Candidate genetic modifiers of retinitis pigmentosa identified by exploiting natural variation in Drosophila

Individuals carrying the same pathogenic mutation can present with a broad range of disease outcomes. While some of this variation arises from environmental factors, it is increasingly recognized that the background genetic variation of each individual can have a profound effect on the expressivity...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Human molecular genetics 2016-02, Vol.25 (4), p.651-659
Hauptverfasser: Chow, Clement Y, Kelsey, Keegan J P, Wolfner, Mariana F, Clark, Andrew G
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 659
container_issue 4
container_start_page 651
container_title Human molecular genetics
container_volume 25
creator Chow, Clement Y
Kelsey, Keegan J P
Wolfner, Mariana F
Clark, Andrew G
description Individuals carrying the same pathogenic mutation can present with a broad range of disease outcomes. While some of this variation arises from environmental factors, it is increasingly recognized that the background genetic variation of each individual can have a profound effect on the expressivity of a pathogenic mutation. In order to understand this background effect on disease-causing mutations, studies need to be performed across a wide range of backgrounds. Recent advancements in model organism biology allow us to test mutations across genetically diverse backgrounds and identify the genes that influence the expressivity of a mutation. In this study, we used the Drosophila Genetic Reference Panel, a collection of ∼200 wild-derived strains, to test the variability of the retinal phenotype of the Rh1(G69D) Drosophila model of retinitis pigmentosa (RP). We found that the Rh1(G69D) retinal phenotype is quite a variable quantitative phenotype. To identify the genes driving this extensive phenotypic variation, we performed a genome-wide association study. We identified 106 candidate genes, including 14 high-priority candidates. Functional testing by RNAi indicates that 10/13 top candidates tested influence the expressivity of Rh1(G69D). The human orthologs of the candidate genes have not previously been implicated as RP modifiers and their functions are diverse, including roles in endoplasmic reticulum stress, apoptosis and retinal degeneration and development. This study demonstrates the utility of studying a pathogenic mutation across a wide range of genetic backgrounds. These candidate modifiers provide new avenues of inquiry that may reveal new RP disease mechanisms and therapies.
doi_str_mv 10.1093/hmg/ddv502
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4743685</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1780530631</sourcerecordid><originalsourceid>FETCH-LOGICAL-c416t-b219d8705b7efdbf68a16cce628b3f37ff17a49b7675322c29308d19ac41bdac3</originalsourceid><addsrcrecordid>eNqNkUtr3TAQhUVJaW6TbvoDipYh4EYPeyRvCuGmLwh006yFrIevii25ku8l-fdVuGlodl1p0HxzODMHofeUfKSk51e7ebyy9tAR9gptaAukYUTyE7QhPbQN9ARO0dtSfhFCoeXiDTplAMBEDxs0bXW0werV4dFFtwaD52SDDy4XnDzO9SuGNRS8hHF2cU1F42Br8chYPDxgd79MqSJxxFGv-6wnfNA56DWkiEPENzmVtOzCpM_Ra6-n4t49vWfo7svnn9tvze2Pr9-317eNaSmszcBob6Ug3SCct4MHqSkY44DJgXsuvKdCt_0gQHScMcN6TqSlva7jg9WGn6FPR91lP8zOmuq2ulJLDrPODyrpoF52YtipMR1UK1oOsqsCF08COf3eu7KqORTjpklHl_ZFUSFJxwlw-h8oSAqCUFnRyyNq6kVKdv7ZESXqMUlVk1THJCv84d8dntG_0fE_eOSeLg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1768167018</pqid></control><display><type>article</type><title>Candidate genetic modifiers of retinitis pigmentosa identified by exploiting natural variation in Drosophila</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Chow, Clement Y ; Kelsey, Keegan J P ; Wolfner, Mariana F ; Clark, Andrew G</creator><creatorcontrib>Chow, Clement Y ; Kelsey, Keegan J P ; Wolfner, Mariana F ; Clark, Andrew G</creatorcontrib><description>Individuals carrying the same pathogenic mutation can present with a broad range of disease outcomes. While some of this variation arises from environmental factors, it is increasingly recognized that the background genetic variation of each individual can have a profound effect on the expressivity of a pathogenic mutation. In order to understand this background effect on disease-causing mutations, studies need to be performed across a wide range of backgrounds. Recent advancements in model organism biology allow us to test mutations across genetically diverse backgrounds and identify the genes that influence the expressivity of a mutation. In this study, we used the Drosophila Genetic Reference Panel, a collection of ∼200 wild-derived strains, to test the variability of the retinal phenotype of the Rh1(G69D) Drosophila model of retinitis pigmentosa (RP). We found that the Rh1(G69D) retinal phenotype is quite a variable quantitative phenotype. To identify the genes driving this extensive phenotypic variation, we performed a genome-wide association study. We identified 106 candidate genes, including 14 high-priority candidates. Functional testing by RNAi indicates that 10/13 top candidates tested influence the expressivity of Rh1(G69D). The human orthologs of the candidate genes have not previously been implicated as RP modifiers and their functions are diverse, including roles in endoplasmic reticulum stress, apoptosis and retinal degeneration and development. This study demonstrates the utility of studying a pathogenic mutation across a wide range of genetic backgrounds. These candidate modifiers provide new avenues of inquiry that may reveal new RP disease mechanisms and therapies.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddv502</identifier><identifier>PMID: 26662796</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Animals ; Drosophila ; Drosophila - genetics ; Female ; Genetic Association Studies ; Genetic Variation ; Genome-Wide Association Study ; Genotype ; Male ; Models, Animal ; Mutation ; Pedigree ; Phenotype ; Retina - pathology ; Retinitis Pigmentosa - genetics ; Rhodopsin - genetics</subject><ispartof>Human molecular genetics, 2016-02, Vol.25 (4), p.651-659</ispartof><rights>The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</rights><rights>The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c416t-b219d8705b7efdbf68a16cce628b3f37ff17a49b7675322c29308d19ac41bdac3</citedby><cites>FETCH-LOGICAL-c416t-b219d8705b7efdbf68a16cce628b3f37ff17a49b7675322c29308d19ac41bdac3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26662796$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chow, Clement Y</creatorcontrib><creatorcontrib>Kelsey, Keegan J P</creatorcontrib><creatorcontrib>Wolfner, Mariana F</creatorcontrib><creatorcontrib>Clark, Andrew G</creatorcontrib><title>Candidate genetic modifiers of retinitis pigmentosa identified by exploiting natural variation in Drosophila</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Individuals carrying the same pathogenic mutation can present with a broad range of disease outcomes. While some of this variation arises from environmental factors, it is increasingly recognized that the background genetic variation of each individual can have a profound effect on the expressivity of a pathogenic mutation. In order to understand this background effect on disease-causing mutations, studies need to be performed across a wide range of backgrounds. Recent advancements in model organism biology allow us to test mutations across genetically diverse backgrounds and identify the genes that influence the expressivity of a mutation. In this study, we used the Drosophila Genetic Reference Panel, a collection of ∼200 wild-derived strains, to test the variability of the retinal phenotype of the Rh1(G69D) Drosophila model of retinitis pigmentosa (RP). We found that the Rh1(G69D) retinal phenotype is quite a variable quantitative phenotype. To identify the genes driving this extensive phenotypic variation, we performed a genome-wide association study. We identified 106 candidate genes, including 14 high-priority candidates. Functional testing by RNAi indicates that 10/13 top candidates tested influence the expressivity of Rh1(G69D). The human orthologs of the candidate genes have not previously been implicated as RP modifiers and their functions are diverse, including roles in endoplasmic reticulum stress, apoptosis and retinal degeneration and development. This study demonstrates the utility of studying a pathogenic mutation across a wide range of genetic backgrounds. These candidate modifiers provide new avenues of inquiry that may reveal new RP disease mechanisms and therapies.</description><subject>Animals</subject><subject>Drosophila</subject><subject>Drosophila - genetics</subject><subject>Female</subject><subject>Genetic Association Studies</subject><subject>Genetic Variation</subject><subject>Genome-Wide Association Study</subject><subject>Genotype</subject><subject>Male</subject><subject>Models, Animal</subject><subject>Mutation</subject><subject>Pedigree</subject><subject>Phenotype</subject><subject>Retina - pathology</subject><subject>Retinitis Pigmentosa - genetics</subject><subject>Rhodopsin - genetics</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUtr3TAQhUVJaW6TbvoDipYh4EYPeyRvCuGmLwh006yFrIevii25ku8l-fdVuGlodl1p0HxzODMHofeUfKSk51e7ebyy9tAR9gptaAukYUTyE7QhPbQN9ARO0dtSfhFCoeXiDTplAMBEDxs0bXW0werV4dFFtwaD52SDDy4XnDzO9SuGNRS8hHF2cU1F42Br8chYPDxgd79MqSJxxFGv-6wnfNA56DWkiEPENzmVtOzCpM_Ra6-n4t49vWfo7svnn9tvze2Pr9-317eNaSmszcBob6Ug3SCct4MHqSkY44DJgXsuvKdCt_0gQHScMcN6TqSlva7jg9WGn6FPR91lP8zOmuq2ulJLDrPODyrpoF52YtipMR1UK1oOsqsCF08COf3eu7KqORTjpklHl_ZFUSFJxwlw-h8oSAqCUFnRyyNq6kVKdv7ZESXqMUlVk1THJCv84d8dntG_0fE_eOSeLg</recordid><startdate>20160215</startdate><enddate>20160215</enddate><creator>Chow, Clement Y</creator><creator>Kelsey, Keegan J P</creator><creator>Wolfner, Mariana F</creator><creator>Clark, Andrew G</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20160215</creationdate><title>Candidate genetic modifiers of retinitis pigmentosa identified by exploiting natural variation in Drosophila</title><author>Chow, Clement Y ; Kelsey, Keegan J P ; Wolfner, Mariana F ; Clark, Andrew G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c416t-b219d8705b7efdbf68a16cce628b3f37ff17a49b7675322c29308d19ac41bdac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Drosophila</topic><topic>Drosophila - genetics</topic><topic>Female</topic><topic>Genetic Association Studies</topic><topic>Genetic Variation</topic><topic>Genome-Wide Association Study</topic><topic>Genotype</topic><topic>Male</topic><topic>Models, Animal</topic><topic>Mutation</topic><topic>Pedigree</topic><topic>Phenotype</topic><topic>Retina - pathology</topic><topic>Retinitis Pigmentosa - genetics</topic><topic>Rhodopsin - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chow, Clement Y</creatorcontrib><creatorcontrib>Kelsey, Keegan J P</creatorcontrib><creatorcontrib>Wolfner, Mariana F</creatorcontrib><creatorcontrib>Clark, Andrew G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chow, Clement Y</au><au>Kelsey, Keegan J P</au><au>Wolfner, Mariana F</au><au>Clark, Andrew G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Candidate genetic modifiers of retinitis pigmentosa identified by exploiting natural variation in Drosophila</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2016-02-15</date><risdate>2016</risdate><volume>25</volume><issue>4</issue><spage>651</spage><epage>659</epage><pages>651-659</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Individuals carrying the same pathogenic mutation can present with a broad range of disease outcomes. While some of this variation arises from environmental factors, it is increasingly recognized that the background genetic variation of each individual can have a profound effect on the expressivity of a pathogenic mutation. In order to understand this background effect on disease-causing mutations, studies need to be performed across a wide range of backgrounds. Recent advancements in model organism biology allow us to test mutations across genetically diverse backgrounds and identify the genes that influence the expressivity of a mutation. In this study, we used the Drosophila Genetic Reference Panel, a collection of ∼200 wild-derived strains, to test the variability of the retinal phenotype of the Rh1(G69D) Drosophila model of retinitis pigmentosa (RP). We found that the Rh1(G69D) retinal phenotype is quite a variable quantitative phenotype. To identify the genes driving this extensive phenotypic variation, we performed a genome-wide association study. We identified 106 candidate genes, including 14 high-priority candidates. Functional testing by RNAi indicates that 10/13 top candidates tested influence the expressivity of Rh1(G69D). The human orthologs of the candidate genes have not previously been implicated as RP modifiers and their functions are diverse, including roles in endoplasmic reticulum stress, apoptosis and retinal degeneration and development. This study demonstrates the utility of studying a pathogenic mutation across a wide range of genetic backgrounds. These candidate modifiers provide new avenues of inquiry that may reveal new RP disease mechanisms and therapies.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>26662796</pmid><doi>10.1093/hmg/ddv502</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0964-6906
ispartof Human molecular genetics, 2016-02, Vol.25 (4), p.651-659
issn 0964-6906
1460-2083
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4743685
source Oxford University Press Journals All Titles (1996-Current); MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection
subjects Animals
Drosophila
Drosophila - genetics
Female
Genetic Association Studies
Genetic Variation
Genome-Wide Association Study
Genotype
Male
Models, Animal
Mutation
Pedigree
Phenotype
Retina - pathology
Retinitis Pigmentosa - genetics
Rhodopsin - genetics
title Candidate genetic modifiers of retinitis pigmentosa identified by exploiting natural variation in Drosophila
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T15%3A02%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Candidate%20genetic%20modifiers%20of%20retinitis%20pigmentosa%20identified%20by%20exploiting%20natural%20variation%20in%20Drosophila&rft.jtitle=Human%20molecular%20genetics&rft.au=Chow,%20Clement%20Y&rft.date=2016-02-15&rft.volume=25&rft.issue=4&rft.spage=651&rft.epage=659&rft.pages=651-659&rft.issn=0964-6906&rft.eissn=1460-2083&rft_id=info:doi/10.1093/hmg/ddv502&rft_dat=%3Cproquest_pubme%3E1780530631%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1768167018&rft_id=info:pmid/26662796&rfr_iscdi=true