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Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome

While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the “low hanging fruit” of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional as...

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Autores principales: Evrony, Gilad D., Cordero, Dwight R., Shen, Jun, Partlow, Jennifer N., Yu, Timothy W., Rodin, Rachel E., Hill, R. Sean, Coulter, Michael E., Lam, Anh-Thu N., Jayaraman, Divya, Gerrelli, Dianne, Diaz, Diana G., Santos, Chloe, Morrison, Victoria, Galli, Antonella, Tschulena, Ulrich, Wiemann, Stefan, Martel, M. Jocelyne, Spooner, Betty, Ryu, Steven C., Elhosary, Princess C., Richardson, Jillian M., Tierney, Danielle, Robinson, Christopher A., Chibbar, Rajni, Diudea, Dana, Folkerth, Rebecca, Wiebe, Sheldon, Barkovich, A. James, Mochida, Ganeshwaran H., Irvine, James, Lemire, Edmond G., Blakley, Patricia, Walsh, Christopher A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538549/
https://www.ncbi.nlm.nih.gov/pubmed/28630177
http://dx.doi.org/10.1101/gr.219899.116
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author Evrony, Gilad D.
Cordero, Dwight R.
Shen, Jun
Partlow, Jennifer N.
Yu, Timothy W.
Rodin, Rachel E.
Hill, R. Sean
Coulter, Michael E.
Lam, Anh-Thu N.
Jayaraman, Divya
Gerrelli, Dianne
Diaz, Diana G.
Santos, Chloe
Morrison, Victoria
Galli, Antonella
Tschulena, Ulrich
Wiemann, Stefan
Martel, M. Jocelyne
Spooner, Betty
Ryu, Steven C.
Elhosary, Princess C.
Richardson, Jillian M.
Tierney, Danielle
Robinson, Christopher A.
Chibbar, Rajni
Diudea, Dana
Folkerth, Rebecca
Wiebe, Sheldon
Barkovich, A. James
Mochida, Ganeshwaran H.
Irvine, James
Lemire, Edmond G.
Blakley, Patricia
Walsh, Christopher A.
author_facet Evrony, Gilad D.
Cordero, Dwight R.
Shen, Jun
Partlow, Jennifer N.
Yu, Timothy W.
Rodin, Rachel E.
Hill, R. Sean
Coulter, Michael E.
Lam, Anh-Thu N.
Jayaraman, Divya
Gerrelli, Dianne
Diaz, Diana G.
Santos, Chloe
Morrison, Victoria
Galli, Antonella
Tschulena, Ulrich
Wiemann, Stefan
Martel, M. Jocelyne
Spooner, Betty
Ryu, Steven C.
Elhosary, Princess C.
Richardson, Jillian M.
Tierney, Danielle
Robinson, Christopher A.
Chibbar, Rajni
Diudea, Dana
Folkerth, Rebecca
Wiebe, Sheldon
Barkovich, A. James
Mochida, Ganeshwaran H.
Irvine, James
Lemire, Edmond G.
Blakley, Patricia
Walsh, Christopher A.
author_sort Evrony, Gilad D.
collection PubMed
description While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the “low hanging fruit” of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation.
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spelling pubmed-55385492017-08-09 Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome Evrony, Gilad D. Cordero, Dwight R. Shen, Jun Partlow, Jennifer N. Yu, Timothy W. Rodin, Rachel E. Hill, R. Sean Coulter, Michael E. Lam, Anh-Thu N. Jayaraman, Divya Gerrelli, Dianne Diaz, Diana G. Santos, Chloe Morrison, Victoria Galli, Antonella Tschulena, Ulrich Wiemann, Stefan Martel, M. Jocelyne Spooner, Betty Ryu, Steven C. Elhosary, Princess C. Richardson, Jillian M. Tierney, Danielle Robinson, Christopher A. Chibbar, Rajni Diudea, Dana Folkerth, Rebecca Wiebe, Sheldon Barkovich, A. James Mochida, Ganeshwaran H. Irvine, James Lemire, Edmond G. Blakley, Patricia Walsh, Christopher A. Genome Res Research While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the “low hanging fruit” of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation. Cold Spring Harbor Laboratory Press 2017-08 /pmc/articles/PMC5538549/ /pubmed/28630177 http://dx.doi.org/10.1101/gr.219899.116 Text en © 2017 Evrony et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research
Evrony, Gilad D.
Cordero, Dwight R.
Shen, Jun
Partlow, Jennifer N.
Yu, Timothy W.
Rodin, Rachel E.
Hill, R. Sean
Coulter, Michael E.
Lam, Anh-Thu N.
Jayaraman, Divya
Gerrelli, Dianne
Diaz, Diana G.
Santos, Chloe
Morrison, Victoria
Galli, Antonella
Tschulena, Ulrich
Wiemann, Stefan
Martel, M. Jocelyne
Spooner, Betty
Ryu, Steven C.
Elhosary, Princess C.
Richardson, Jillian M.
Tierney, Danielle
Robinson, Christopher A.
Chibbar, Rajni
Diudea, Dana
Folkerth, Rebecca
Wiebe, Sheldon
Barkovich, A. James
Mochida, Ganeshwaran H.
Irvine, James
Lemire, Edmond G.
Blakley, Patricia
Walsh, Christopher A.
Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome
title Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome
title_full Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome
title_fullStr Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome
title_full_unstemmed Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome
title_short Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome
title_sort integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor donson as the cause of microcephaly-micromelia syndrome
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538549/
https://www.ncbi.nlm.nih.gov/pubmed/28630177
http://dx.doi.org/10.1101/gr.219899.116
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