemmell Emmanuel Buschiazzo Iris M Vargas Jentzsch Angelika Merkel Juergen Schmitz Anja Zemann Gennady Churakov Jan Ole Kriegs Juergen Brosius Elizabeth P Murchison Ravi Sachidanandam Carly Smith Gregory J Hannon Enkhjargal Tsend-Ayush Daniel McMillan Rosalind Attenborough Willem Rens Malcolm Ferguson-Smith Christophe M Lefèvre Julie A Sharp Kevin R Nicholas David A Ray Michael Kube Richard Reinhardt Thomas H Pringle James Taylor Russell C Jones Brett Nixon Jean-Louis Dacheux Hitoshi Niwa Yoko Sekita Xiaoqiu Huang Alexander Stark Pouya Kheradpour Manolis Kellis Paul Flicek Yuan Chen Caleb Webber Ross Hardison Joanne Nelson Kym Hallsworth-Pepin Kim Delehaunty Chris Markovic Pat Minx Yucheng Feng Colin Kremitzki Makedonka Mitreva Jarret Glasscock Todd Wylie Patricia Wohldmann Prathapan Thiru Michael N Nhan Craig S Pohl Scott M Smith Shunfeng Hou Mikhail Nefedov Pieter J de Jong Marilyn B Renfree Elaine R Mardis Richard K Wilson

Nature 2008 May;453(7192):175-83

Genome Sequencing Center, Washington University School of Medicine, Campus Box 8501, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA.

We present a draft genome sequence of the platypus, Ornithorhynchus anatinus. This monotreme exhibits a fascinating combination of reptilian and mammalian characters. For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles. Analysis of the first monotreme genome aligned these features with genetic innovations. We find that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology. Expansions of protein, non-protein-coding RNA and microRNA families, as well as repeat elements, are identified. Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation.
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http://dx.doi.org/10.1038/nature06936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803040PMC
May 2008

Mapping and sequencing of structural variation from eight human genomes.

Nature 2008 May;453(7191):56-64

Department of Genome Sciences and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.

Genetic variation among individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes. Here we explore variation on an intermediate scale--particularly insertions, deletions and inversions affecting from a few thousand to a few million base pairs. We employed a clone-based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive overview of the normal pattern of structural variation present in these genomes, refining the location of 1,695 structural variants. We find that 50% were seen in more than one individual and that nearly half lay outside regions of the genome previously described as structurally variant. We discover 525 new insertion sequences that are not present in the human reference genome and show that many of these are variable in copy number between individuals. Complete sequencing of 261 structural variants reveals considerable locus complexity and provides insights into the different mutational processes that have shaped the human genome. These data provide the first high-resolution sequence map of human structural variation--a standard for genotyping platforms and a prelude to future individual genome sequencing projects.
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http://dx.doi.org/10.1038/nature06862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2424287PMC
May 2008

Evolutionary dynamics of segmental duplications from human Y-chromosomal euchromatin/heterochromatin transition regions.

Genome Res 2008 Jul 29;18(7):1030-42. Epub 2008 Apr 29.

Institute of Human Genetics, University of Freiburg, 79106 Freiburg, Germany.

Human chromosomal regions enriched in segmental duplications are subject to extensive genomic reorganization. Such regions are particularly informative for illuminating the evolutionary history of a given chromosome. We have analyzed 866 kb of Y-chromosomal non-palindromic segmental duplications delineating four euchromatin/heterochromatin transition regions (Yp11.2/Yp11.1, Yq11.1/Yq11.21, Yq11.23/Yq12, and Yq12/PAR2). Several computational methods were applied to decipher the segmental duplication architecture and identify the ancestral origin of the 41 different duplicons. Combining computational and comparative FISH analysis, we reconstruct the evolutionary history of these regions. Our analysis indicates a continuous process of transposition of duplicated sequences onto the evolving higher primate Y chromosome, providing unique insights into the development of species-specific Y-chromosomal and autosomal duplicons. Phylogenetic sequence comparisons show that duplicons of the human Yp11.2/Yp11.1 region were already present in the macaque-human ancestor as multiple paralogs located predominantly in subtelomeric regions. In contrast, duplicons from the Yq11.1/Yq11.21, Yq11.23/Yq12, and Yq12/PAR2 regions show no evidence of duplication in rhesus macaque, but map to the pericentromeric regions in chimpanzee and human. This suggests an evolutionary shift in the direction of duplicative transposition events from subtelomeric in Old World monkeys to pericentromeric in the human/ape lineage. Extensive chromosomal relocation of autosomal-duplicated sequences from euchromatin/heterochromatin transition regions to interstitial regions as demonstrated on the pygmy chimpanzee Y chromosome support a model in which substantial reorganization and amplification of duplicated sequences may contribute to speciation.
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http://dx.doi.org/10.1101/gr.076711.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493392PMC
July 2008

Optimal design of oligonucleotide microarrays for measurement of DNA copy-number.

Hum Mol Genet 2007 Nov 28;16(22):2770-9. Epub 2007 Aug 28.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.

Copy-number variants (CNVs) occur frequently within the human genome, and may be associated with many human phenotypes. If disease association studies of CNVs are to be performed routinely, it is essential that the copy-number status be accurately genotyped. We systematically assessed the dynamic range response of an oligonucleotide microarray platform to accurately predict copy-number in a set of seven patients who had previously been shown to carry between 1 and 6 copies of an approximately 4 Mb region of 15q12.2-q13.1. We identify probe uniqueness, probe length, uniformity of probe melting temperature, overlap with SNPs and common repeats (particularly Alu elements) and guanine homopolymer content as parameters that significantly affect probe performance. Further, we prove the influence of these criteria on array performance by using these parameters to prospectively filter data from a second array design covering an independent genomic region and observing significant improvements in data quality. The informed selection of probes which have superior performance characteristics allows the prospective design of oligonucleotide arrays which show increased sensitivity and specificity compared with current designs. Although based on the analysis of data from comparative genomic hybridization experiments, we anticipate that our results are relevant to the design of improved oligonucleotide arrays for high-throughput copy-number genotyping of complex regions of the human genome.
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http://dx.doi.org/10.1093/hmg/ddm234DOI Listing
November 2007

Evolutionary and biomedical insights from the rhesus macaque genome.

Authors:
Richard A Gibbs Jeffrey Rogers Michael G Katze Roger Bumgarner George M Weinstock Elaine R Mardis Karin A Remington Robert L Strausberg J Craig Venter Richard K Wilson Mark A Batzer Carlos D Bustamante Evan E Eichler Matthew W Hahn Ross C Hardison Kateryna D Makova Webb Miller Aleksandar Milosavljevic Robert E Palermo Adam Siepel James M Sikela Tony Attaway Stephanie Bell Kelly E Bernard Christian J Buhay Mimi N Chandrabose Marvin Dao Clay Davis Kimberly D Delehaunty Yan Ding Huyen H Dinh Shannon Dugan-Rocha Lucinda A Fulton Ramatu Ayiesha Gabisi Toni T Garner Jennifer Godfrey Alicia C Hawes Judith Hernandez Sandra Hines Michael Holder Jennifer Hume Shalini N Jhangiani Vandita Joshi Ziad Mohid Khan Ewen F Kirkness Andrew Cree R Gerald Fowler Sandra Lee Lora R Lewis Zhangwan Li Yih-Shin Liu Stephanie M Moore Donna Muzny Lynne V Nazareth Dinh Ngoc Ngo Geoffrey O Okwuonu Grace Pai David Parker Heidie A Paul Cynthia Pfannkoch Craig S Pohl Yu-Hui Rogers San Juana Ruiz Aniko Sabo Jireh Santibanez Brian W Schneider Scott M Smith Erica Sodergren Amanda F Svatek Teresa R Utterback Selina Vattathil Wesley Warren Courtney Sherell White Asif T Chinwalla Yucheng Feng Aaron L Halpern Ladeana W Hillier Xiaoqiu Huang Pat Minx Joanne O Nelson Kymberlie H Pepin Xiang Qin Granger G Sutton Eli Venter Brian P Walenz John W Wallis Kim C Worley Shiaw-Pyng Yang Steven M Jones Marco A Marra Mariano Rocchi Jacqueline E Schein Robert Baertsch Laura Clarke Miklós Csürös Jarret Glasscock R Alan Harris Paul Havlak Andrew R Jackson Huaiyang Jiang Yue Liu David N Messina Yufeng Shen Henry Xing-Zhi Song Todd Wylie Lan Zhang Ewan Birney Kyudong Han Miriam K Konkel Jungnam Lee Arian F A Smit Brygg Ullmer Hui Wang Jinchuan Xing Richard Burhans Ze Cheng John E Karro Jian Ma Brian Raney Xinwei She Michael J Cox Jeffery P Demuth Laura J Dumas Sang-Gook Han Janet Hopkins Anis Karimpour-Fard Young H Kim Jonathan R Pollack Tomas Vinar Charles Addo-Quaye Jeremiah Degenhardt Alexandra Denby Melissa J Hubisz Amit Indap Carolin Kosiol Bruce T Lahn Heather A Lawson Alison Marklein Rasmus Nielsen Eric J Vallender Andrew G Clark Betsy Ferguson Ryan D Hernandez Kashif Hirani Hildegard Kehrer-Sawatzki Jessica Kolb Shobha Patil Ling-Ling Pu Yanru Ren David Glenn Smith David A Wheeler Ian Schenck Edward V Ball Rui Chen David N Cooper Belinda Giardine Fan Hsu W James Kent Arthur Lesk David L Nelson William E O'brien Kay Prüfer Peter D Stenson James C Wallace Hui Ke Xiao-Ming Liu Peng Wang Andy Peng Xiang Fan Yang Galt P Barber David Haussler Donna Karolchik Andy D Kern Robert M Kuhn Kayla E Smith Ann S Zwieg

Science 2007 Apr;316(5822):222-34

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.

The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied biomedical research. We determined the genome sequence of an Indian-origin Macaca mulatta female and compared the data with chimpanzees and humans to reveal the structure of ancestral primate genomes and to identify evidence for positive selection and lineage-specific expansions and contractions of gene families. A comparison of sequences from individual animals was used to investigate their underlying genetic diversity. The complete description of the macaque genome blueprint enhances the utility of this animal model for biomedical research and improves our understanding of the basic biology of the species.
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http://dx.doi.org/10.1126/science.1139247DOI Listing
April 2007

Molecular refinement of gibbon genome rearrangements.

Genome Res 2007 Feb 21;17(2):249-57. Epub 2006 Dec 21.

Department of Genetics and Microbiology, University of Bari, 70126 Bari, Italy.

The gibbon karyotype is known to be extensively rearranged when compared to the human and to the ancestral primate karyotype. By combining a bioinformatics (paired-end sequence analysis) approach and a molecular cytogenetics approach, we have refined the synteny block arrangement of the white-cheeked gibbon (Nomascus leucogenys, NLE) with respect to the human genome. We provide the first detailed clone framework map of the gibbon genome and refine the location of 86 evolutionary breakpoints to <1 Mb resolution. An additional 12 breakpoints, mapping primarily to centromeric and telomeric regions, were mapped to approximately 5 Mb resolution. Our combined FISH and BES analysis indicates that we have effectively subcloned 49 of these breakpoints within NLE gibbon BAC clones, mapped to a median resolution of 79.7 kb. Interestingly, many of the intervals associated with translocations were gene-rich, including some genes associated with normal skeletal development. Comparisons of NLE breakpoints with those of other gibbon species reveal variability in the position, suggesting that chromosomal rearrangement has been a longstanding property of this particular ape lineage. Our data emphasize the synergistic effect of combining computational genomics and cytogenetics and provide a framework for ultimate sequence and assembly of the gibbon genome.
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http://dx.doi.org/10.1101/gr.6052507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781357PMC
February 2007

A comprehensive analysis of common copy-number variations in the human genome.

Am J Hum Genet 2007 Jan 5;80(1):91-104. Epub 2006 Dec 5.

Department of Cancer Genetics and Developmental Biology, University of British Columbia, Vancouver, BC, Canada.

Segmental copy-number variations (CNVs) in the human genome are associated with developmental disorders and susceptibility to diseases. More importantly, CNVs may represent a major genetic component of our phenotypic diversity. In this study, using a whole-genome array comparative genomic hybridization assay, we identified 3,654 autosomal segmental CNVs, 800 of which appeared at a frequency of at least 3%. Of these frequent CNVs, 77% are novel. In the 95 individuals analyzed, the two most diverse genomes differed by at least 9 Mb in size or varied by at least 266 loci in content. Approximately 68% of the 800 polymorphic regions overlap with genes, which may reflect human diversity in senses (smell, hearing, taste, and sight), rhesus phenotype, metabolism, and disease susceptibility. Intriguingly, 14 polymorphic regions harbor 21 of the known human microRNAs, raising the possibility of the contribution of microRNAs to phenotypic diversity in humans. This in-depth survey of CNVs across the human genome provides a valuable baseline for studies involving human genetics.
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http://dx.doi.org/10.1086/510560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785303PMC
January 2007