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2. Characterization of an eye field-like state during optic vesicle organoid development.

Author

Owen, Liusaidh J., Rainger, Jacqueline, Bengani, Hemant, Kilanowski, Fiona, FitzPatrick, David R., and Papanastasiou, Andrew S.

Subjects
TRANSCRIPTION factors, GENE expression, NUCLEOTIDE sequence, GENE regulatory networks, GROUP formation
Abstract

Specification of the eye field (EF) within the neural plate marks the earliest detectable stage of eye development. Experimental evidence, primarily from non-mammalian model systems, indicates that the stable formation of this group of cells requires the activation of a set of key transcription factors. This crucial event is challenging to probe in mammals and, quantitatively, little is known regarding the regulation of the transition of cells to this ocular fate. Using optic vesicle organoids to model the onset of the EF, we generate timecourse transcriptomic data allowing us to identify dynamic gene expression programmes that characterize this cellular-state transition. Integrating this with chromatin accessibility data suggests a direct role of canonical EF transcription factors in regulating these gene expression changes, and highlights candidate cis-regulatory elements through which these transcription factors act. Finally, we begin to test a subset of these candidate enhancer elements, within the organoid system, by perturbing the underlying DNA sequence and measuring transcriptomic changes during EF activation. [ABSTRACT FROM AUTHOR]

Published
2023
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3. Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia

Author

Hall, Hildegard Nikki, primary, Bengani, Hemant, additional, Hufnagel, Robert B., additional, Damante, Giuseppe, additional, Ansari, Morad, additional, Marsh, Joseph A., additional, Grimes, Graeme R., additional, Kriegsheim, Alex von, additional, Moore, David, additional, McKie, Lisa, additional, Rahmat, Jamalia, additional, Mio, Catia, additional, Blyth, Moira, additional, Keng, Wee Teik, additional, Islam, Lily, additional, McEntargart, Meriel, additional, Mannens, Marcel M., additional, Heyningen, Veronica Van, additional, Rainger, Joe, additional, Brooks, Brian P., additional, and FitzPatrick, David R., additional

Published
2022
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5. Robust Genetic Analysis of the X-Linked Anophthalmic (Ie) Mouse

Author

Hernandez-Moran, Brianda A., primary, Papanastasiou, Andrew S., additional, Parry, David, additional, Meynert, Alison, additional, Gautier, Philippe, additional, Grimes, Graeme, additional, Adams, Ian R., additional, Trejo-Reveles, Violeta, additional, Bengani, Hemant, additional, Keighren, Margaret, additional, Jackson, Ian J., additional, Adams, David J., additional, FitzPatrick, David R., additional, and Rainger, Joe, additional

Published
2022
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7. Robust genetic analysis of the X-linked anophthalmic (Ie) mouse

Author

Hernandez-Moran, Brianda Areli, primary, Papanastasiou, Andrew S, additional, Parry, Dave, additional, Meynert, Alison, additional, Gautier, Phillipe, additional, Grimes, Graeme, additional, Adams, Ian R, additional, Trejo-Reveles, Violeta, additional, Bengani, Hemant, additional, Keighren, Margaret, additional, Jackson, Ian J, additional, Adams, David J, additional, FitzPatrick, David R, additional, and Rainger, Joe, additional

Published
2022
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9. Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability

Author

Bengani, Hemant, primary, Grozeva, Detelina, additional, Moyon, Lambert, additional, Bhatia, Shipra, additional, Louros, Susana R., additional, Hope, Jilly, additional, Jackson, Adam, additional, Prendergast, James G., additional, Owen, Liusaidh J., additional, Naville, Magali, additional, Rainger, Jacqueline, additional, Grimes, Graeme, additional, Halachev, Mihail, additional, Murphy, Laura C., additional, Spasic-Boskovic, Olivera, additional, van Heyningen, Veronica, additional, Kind, Peter, additional, Abbott, Catherine M., additional, Osterweil, Emily, additional, Raymond, F. Lucy, additional, Roest Crollius, Hugues, additional, and FitzPatrick, David R., additional

Published
2021
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11. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

Author

Ansari, Morad, Poke, Gemma, Ferry, Quentin, Williamson, Kathleen, Aldridge, Roland, Meynert, Alison M, Bengani, Hemant, Chan, Cheng Yee, Kayserili, Hülya, Avci, Şahin, Hennekam, Raoul C M, Lampe, Anne K, Redeker, Egbert, Homfray, Tessa, Ross, Alison, Falkenberg Smeland, Marie, Mansour, Sahar, Parker, Michael J, Cook, Jacqueline A, Splitt, Miranda, Fisher, Richard B, Fryer, Alan, Magee, Alex C, Wilkie, Andrew, Barnicoat, Angela, Brady, Angela F, Cooper, Nicola S, Mercer, Catherine, Deshpande, Charu, Bennett, Christopher P, Pilz, Daniela T, Ruddy, Deborah, Cilliers, Deirdre, Johnson, Diana S, Josifova, Dragana, Rosser, Elisabeth, Thompson, Elizabeth M, Wakeling, Emma, Kinning, Esther, Stewart, Fiona, Flinter, Frances, Girisha, Katta M, Cox, Helen, Firth, Helen V, Kingston, Helen, Wee, Jamie S, Hurst, Jane A, Clayton-Smith, Jill, Tolmie, John, Vogt, Julie, Tatton–Brown, Katrina, Chandler, Kate, Prescott, Katrina, Wilson, Louise, Behnam, Mahdiyeh, McEntagart, Meriel, Davidson, Rosemarie, Lynch, Sally-Ann, Sisodiya, Sanjay, Mehta, Sarju G, McKee, Shane A, Mohammed, Shehla, Holden, Simon, Park, Soo-Mi, Holder, Susan E, Harrison, Victoria, McConnell, Vivienne, Lam, Wayne K, Green, Andrew J, Donnai, Dian, Bitner-Glindzicz, Maria, Donnelly, Deirdre E, Nellåker, Christoffer, Taylor, Martin S, and FitzPatrick, David R

Published
2014
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13. Miller (Genée–Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH

Author

Rainger, Joe, Bengani, Hemant, Campbell, Leigh, Anderson, Eve, Sokhi, Kishan, Lam, Wayne, Riess, Angelika, Ansari, Morad, Smithson, Sarah, Lees, Melissa, Mercer, Catherine, McKenzie, Kathryn, Lengfeld, Tobias, Gener Querol, Blanca, Branney, Peter, McKay, Stewart, Morrison, Harris, Medina, Bethan, Robertson, Morag, Kohlhase, Jürgen, Gordon, Colin, Kirk, Jean, Wieczorek, Dagmar, and FitzPatrick, David R.

Published
2012
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14. Functional Predictors of Causative Cis-Regulatory Mutations in Mendelian Disease

Author

Bengani, Hemant, primary, Grozeva, Detelina, additional, Moyon, Lambert, additional, Bhatia, Shipra, additional, Louros, Susana R, additional, Hope, Jilly, additional, Jackson, Adam, additional, Prendergast, James G, additional, Owen, Liusaidh J., additional, Naville, Magali, additional, Rainger, Jacqueline, additional, Grimes, Graeme, additional, Halachev, Mihail, additional, Murphy, Laura C, additional, Spasic-Boskovic, Olivera, additional, van Heyningen, Veronica, additional, Kind, Peter, additional, Abbott, Catherine M, additional, Osterweil, Emily, additional, Raymond, F Lucy, additional, Crollius, Hugues Roest, additional, and FitzPatrick, David R, additional

Published
2020
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15. Clinical and molecular consequences of disease-associated de novo mutations in SATB2

Author

Bengani, Hemant, Handley, Mark, Alvi, Mohsan, Ibitoye, Rita, Lees, Melissa, Lynch, Sally Ann, Lam, Wayne, Fannemel, Madeleine, Nordgren, Ann, Malmgren, H, Kvarnung, M, Mehta, Sarju, McKee, Shane, Whiteford, Margo, Stewart, Fiona, Connell, Fiona, Clayton-Smith, Jill, Mansour, Sahar, Mohammed, Shehla, Fryer, Alan, Morton, Jenny, UK10K Consortium, Grozeva, Detelina, Asam, Tara, Moore, David, Sifrim, Alejandro, McRae, Jeremy, Hurles, Matthew E, Firth, Helen V, Raymond, F Lucy, Kini, Usha, Nellåker, Christoffer, Ddd Study, FitzPatrick, David R, Alvi, Mohsan [0000-0003-4331-7078], Ibitoye, Rita [0000-0002-2887-2068], Lynch, Sally Ann [0000-0003-0287-4134], Nordgren, Ann [0000-0003-3338-8382], Malmgren, H [0000-0003-3285-4281], McKee, Shane [0000-0003-0446-3435], Whiteford, Margo [0000-0002-1772-0106], Connell, Fiona [0000-0002-0444-8203], Mohammed, Shehla [0000-0001-6629-4118], Sifrim, Alejandro [0000-0001-9308-5741], McRae, Jeremy [0000-0001-8247-4020], Kini, Usha [0000-0003-2652-3355], FitzPatrick, David R [0000-0001-7609-3504], and Apollo - University of Cambridge Repository

Subjects
Cohort Studies, Whole Genome Sequencing, Loss of Function Mutation, Intellectual Disability, Mutation, Missense, Humans, Haploinsufficiency, Matrix Attachment Region Binding Proteins, Genetic Association Studies, Cell Line, HeLa Cells, Protein Binding, Transcription Factors
Abstract

PURPOSE: To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability. METHODS: Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production. Subcellular localization and mobility of wild-type and mutant SATB2 were assessed using fluorescently tagged protein. RESULTS: Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19). Six of eight missense variants clustered in the first CUT domain. Sibling recurrence due to gonadal mosaicism was seen in one family. A nonsense mutation in the last exon resulted in production of a truncated protein retaining all three DNA-binding domains. SATB2 nuclear mobility was mutation-dependent; p.Arg389Cys in CUT1 increased mobility and both p.Gly515Ser in CUT2 and p.Gln566Lys between CUT2 and HOX reduced mobility. The clinical features in individuals with missense variants were indistinguishable from those with loss of function. CONCLUSION: SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. When mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association.Genet Med advance online publication 02 February 2017.

Published
2017

16. Corrigendum: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author

Shaw, Natalie D, Brand, Harrison, Kupchinsky, Zachary A, Bengani, Hemant, Plummer, Lacey, Jones, Takako I, Erdin, Serkan, Williamson, Kathleen A, Rainger, Joe, Stortchevoi, Alexei, Samocha, Kaitlin, Currall, Benjamin B, Dunican, Donncha S, Collins, Ryan L, Willer, Jason R, Lek, Angela, Lek, Monkol, Nassan, Malik, Pereira, Shahrin, Kammin, Tammy, Lucente, Diane, Silva, Alexandra, Seabra, Catarina M, Chiang, Colby, An, Yu, Ansari, Morad, Rainger, Jacqueline K, Joss, Shelagh, Smith, Jill Clayton, Lippincott, Margaret F, et al, and University of Zurich

Subjects
1311 Genetics, 10039 Institute of Medical Genetics, 570 Life sciences, biology, 610 Medicine & health
Published
2017

17. Biallelic mutations in the gene encoding eEF1A2 cause seizures and sudden death in F0 mice

Author

Davies, Faith, Hope, Jilly, McLachlan, Fiona, Nunez, Francis, Doig, Jennifer, Bengani, Hemant, Smith, Colin, and Abbott, Catherine M

Subjects
Gene Editing, Genome, Base Sequence, Genotype, Body Weight, Article, Death, Sudden, Mice, Peptide Elongation Factor 1, Gene Expression Regulation, Spinal Cord, Seizures, Mutation, Nerve Degeneration, Animals, CRISPR-Cas Systems, Alleles
Abstract

De novo heterozygous missense mutations in the gene encoding translation elongation factor eEF1A2 have recently been found to give rise to neurodevelopmental disorders. Children with mutations in this gene have developmental delay, epilepsy, intellectual disability and often autism; the most frequently occurring mutation is G70S. It has been known for many years that complete loss of eEF1A2 in mice causes motor neuron degeneration and early death; on the other hand heterozygous null mice are apparently normal. We have used CRISPR/Cas9 gene editing in the mouse to mutate the gene encoding eEF1A2, obtaining a high frequency of biallelic mutations. Whilst many of the resulting founder (F0) mice developed motor neuron degeneration, others displayed phenotypes consistent with a severe neurodevelopmental disorder, including sudden unexplained deaths and audiogenic seizures. The presence of G70S protein was not sufficient to protect mice from neurodegeneration in G70S/− mice, showing that the mutant protein is essentially non-functional.

Published
2017
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18. Psip1/p52 regulates posterior Hoxa genes through activation of lncRNA Hottip

Author

Pradeepa, Madapura M., McKenna, Fionnuala, Taylor, Gillian C. A., Bengani, Hemant, Grimes, Graeme R., Wood, Andrew J., Bhatia, Shipra, and Bickmore, Wendy A.

Subjects
lcsh:Genetics, lcsh:QH426-470
Abstract

Long noncoding RNAs (lncRNAs) have been implicated in various biological functions including the regulation of gene expression, however, the functionality of lncRNAs is not clearly understood and conflicting conclusions have often been reached when comparing different methods to investigate them. Moreover, little is known about the upstream regulation of lncRNAs. Here we show that the short isoform (p52) of a transcriptional co-activator—PC4 and SF2 interacting protein (Psip1), which is known to be involved in linking transcription to RNA processing, specifically regulates the expression of the lncRNA Hottip–located at the 5’ end of the Hoxa locus. Using both knockdown and knockout approaches we show that Hottip expression is required for activation of the 5’ Hoxa genes (Hoxa13 and Hoxa10/11) and for retaining Mll1 at the 5’ end of Hoxa. Moreover, we demonstrate that artificially inducing Hottip expression is sufficient to activate the 5’ Hoxa genes and that Hottip RNA binds to the 5’ end of Hoxa. By engineering premature transcription termination, we show that it is the Hottip lncRNA molecule itself, not just Hottip transcription that is required to maintains active expression of posterior Hox genes. Our data show a direct role for a lncRNA molecule in regulating the expression of developmentally-regulated mRNA genes in cis.

Published
2017

19. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author

Shaw, Natalie D, Brand, Harrison, Kupchinsky, Zachary A, Bengani, Hemant, Plummer, Lacey, Jones, Takako I, Erdin, Serkan, Williamson, Kathleen A, Rainger, Joe, Stortchevoi, Alexei, Samocha, Kaitlin, Currall, Benjamin B, Dunican, Donncha S, Collins, Ryan L, Willer, Jason R, Lek, Angela, Lek, Monkol, Nassan, Malik, Pereira, Shahrin, Kammin, Tammy, Lucente, Diane, Silva, Alexandra, Seabra, Catarina M, Chiang, Colby, An, Yu, Ansari, Morad, Rainger, Jacqueline K, Joss, Shelagh, Smith, Jill Clayton, Lippincott, Margaret F, et al, and University of Zurich

Subjects
1311 Genetics, 10039 Institute of Medical Genetics, 570 Life sciences, biology, 610 Medicine & health
Published
2017

20. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect

Author

McEntagart, Meriel, Williamson, Kathleen A, Rainger, Jacqueline K, Wheeler, Ann, Seawright, Anne, De Baere, Elfride, Verdin, Hannah, Bergendahl, L Therese, Quigley, Alan, Rainger, Joe, Dixit, Abhijit, Sarkar, Ajoy, López Laso, Eduardo, Sanchez-Carpintero, Rocio, Barrio, Jesus, Bitoun, Pierre, Prescott, Trine, Riise, Ruth, McKee, Shane, Cook, Jackie, McKie, Lisa, Ceulemans, Berten, Meire, Françoise, Temple, I Karen, Prieur, Fabienne, Williams, Jonathan, Clouston, Penny, Németh, Andrea H, Banka, Siddharth, Bengani, Hemant, Handley, Mark, Freyer, Elisabeth, Ross, Allyson, DDD Study, van Heyningen, Veronica, Marsh, Joseph A, Elmslie, Frances, and FitzPatrick, David R

Subjects
Adult, Male, cerebellar hypoplasia, inositol triphosphate, Adolescent, Cerebellar Ataxia, Protein Conformation, aniridia, Mice, Intellectual Disability, cerebellar vermis, Animals, Humans, Inositol 1,4,5-Trisphosphate Receptors, Lymphocytes, Child, Cells, Cultured, iris, Genes, Dominant, ITPR1, calcium, Microscopy, Confocal, Middle Aged, Pedigree, Mutation, Female, ACTA2
Abstract

Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions.

Published
2016

21. Correction: Corrigendum: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author

Shaw, Natalie D, primary, Brand, Harrison, additional, Kupchinsky, Zachary A, additional, Bengani, Hemant, additional, Plummer, Lacey, additional, Jones, Takako I, additional, Erdin, Serkan, additional, Williamson, Kathleen A, additional, Rainger, Joe, additional, Stortchevoi, Alexei, additional, Samocha, Kaitlin, additional, Currall, Benjamin B, additional, Dunican, Donncha S, additional, Collins, Ryan L, additional, Willer, Jason R, additional, Lek, Angela, additional, Lek, Monkol, additional, Nassan, Malik, additional, Pereira, Shahrin, additional, Kammin, Tammy, additional, Lucente, Diane, additional, Silva, Alexandra, additional, Seabra, Catarina M, additional, Chiang, Colby, additional, An, Yu, additional, Ansari, Morad, additional, Rainger, Jacqueline K, additional, Joss, Shelagh, additional, Smith, Jill Clayton, additional, Lippincott, Margaret F, additional, Singh, Sylvia S, additional, Patel, Nirav, additional, Jing, Jenny W, additional, Law, Jennifer R, additional, Ferraro, Nalton, additional, Verloes, Alain, additional, Rauch, Anita, additional, Steindl, Katharina, additional, Zweier, Markus, additional, Scheer, Ianina, additional, Sato, Daisuke, additional, Okamoto, Nobuhiko, additional, Jacobsen, Christina, additional, Tryggestad, Jeanie, additional, Chernausek, Steven, additional, Schimmenti, Lisa A, additional, Brasseur, Benjamin, additional, Cesaretti, Claudia, additional, García-Ortiz, Jose E, additional, Buitrago, Tatiana Pineda, additional, Silva, Orlando Perez, additional, Hoffman, Jodi D, additional, Mühlbauer, Wolfgang, additional, Ruprecht, Klaus W, additional, Loeys, Bart L, additional, Shino, Masato, additional, Kaindl, Angela M, additional, Cho, Chie-Hee, additional, Morton, Cynthia C, additional, Meehan, Richard R, additional, van Heyningen, Veronica, additional, Liao, Eric C, additional, Balasubramanian, Ravikumar, additional, Hall, Janet E, additional, Seminara, Stephanie B, additional, Macarthur, Daniel, additional, Moore, Steven A, additional, Yoshiura, Koh-ichiro, additional, Gusella, James F, additional, Marsh, Joseph A, additional, Graham, John M, additional, Lin, Angela E, additional, Katsanis, Nicholas, additional, Jones, Peter L, additional, Crowley, William F, additional, Davis, Erica E, additional, FitzPatrick, David R, additional, and Talkowski, Michael E, additional

Published
2017
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22. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Author

Shaw, Natalie D, primary, Brand, Harrison, additional, Kupchinsky, Zachary A, additional, Bengani, Hemant, additional, Plummer, Lacey, additional, Jones, Takako I, additional, Erdin, Serkan, additional, Williamson, Kathleen A, additional, Rainger, Joe, additional, Stortchevoi, Alexei, additional, Samocha, Kaitlin, additional, Currall, Benjamin B, additional, Dunican, Donncha S, additional, Collins, Ryan L, additional, Willer, Jason R, additional, Lek, Angela, additional, Lek, Monkol, additional, Nassan, Malik, additional, Pereira, Shahrin, additional, Kammin, Tammy, additional, Lucente, Diane, additional, Silva, Alexandra, additional, Seabra, Catarina M, additional, Chiang, Colby, additional, An, Yu, additional, Ansari, Morad, additional, Rainger, Jacqueline K, additional, Joss, Shelagh, additional, Smith, Jill Clayton, additional, Lippincott, Margaret F, additional, Singh, Sylvia S, additional, Patel, Nirav, additional, Jing, Jenny W, additional, Law, Jennifer R, additional, Ferraro, Nalton, additional, Verloes, Alain, additional, Rauch, Anita, additional, Steindl, Katharina, additional, Zweier, Markus, additional, Scheer, Ianina, additional, Sato, Daisuke, additional, Okamoto, Nobuhiko, additional, Jacobsen, Christina, additional, Tryggestad, Jeanie, additional, Chernausek, Steven, additional, Schimmenti, Lisa A, additional, Brasseur, Benjamin, additional, Cesaretti, Claudia, additional, García-Ortiz, Jose E, additional, Buitrago, Tatiana Pineda, additional, Silva, Orlando Perez, additional, Hoffman, Jodi D, additional, Mühlbauer, Wolfgang, additional, Ruprecht, Klaus W, additional, Loeys, Bart L, additional, Shino, Masato, additional, Kaindl, Angela M, additional, Cho, Chie-Hee, additional, Morton, Cynthia C, additional, Meehan, Richard R, additional, van Heyningen, Veronica, additional, Liao, Eric C, additional, Balasubramanian, Ravikumar, additional, Hall, Janet E, additional, Seminara, Stephanie B, additional, Macarthur, Daniel, additional, Moore, Steven A, additional, Yoshiura, Koh-ichiro, additional, Gusella, James F, additional, Marsh, Joseph A, additional, Graham, John M, additional, Lin, Angela E, additional, Katsanis, Nicholas, additional, Jones, Peter L, additional, Crowley, William F, additional, Davis, Erica E, additional, FitzPatrick, David R, additional, and Talkowski, Michael E, additional

Published
2017
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23. Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome

Author

Naville, Magali, Ishibashi, Minaka, Ferg, Marco, Bengani, Hemant, Rinkwitz, Silke, Krecsmarik, Monika, Hawkins, Thomas A., Wilson, Stephen W., Manning, Elizabeth, Chilamakuri, Chandra S. R., Wilson, David I., Louis, Alexandra, Lucy Raymond, F., Rastegar, Sepand, Strähle, Uwe, Lenhard, Boris, Bally-Cuif, Laure, van Heyningen, Veronica, FitzPatrick, David R., Becker, Thomas S., Roest Crollius, Hugues, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brain and Mind Research Institute, University of Technology Sydney (UTS), Karlsruhe Institute of Technology (KIT), MRC Human Genetics Unit, MRC Institute of Medical Genetic and Molecular Medicine, Institut des Neurosciences de Paris-Saclay (Neuro-PSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), C.D.B. Division of Biosciences, Anatomy building UCL, Department of Tumor Biology, The Norwegian Radium Hospital, University of Southampton and University Hospital Southampton NHS Foundation Trust, Centre for Human Development, Stem Cells and Regeneration, MP808, Faculty of Medicine, Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Institute of Clinical Sciences, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, University of Bergen (UIB), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Paris-Saclay (NeuroPSI), University of Bergen (UiB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris

Subjects
Life sciences, biology, Genetic Linkage, DATABASE, Evolution, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, Article, DISEASE, Animals, Genetically Modified, Evolution, Molecular, Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714 [VDP], Medisinske Fag: 700 [VDP], ddc:570, ELEMENTS, Genetics, Animals, Humans, Selection, Genetic, Zebrafish, GENE-EXPRESSION, Gene Rearrangement, TOOLS, Chromosomes, Human, X, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, GENOMIC SEQUENCES, IN-SITU HYBRIDIZATION, ENHANCERS, Biological sciences, Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], Enhancer Elements, Genetic, HUMAN CELL-TYPES, CONSERVED SYNTENY
Abstract

Enhancers can regulate the transcription of genes over long genomic distances. This is thought to lead to selection against genomic rearrangements within such regions that may disrupt this functional linkage. Here we test this concept experimentally using the human X chromosome. We describe a scoring method to identify evolutionary maintenance of linkage between conserved noncoding elements and neighbouring genes. Chromatin marks associated with enhancer function are strongly correlated with this linkage score. We test >1,000 putative enhancers by transgenesis assays in zebrafish to ascertain the identity of the target gene. The majority of active enhancers drive a transgenic expression in a pattern consistent with the known expression of a linked gene. These results show that evolutionary maintenance of linkage is a reliable predictor of an enhancer's function, and provide new information to discover the genetic basis of diseases caused by the mis-regulation of gene expression., Enhancers regulate the transcription of genes over long genomic distances. Here, the authors show that enhancer function is correlated with maintenance of linkage between non-coding elements and neighbouring genes in the human X chromosome and that enhancers in zebrafish drive expression in a pattern consistent with the expression of a linked gene.

Published
2015
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24. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect

Author

McEntagart, Meriel, primary, Williamson, Kathleen A., additional, Rainger, Jacqueline K., additional, Wheeler, Ann, additional, Seawright, Anne, additional, De Baere, Elfride, additional, Verdin, Hannah, additional, Bergendahl, L. Therese, additional, Quigley, Alan, additional, Rainger, Joe, additional, Dixit, Abhijit, additional, Sarkar, Ajoy, additional, López Laso, Eduardo, additional, Sanchez-Carpintero, Rocio, additional, Barrio, Jesus, additional, Bitoun, Pierre, additional, Prescott, Trine, additional, Riise, Ruth, additional, McKee, Shane, additional, Cook, Jackie, additional, McKie, Lisa, additional, Ceulemans, Berten, additional, Meire, Françoise, additional, Temple, I. Karen, additional, Prieur, Fabienne, additional, Williams, Jonathan, additional, Clouston, Penny, additional, Németh, Andrea H., additional, Banka, Siddharth, additional, Bengani, Hemant, additional, Handley, Mark, additional, Freyer, Elisabeth, additional, Ross, Allyson, additional, van Heyningen, Veronica, additional, Marsh, Joseph A., additional, Elmslie, Frances, additional, and FitzPatrick, David R., additional

Published
2016
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25. Monoallelic and Biallelic Mutations in MAB21L2 Cause a Spectrum of Major Eye Malformations

Author

Rainger, Joe, primary, Pehlivan, Davut, additional, Johansson, Stefan, additional, Bengani, Hemant, additional, Sanchez-Pulido, Luis, additional, Williamson, Kathleen A., additional, Ture, Mehmet, additional, Barker, Heather, additional, Rosendahl, Karen, additional, Spranger, Jürgen, additional, Horn, Denise, additional, Meynert, Alison, additional, Floyd, James A.B., additional, Prescott, Trine, additional, Anderson, Carl A., additional, Rainger, Jacqueline K., additional, Karaca, Ender, additional, Gonzaga-Jauregui, Claudia, additional, Jhangiani, Shalini, additional, Muzny, Donna M., additional, Seawright, Anne, additional, Soares, Dinesh C., additional, Kharbanda, Mira, additional, Murday, Victoria, additional, Finch, Andrew, additional, Gibbs, Richard A., additional, van Heyningen, Veronica, additional, Taylor, Martin S., additional, Yakut, Tahsin, additional, Knappskog, Per M., additional, Hurles, Matthew E., additional, Ponting, Chris P., additional, Lupski, James R., additional, Houge, Gunnar, additional, FitzPatrick, David R., additional, Hurles, Matthew, additional, FitzPatrick, David R., additional, Al-Turki, Saeed, additional, Anderson, Carl, additional, Barroso, Inês, additional, Beales, Philip, additional, Bentham, Jamie, additional, Bhattacharya, Shoumo, additional, Carss, Keren, additional, Chatterjee, Krishna, additional, Cirak, Sebhattin, additional, Cosgrove, Catherine, additional, Daly, Allan, additional, Floyd, Jamie, additional, Franklin, Chris, additional, Futema, Marta, additional, Humphries, Steve, additional, McCarthy, Shane, additional, Mitchison, Hannah, additional, Muntoni, Francesco, additional, Onoufriadis, Alexandros, additional, Parker, Victoria, additional, Payne, Felicity, additional, Plagnol, Vincent, additional, Raymond, Lucy, additional, Savage, David, additional, Scambler, Peter, additional, Schmidts, Miriam, additional, Semple, Robert, additional, Serra, Eva, additional, Stalker, Jim, additional, van Kogelenberg, Margriet, additional, Vijayarangakannan, Parthiban, additional, Walter, Klaudia, additional, and Wood, Gretta, additional

Published
2014
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26. FRA2A Is a CGG Repeat Expansion Associated with Silencing of AFF3

Author

Metsu, Sofie, primary, Rooms, Liesbeth, additional, Rainger, Jacqueline, additional, Taylor, Martin S., additional, Bengani, Hemant, additional, Wilson, David I., additional, Chilamakuri, Chandra Sekhar Reddy, additional, Morrison, Harris, additional, Vandeweyer, Geert, additional, Reyniers, Edwin, additional, Douglas, Evelyn, additional, Thompson, Geoffrey, additional, Haan, Eric, additional, Gecz, Jozef, additional, FitzPatrick, David R., additional, and Kooy, R. Frank, additional

Published
2014
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27. BRD4 interacts with NIPBL and BRD4is mutated in a Cornelia de Lange–like syndrome

Author

Olley, Gabrielle, Ansari, Morad, Bengani, Hemant, Grimes, Graeme, Rhodes, James, von Kriegsheim, Alex, Blatnik, Ana, Stewart, Fiona, Wakeling, Emma, Carroll, Nicola, Ross, Alison, Park, Soo-Mi, Bickmore, Wendy, Pradeepa, Madapura, and FitzPatrick, David

Abstract

We found that the clinical phenotype associated with BRD4haploinsufficiency overlapped with that of Cornelia de Lange syndrome (CdLS), which is most often caused by mutation of NIPBL. More typical CdLS was observed with a de novo BRD4 missense variant, which retained the ability to coimmunoprecipitate with NIPBL, but bound poorly to acetylated histones. BRD4 and NIPBL displayed correlated binding at super-enhancers and appeared to co-regulate developmental gene expression. The clinical phenotype associated with BRD4 haploinsufficiency overlaps with Cornelia de Lange syndrome, which is often caused by mutations in NIPBL. The authors show that BRD4 and NIPBL physically interact and co-bind at super-enhancers.

Published
2018
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31. FRA2A Is a CGG Repeat Expansion Associated with Silencing of AFF3.

Author

Metsu, Sofie, Rooms, Liesbeth, Rainger, Jacqueline, Taylor, Martin S., Bengani, Hemant, Wilson, David I., Chilamakuri, Chandra Sekhar Reddy, Morrison, Harris, Vandeweyer, Geert, Reyniers, Edwin, Douglas, Evelyn, Thompson, Geoffrey, Haan, Eric, Gecz, Jozef, FitzPatrick, David R., and Kooy, R. Frank

Subjects
GENE silencing, GENETIC regulation, GENETIC mutation, GENE expression, GENETIC polymorphism research, IN situ hybridization
Abstract

Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5–12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship. [ABSTRACT FROM AUTHOR]

Published
2014
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32. A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect

Author

McEntagart, Meriel, Williamson, Kathleen A, Rainger, Jacqueline K, Wheeler, Ann, Seawright, Anne, De Baere, Elfride, Verdin, Hannah, Bergendahl, L Therese, Quigley, Alan, Rainger, Joe, Dixit, Abhijit, Sarkar, Ajoy, López Laso, Eduardo, Sanchez-Carpintero, Rocio, Barrio, Jesus, Bitoun, Pierre, Prescott, Trine, Riise, Ruth, McKee, Shane, Cook, Jackie, McKie, Lisa, Ceulemans, Berten, Meire, Françoise, Temple, I Karen, Prieur, Fabienne, Williams, Jonathan, Clouston, Penny, Németh, Andrea H, Banka, Siddharth, Bengani, Hemant, Handley, Mark, Freyer, Elisabeth, Ross, Allyson, van Heyningen, Veronica, Marsh, Joseph A, Elmslie, Frances, FitzPatrick, David R, and DDD Study

Subjects
Adult, Male, MISSENSE MUTATIONS, cerebellar hypoplasia, Génétique clinique, inositol triphosphate, Adolescent, Protein Conformation, aniridia, PHENOTYPE, FAMILIES, GENE DELETION, PROTEIN COMPLEXES, Mice, Report, Intellectual Disability, cerebellar vermis, Journal Article, Genetics, Animals, Humans, Inositol 1,4,5-Trisphosphate Receptors, Genetics(clinical), Lymphocytes, Child, Cells, Cultured, CEREBELLAR-ATAXIA, Genes, Dominant, iris, SPINOCEREBELLAR ATAXIA, ITPR1, Microscopy, Confocal, calcium, Biology and Life Sciences, ANIRIDIA, Middle Aged, Pedigree, ATAXIA TYPE 15, CHANNELOPATHIES, Mutation, Female, Human medicine, cerebellar ataxia, ACTA2, Biologie
Abstract

Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions., SCOPUS: ar.j, info:eu-repo/semantics/published

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33. Publisher Correction: BRD4 interacts with NIPBL and BRD4is mutated in a Cornelia de Lange–like syndrome

Author

Olley, Gabrielle, Ansari, Morad, Bengani, Hemant, Grimes, Graeme, Rhodes, James, von Kriegsheim, Alex, Blatnik, Ana, Stewart, Fiona, Wakeling, Emma, Carroll, Nicola, Ross, Alison, Park, Soo-Mi, Bickmore, Wendy, Pradeepa, Madapura, and FitzPatrick, David

Abstract

In the version of this article initially published, Wendy Bickmore and Madapura Pradeepa were incorrectly not indicated as corresponding authors. The error has been corrected in the HTML and PDF versions of the paper.

Published
2018
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34. FRA2A Is a CGG Repeat Expansion Associated with Silencing of AFF3.

Author

Metsu, Sofie, Rooms, Liesbeth, Rainger, Jacqueline, Taylor, Martin S., Bengani, Hemant, Wilson, David I., Chilamakuri, Chandra Sekhar Reddy, Morrison, Harris, Vandeweyer, Geert, Reyniers, Edwin, Douglas, Evelyn, Thompson, Geoffrey, Haan, Eric, Gecz, Jozef, FitzPatrick, David R., and Kooy, R. Frank

Subjects
*GENE silencing, *GENETIC regulation, *GENETIC mutation, *GENE expression, *GENETIC polymorphism research, *IN situ hybridization
Abstract

Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5–12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship. [ABSTRACT FROM AUTHOR]

Published
2014
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35. Clinical and molecular consequences of disease-associated de novo mutations in SATB2.

Author

Bengani H, Handley M, Alvi M, Ibitoye R, Lees M, Lynch SA, Lam W, Fannemel M, Nordgren A, Malmgren H, Kvarnung M, Mehta S, McKee S, Whiteford M, Stewart F, Connell F, Clayton-Smith J, Mansour S, Mohammed S, Fryer A, Morton J, Grozeva D, Asam T, Moore D, Sifrim A, McRae J, Hurles ME, Firth HV, Raymond FL, Kini U, Nellåker C, Ddd Study, and FitzPatrick DR

Subjects
Cell Line, Cohort Studies, Genetic Association Studies, Haploinsufficiency genetics, HeLa Cells, Humans, Intellectual Disability physiopathology, Matrix Attachment Region Binding Proteins physiology, Protein Binding genetics, Transcription Factors physiology, Whole Genome Sequencing, Intellectual Disability genetics, Loss of Function Mutation, Matrix Attachment Region Binding Proteins genetics, Mutation, Missense, Transcription Factors genetics
Abstract

Purpose: To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability., Methods: Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production. Subcellular localization and mobility of wild-type and mutant SATB2 were assessed using fluorescently tagged protein., Results: Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19). Six of eight missense variants clustered in the first CUT domain. Sibling recurrence due to gonadal mosaicism was seen in one family. A nonsense mutation in the last exon resulted in production of a truncated protein retaining all three DNA-binding domains. SATB2 nuclear mobility was mutation-dependent; p.Arg389Cys in CUT1 increased mobility and both p.Gly515Ser in CUT2 and p.Gln566Lys between CUT2 and HOX reduced mobility. The clinical features in individuals with missense variants were indistinguishable from those with loss of function., Conclusion: SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. When mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association.Genet Med advance online publication 02 February 2017.

Published
2017
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36. Corrigendum: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Author

Shaw ND, Brand H, Kupchinsky ZA, Bengani H, Plummer L, Jones TI, Erdin S, Williamson KA, Rainger J, Stortchevoi A, Samocha K, Currall BB, Dunican DS, Collins RL, Willer JR, Lek A, Lek M, Nassan M, Pereira S, Kammin T, Lucente D, Silva A, Seabra CM, Chiang C, An Y, Ansari M, Rainger JK, Joss S, Smith JC, Lippincott MF, Singh SS, Patel N, Jing JW, Law JR, Ferraro N, Verloes A, Rauch A, Steindl K, Zweier M, Scheer I, Sato D, Okamoto N, Jacobsen C, Tryggestad J, Chernausek S, Schimmenti LA, Brasseur B, Cesaretti C, García-Ortiz JE, Buitrago TP, Silva OP, Hoffman JD, Mühlbauer W, Ruprecht KW, Loeys BL, Shino M, Kaindl AM, Cho CH, Morton CC, Meehan RR, van Heyningen V, Liao EC, Balasubramanian R, Hall JE, Seminara SB, Macarthur D, Moore SA, Yoshiura KI, Gusella JF, Marsh JA, Graham JM Jr, Lin AE, Katsanis N, Jones PL, Crowley WF Jr, Davis EE, FitzPatrick DR, and Talkowski ME

Published
2017
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37. Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome.

Author

Naville M, Ishibashi M, Ferg M, Bengani H, Rinkwitz S, Krecsmarik M, Hawkins TA, Wilson SW, Manning E, Chilamakuri CS, Wilson DI, Louis A, Lucy Raymond F, Rastegar S, Strähle U, Lenhard B, Bally-Cuif L, van Heyningen V, FitzPatrick DR, Becker TS, and Roest Crollius H

Subjects
Animals, Animals, Genetically Modified, Evolution, Molecular, Gene Rearrangement genetics, Humans, Zebrafish, Chromosomes, Human, X genetics, Enhancer Elements, Genetic genetics, Gene Expression genetics, Genetic Linkage genetics, Selection, Genetic genetics
Abstract

Enhancers can regulate the transcription of genes over long genomic distances. This is thought to lead to selection against genomic rearrangements within such regions that may disrupt this functional linkage. Here we test this concept experimentally using the human X chromosome. We describe a scoring method to identify evolutionary maintenance of linkage between conserved noncoding elements and neighbouring genes. Chromatin marks associated with enhancer function are strongly correlated with this linkage score. We test >1,000 putative enhancers by transgenesis assays in zebrafish to ascertain the identity of the target gene. The majority of active enhancers drive a transgenic expression in a pattern consistent with the known expression of a linked gene. These results show that evolutionary maintenance of linkage is a reliable predictor of an enhancer's function, and provide new information to discover the genetic basis of diseases caused by the mis-regulation of gene expression.

Published
2015
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