19th International Chromosome Conference 19th International Chromosome Conference Bologna Dipartimento BiGeA Complesso Belmeloro 2nd – 6th September 2013 - 1 - 19th International Chromosome Conference ORGANIZING COMMITTEE Barbara Mantovani University of Bologna, IT Darren Griffin University of Kent, UK Ettore Olmo Marche’s Polytechnic University, IT Gaetano Ciarcia University of Naples “Federico II”, IT Eva Pisano University of Genoa, IT Livia Bonandin University of Bologna IT Adriana Canapa Marche’s Polytechnic University, IT Vincenzo Caputo Marche’s Polytechnic University, IT Fabrizio Ghiselli University of Bologna, IT Andrea Luchetti University of Bologna, IT Liliana Milani University of Bologna, IT Marco Passamonti University of Bologna, IT Claudia Scavariello University of Bologna, IT - 2 - 19th International Chromosome Conference SCIENTIFIC COMMITTEE Giorgio Bernardi 3rd University Rome, IT Teresa Capriglione University of Naples “Federico II”, IT Thomas Cremer Ludwig Maximilian University, D Giuliano Della Valle University of Bologna, IT Malcolm Ferguson-Smith University of Cambridge, UK Darren Griffin University of Kent, UK Leopoldo Iannuzzi ISPAAM, CNR, Naples IT Dean Jackson University of Manchester, UK Herbert Macgregor Exeter, past Editor of Chromosome Research, UK Jennifer Marshall Graves La Trobe University and University of Camberra, AU Eric Nigg Biozentrum, University of Basel, Editor of Chromosoma, CH Rachel O’Neill University of Connecticut, USA Willem Rens University of Cambridge, UK Conly Rieder New York, Editor of Chromosome Research, USA Terry Robinson University of Stellenbosch, SAF Mariano Rocchi University of Bari, IT Giovanni Romeo University of Bologna and European Genetic Foundation, IT Susanna Salvadori University of Cagliari, IT Manfred Schartl University of Wuerzburg, D Michael Schmid University of Wuerzburg, Editor of Cytogenetics and Genome Rsearch, D Luciana Sola University of Rome “La Sapienza”, IT Beth Sullivan Duke University, USA Helen Tempest Florida International University, USA ORGANIZING SECRETARIAT MI&T – Viale Carducci 50, Bologna – [email protected] - 3 - 19th International Chromosome Conference - 4 - 19th International Chromosome Conference CONTENTS Plenary lecture page 7 Chromosome structure and function page 11 Sex chromosomes page 55 Nuclear organization and dynamics page 77 Epigenetics and gene expression page 103 Chromosome and genome evolution page 113 Chromosomal aberrations and disease page 173 Advances in imaging and molecular technology page 197 Authors’ Index page 207 - 5 - 19th International Chromosome Conference - 6 - 19th International Chromosome Conference PLENARY LECTURE - 7 - 19th International Chromosome Conference - 8 - 19th International Chromosome Conference THE ROLE OF STRUCTURAL GENOMIC VARIANTS ACCURATELY IDENTIFIED FROM WHOLE GENOME SEQUENCES LEE C. Director, Jackson Laboratory Institute for Genomic Medicine, Farmington, CT, USA As more whole genomes become sequenced, the challenge remains to accurately identify structural genomic variants and to deduce the role of these genetic variants in human pathology and genome evolution. In whole-genome sequences of different tumors, somatic insertions of transposable elements (and other types of structural variants) highlight their potential impact in tumorigenesis. In non-human primate genomes, structural genomic variants can dramatically alter the architecture of specific species’ genomes. Moreover, transcriptome analyses across nonhuman primates and humans demonstrates significant effects of species-specific gene duplications on gene expression. Indeed, certain inter-species gene duplications coincide with species-specific gain of expression in a new tissue, implicating these duplications in function acquisition - 9 - th 19 International Chromosome Conference - 10 - 19th International Chromosome Conference CHROMOSOME STRUCTURE AND FUNCTION - 11 - 19th International Chromosome Conference - 12 - 19th International Chromosome Conference LINKING CHROMOSOME STRUCTURE TO THE ORGANISATION OF S PHASE IN HUMAN CELLS OLIVARES-CHAUVET P., MAYA-MENDOZA A., JACKSON D.A. University of Manchester, Faculty of Life Sciences, Michael Smith Building, Oxford Road, Manchester Eukaryotic DNA synthesis is regulated with exquisite precision so that genomes are replicated exactly once before mitosis and cell division occurs. The size and structure of mammalian genomes requires that the initiation of DNA synthesis is activated at about 50,000 sites – the average inter-replicon spacing is ~120kbp - in order to complete synthesis within an S phase that is typically 9-10 hours in length. During the process of DNA synthesis, different regions of the genome are replicated at different but broadly predictable times. Such patterns of replication timing, which define a temporal program during S phase progression, are seen to alter during cell differentiation and correlate with establishing different classes of chromatin on DNA that is replicated at different times of S phase. In understanding this process, significant progress has been made in recent years using population based studies and ‘omics’ technologies – e.g., advanced sequencing and chromatin immuno-precipitation. However, as the selection of origins for activation at different times of S phase is known to be significantly probabilistic in nature in mammals we have adopted a suite of single cell approaches to compliment the population studies. By analysing individual chromosomes, within living cells, and replicon organisation on spread DNA fibres we have shown that a major mechanism regulating transitions in the S phase timing program involves the sequential activation of replication domains based on their genetic continuity. Our analysis shows that replicons are generally activated in small clusters, which represent the higher order units of DNA synthesis – replicons are typically ~120kbp in somatic human cells and most clusters contain 500-1000kbp of DNA. These ~1Mbp regions of DNA also correlate with major units of higher order chromosome organisation, which can be visualised as DNA foci within individual chromosome territories and seen as stable entities using genome-wide analysis of chromatin interactions. To expand these experimental studies, we have also used in silico approaches to explore how a complex composite of genomic features links chromosome structure, at a range of scales, to fundamental principles of nuclear function - such as DNA sequence, chromatin epistates and the location of different protein molecules bound to DNA. Together these studies show how a complex composite of interactions defines both chromosome structure and the efficacy of genome duplication in mammalian cells. - 13 - 19th International Chromosome Conference CELL-LINEAGE-SPECIFIC CONSEQUENCES OF CONDENSIN II-DEFICIENCY ON PLOIDY AND HAEMATOPOIETIC DEVELOPMENT WOOD A.J., WOODWARD J., BOYLE S., BICKMORE W.A. Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK Chromosomal Instability (CIN) and aneuploidy are common features in most human tumours, but their prevalence during normal development is less clear. We profiled ploidy during normal development of mouse B, T and erythroid cells, and uncovered marked variability in the frequency of cells with abnormal DNA content both within and between lineages. Frequencies of aneuploidy were elevated during stages of development characterised by rapid cellular proliferation but decreased at subsequent stages, suggesting that aneuploid cells experience a competitive disadvantage. To assess the consequences of elevated CIN during development, we have used mice carrying germline hypomorphic mutations in Caph2, a component of the chromosome restructuring complex condensin II. Homozygous mutants were viable, fertile, and of normal size, but accumulated cells with abnormal DNA content in several cell lineages. The effects on haematopoietic development were remarkably tissue-specific: B cell and erythroid lineages were largely unaffected, whereas CD4+CD8+ thymic T cells were reduced in number by two orders of magnitude. This developmental block could not be attributed to major abnormalities in transcription or interphase chromosome structure. Instead, thymocytes showed defects in both proliferation and differentiation arising from failed cytokinesis, and a build up of tetraploid, non-cycling cells. Concomitant deletion of p53 restored thymic cellularity, but led to the rapid development of aneuploid thymic lymphomas. P53 mutations had no detectable effect on the development of Caph2-deficient B cells or erythrocytes. These data provide a systematic analysis of ploidy across a cellular differentiation hierarchy, and demonstrate that thymocytes are uniquely vulnerable to condensin II deficiency. We uncover a stage-specific p53 checkpoint that protects from CIN-induced thymic lymphoma at the expense of thymic T-cell output. - 14 - 19th International Chromosome Conference GENOMIC COMPOSITION AND TURNOVER OF SATELLITE DNA REPEATS PLOHL M. Department of Molecular Biology, Ruder Boskovic Institute, Croatia Eukaryotic genomes are to a large extent structured by repetitive sequences and remodeled by their evolution. Among them, satellite DNAs, non-coding DNA sequences repeated in tandem, are principal DNA components of heterochromatic chromosomal regions but can also appear as single units or as short arrays interspersed in euchromatic portions of the genome. Each genome can harbor many satellite