An intronic LINE-1 insertion in MERTK is strongly associated with retinopathy in Swedish Vallhund dogs
The domestic dog segregates a significant number of inherited progressive retinal diseases, several of which mirror human retinal diseases and which are collectively termed progressive retinal atrophy (PRA). In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was...
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| creator | Everson, Richard Pettitt, Louise Forman, Oliver P Dower-Tylee, Olivia McLaughlin, Bryan Ahonen, Saija Kaukonen, Maria Komáromy, András M Lohi, Hannes Mellersh, Cathryn S Sansom, Jane Ricketts, Sally L |
| description | The domestic dog segregates a significant number of inherited progressive retinal diseases, several of which mirror human retinal diseases and which are collectively termed progressive retinal atrophy (PRA). In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was mapped to canine chromosome 17. The causal mutation was not identified, but expression analyses of the retinas of affected Vallhunds demonstrated a 6-fold increased expression of the MERTK gene compared to unaffected dogs. Using 24 retinopathy cases and 97 controls with no clinical signs of retinopathy, we replicated the chromosome 17 association in Swedish Vallhunds from the UK and aimed to elucidate the causal variant underlying this association using whole genome sequencing (WGS) of an affected dog. This revealed a 6-8 kb insertion in intron 1 of MERTK that was not present in WGS of 49 dogs of other breeds. Sequencing and BLASTN analysis of the inserted segment was consistent with the insertion comprising a full-length intact LINE-1 retroelement. Testing of the LINE-1 insertion for association with retinopathy in the UK set of 24 cases and 97 controls revealed a strong statistical association (P-value 6.0 x 10-11) that was subsequently replicated in the original Finnish study set (49 cases and 89 controls (P-value 4.3 x 10-19). In a pooled analysis of both studies (73 cases and 186 controls), the LINE-1 insertion was associated with a ~20-fold increased risk of retinopathy (odds ratio 23.41, 95% confidence intervals 10.99-49.86, P-value 1.3 x 10-27). Our study adds further support for regulatory disruption of MERTK in Swedish Vallhund retinopathy; however, further work is required to establish a functional overexpression model. Future work to characterise the mechanism by which this intronic mutation disrupts gene regulation will further improve the understanding of MERTK biology and its role in retinal function. |
| doi_str_mv | 10.1371/journal.pone.0183021 |
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In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was mapped to canine chromosome 17. The causal mutation was not identified, but expression analyses of the retinas of affected Vallhunds demonstrated a 6-fold increased expression of the MERTK gene compared to unaffected dogs. Using 24 retinopathy cases and 97 controls with no clinical signs of retinopathy, we replicated the chromosome 17 association in Swedish Vallhunds from the UK and aimed to elucidate the causal variant underlying this association using whole genome sequencing (WGS) of an affected dog. This revealed a 6-8 kb insertion in intron 1 of MERTK that was not present in WGS of 49 dogs of other breeds. Sequencing and BLASTN analysis of the inserted segment was consistent with the insertion comprising a full-length intact LINE-1 retroelement. Testing of the LINE-1 insertion for association with retinopathy in the UK set of 24 cases and 97 controls revealed a strong statistical association (P-value 6.0 x 10-11) that was subsequently replicated in the original Finnish study set (49 cases and 89 controls (P-value 4.3 x 10-19). In a pooled analysis of both studies (73 cases and 186 controls), the LINE-1 insertion was associated with a ~20-fold increased risk of retinopathy (odds ratio 23.41, 95% confidence intervals 10.99-49.86, P-value 1.3 x 10-27). Our study adds further support for regulatory disruption of MERTK in Swedish Vallhund retinopathy; however, further work is required to establish a functional overexpression model. Future work to characterise the mechanism by which this intronic mutation disrupts gene regulation will further improve the understanding of MERTK biology and its role in retinal function.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0183021</identifier><identifier>PMID: 28813472</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Atrophy ; Biology and Life Sciences ; Breeding of animals ; Chromosome 17 ; Comparative analysis ; Confidence intervals ; Disease ; Disruption ; DNA sequencing ; Dogs ; Finland ; Gene expression ; Gene regulation ; Gene sequencing ; Genetic aspects ; Genetics ; Genome-Wide Association Study ; Genomes ; Genotype ; Health aspects ; Insertion ; Introns ; Kinases ; Long Interspersed Nucleotide Elements ; Medicine and Health Sciences ; MERTK gene ; Mutagenesis, Insertional ; Mutation ; Neurology ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins - genetics ; Receptor Protein-Tyrosine Kinases - genetics ; Research and Analysis Methods ; Retina ; Retinal degeneration ; Retinal diseases ; Retinal Diseases - genetics ; Retinopathy ; Studies ; United Kingdom ; Veterinary medicine</subject><ispartof>PloS one, 2017-08, Vol.12 (8), p.e0183021-e0183021</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Everson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Everson et al 2017 Everson et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-daab1f925bf5a707ed55fb4f75ed5345d7b0d46d0213051af5c250e6741451ca3</citedby><cites>FETCH-LOGICAL-c692t-daab1f925bf5a707ed55fb4f75ed5345d7b0d46d0213051af5c250e6741451ca3</cites><orcidid>0000-0002-5644-7958</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558984/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558984/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28813472$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Wade, Claire</contributor><creatorcontrib>Everson, Richard</creatorcontrib><creatorcontrib>Pettitt, Louise</creatorcontrib><creatorcontrib>Forman, Oliver P</creatorcontrib><creatorcontrib>Dower-Tylee, Olivia</creatorcontrib><creatorcontrib>McLaughlin, Bryan</creatorcontrib><creatorcontrib>Ahonen, Saija</creatorcontrib><creatorcontrib>Kaukonen, Maria</creatorcontrib><creatorcontrib>Komáromy, András M</creatorcontrib><creatorcontrib>Lohi, Hannes</creatorcontrib><creatorcontrib>Mellersh, Cathryn S</creatorcontrib><creatorcontrib>Sansom, Jane</creatorcontrib><creatorcontrib>Ricketts, Sally L</creatorcontrib><title>An intronic LINE-1 insertion in MERTK is strongly associated with retinopathy in Swedish Vallhund dogs</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The domestic dog segregates a significant number of inherited progressive retinal diseases, several of which mirror human retinal diseases and which are collectively termed progressive retinal atrophy (PRA). In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was mapped to canine chromosome 17. The causal mutation was not identified, but expression analyses of the retinas of affected Vallhunds demonstrated a 6-fold increased expression of the MERTK gene compared to unaffected dogs. Using 24 retinopathy cases and 97 controls with no clinical signs of retinopathy, we replicated the chromosome 17 association in Swedish Vallhunds from the UK and aimed to elucidate the causal variant underlying this association using whole genome sequencing (WGS) of an affected dog. This revealed a 6-8 kb insertion in intron 1 of MERTK that was not present in WGS of 49 dogs of other breeds. Sequencing and BLASTN analysis of the inserted segment was consistent with the insertion comprising a full-length intact LINE-1 retroelement. Testing of the LINE-1 insertion for association with retinopathy in the UK set of 24 cases and 97 controls revealed a strong statistical association (P-value 6.0 x 10-11) that was subsequently replicated in the original Finnish study set (49 cases and 89 controls (P-value 4.3 x 10-19). In a pooled analysis of both studies (73 cases and 186 controls), the LINE-1 insertion was associated with a ~20-fold increased risk of retinopathy (odds ratio 23.41, 95% confidence intervals 10.99-49.86, P-value 1.3 x 10-27). Our study adds further support for regulatory disruption of MERTK in Swedish Vallhund retinopathy; however, further work is required to establish a functional overexpression model. Future work to characterise the mechanism by which this intronic mutation disrupts gene regulation will further improve the understanding of MERTK biology and its role in retinal function.</description><subject>Animals</subject><subject>Atrophy</subject><subject>Biology and Life Sciences</subject><subject>Breeding of animals</subject><subject>Chromosome 17</subject><subject>Comparative analysis</subject><subject>Confidence intervals</subject><subject>Disease</subject><subject>Disruption</subject><subject>DNA sequencing</subject><subject>Dogs</subject><subject>Finland</subject><subject>Gene expression</subject><subject>Gene regulation</subject><subject>Gene sequencing</subject><subject>Genetic aspects</subject><subject>Genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genotype</subject><subject>Health aspects</subject><subject>Insertion</subject><subject>Introns</subject><subject>Kinases</subject><subject>Long Interspersed Nucleotide Elements</subject><subject>Medicine and Health Sciences</subject><subject>MERTK gene</subject><subject>Mutagenesis, Insertional</subject><subject>Mutation</subject><subject>Neurology</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Receptor Protein-Tyrosine Kinases - genetics</subject><subject>Research and Analysis Methods</subject><subject>Retina</subject><subject>Retinal degeneration</subject><subject>Retinal diseases</subject><subject>Retinal Diseases - genetics</subject><subject>Retinopathy</subject><subject>Studies</subject><subject>United Kingdom</subject><subject>Veterinary 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intronic LINE-1 insertion in MERTK is strongly associated with retinopathy in Swedish Vallhund dogs</title><author>Everson, Richard ; Pettitt, Louise ; Forman, Oliver P ; Dower-Tylee, Olivia ; McLaughlin, Bryan ; Ahonen, Saija ; Kaukonen, Maria ; Komáromy, András M ; Lohi, Hannes ; Mellersh, Cathryn S ; Sansom, Jane ; Ricketts, Sally L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-daab1f925bf5a707ed55fb4f75ed5345d7b0d46d0213051af5c250e6741451ca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Atrophy</topic><topic>Biology and Life Sciences</topic><topic>Breeding of animals</topic><topic>Chromosome 17</topic><topic>Comparative analysis</topic><topic>Confidence intervals</topic><topic>Disease</topic><topic>Disruption</topic><topic>DNA sequencing</topic><topic>Dogs</topic><topic>Finland</topic><topic>Gene expression</topic><topic>Gene 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One</addtitle><date>2017-08-16</date><risdate>2017</risdate><volume>12</volume><issue>8</issue><spage>e0183021</spage><epage>e0183021</epage><pages>e0183021-e0183021</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The domestic dog segregates a significant number of inherited progressive retinal diseases, several of which mirror human retinal diseases and which are collectively termed progressive retinal atrophy (PRA). In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was mapped to canine chromosome 17. The causal mutation was not identified, but expression analyses of the retinas of affected Vallhunds demonstrated a 6-fold increased expression of the MERTK gene compared to unaffected dogs. Using 24 retinopathy cases and 97 controls with no clinical signs of retinopathy, we replicated the chromosome 17 association in Swedish Vallhunds from the UK and aimed to elucidate the causal variant underlying this association using whole genome sequencing (WGS) of an affected dog. This revealed a 6-8 kb insertion in intron 1 of MERTK that was not present in WGS of 49 dogs of other breeds. Sequencing and BLASTN analysis of the inserted segment was consistent with the insertion comprising a full-length intact LINE-1 retroelement. Testing of the LINE-1 insertion for association with retinopathy in the UK set of 24 cases and 97 controls revealed a strong statistical association (P-value 6.0 x 10-11) that was subsequently replicated in the original Finnish study set (49 cases and 89 controls (P-value 4.3 x 10-19). In a pooled analysis of both studies (73 cases and 186 controls), the LINE-1 insertion was associated with a ~20-fold increased risk of retinopathy (odds ratio 23.41, 95% confidence intervals 10.99-49.86, P-value 1.3 x 10-27). Our study adds further support for regulatory disruption of MERTK in Swedish Vallhund retinopathy; however, further work is required to establish a functional overexpression model. Future work to characterise the mechanism by which this intronic mutation disrupts gene regulation will further improve the understanding of MERTK biology and its role in retinal function.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28813472</pmid><doi>10.1371/journal.pone.0183021</doi><tpages>e0183021</tpages><orcidid>https://orcid.org/0000-0002-5644-7958</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-08, Vol.12 (8), p.e0183021-e0183021 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1929405143 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Atrophy Biology and Life Sciences Breeding of animals Chromosome 17 Comparative analysis Confidence intervals Disease Disruption DNA sequencing Dogs Finland Gene expression Gene regulation Gene sequencing Genetic aspects Genetics Genome-Wide Association Study Genomes Genotype Health aspects Insertion Introns Kinases Long Interspersed Nucleotide Elements Medicine and Health Sciences MERTK gene Mutagenesis, Insertional Mutation Neurology Polymorphism, Single Nucleotide Proto-Oncogene Proteins - genetics Receptor Protein-Tyrosine Kinases - genetics Research and Analysis Methods Retina Retinal degeneration Retinal diseases Retinal Diseases - genetics Retinopathy Studies United Kingdom Veterinary medicine |
| title | An intronic LINE-1 insertion in MERTK is strongly associated with retinopathy in Swedish Vallhund dogs |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T13%3A08%3A30IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=An%20intronic%20LINE-1%20insertion%20in%20MERTK%20is%20strongly%20associated%20with%20retinopathy%20in%20Swedish%20Vallhund%20dogs&rft.jtitle=PloS%20one&rft.au=Everson,%20Richard&rft.date=2017-08-16&rft.volume=12&rft.issue=8&rft.spage=e0183021&rft.epage=e0183021&rft.pages=e0183021-e0183021&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0183021&rft_dat=%3Cgale_plos_%3EA500760862%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1929405143&rft_id=info:pmid/28813472&rft_galeid=A500760862&rft_doaj_id=oai_doaj_org_article_873c6725aaf14efea311625277834d7f&rfr_iscdi=true |