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Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance

Endogenous retrotransposons have caused extensive genomic variation within mammalian species, but the functional implications of such mobilization are mostly unknown. We mapped thousands of endogenous retrovirus (ERV) germline integrants in highly divergent, previously unsequenced mouse lineages, fa...

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Autores principales: Li, Jingfeng, Akagi, Keiko, Hu, Yongjun, Trivett, Anna L., Hlynialuk, Christopher J.W., Swing, Deborah A., Volfovsky, Natalia, Morgan, Tamara C., Golubeva, Yelena, Stephens, Robert M., Smith, David E., Symer, David E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337433/
https://www.ncbi.nlm.nih.gov/pubmed/22367191
http://dx.doi.org/10.1101/gr.130740.111
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author Li, Jingfeng
Akagi, Keiko
Hu, Yongjun
Trivett, Anna L.
Hlynialuk, Christopher J.W.
Swing, Deborah A.
Volfovsky, Natalia
Morgan, Tamara C.
Golubeva, Yelena
Stephens, Robert M.
Smith, David E.
Symer, David E.
author_facet Li, Jingfeng
Akagi, Keiko
Hu, Yongjun
Trivett, Anna L.
Hlynialuk, Christopher J.W.
Swing, Deborah A.
Volfovsky, Natalia
Morgan, Tamara C.
Golubeva, Yelena
Stephens, Robert M.
Smith, David E.
Symer, David E.
author_sort Li, Jingfeng
collection PubMed
description Endogenous retrotransposons have caused extensive genomic variation within mammalian species, but the functional implications of such mobilization are mostly unknown. We mapped thousands of endogenous retrovirus (ERV) germline integrants in highly divergent, previously unsequenced mouse lineages, facilitating a comparison of gene expression in the presence or absence of local insertions. Polymorphic ERVs occur relatively infrequently in gene introns and are particularly depleted from genes involved in embryogenesis or that are highly expressed in embryonic stem cells. Their genomic distribution implies ongoing negative selection due to deleterious effects on gene expression and function. A polymorphic, intronic ERV at Slc15a2 triggers up to 49-fold increases in premature transcriptional termination and up to 39-fold reductions in full-length transcripts in adult mouse tissues, thereby disrupting protein expression and functional activity. Prematurely truncated transcripts also occur at Polr1a, Spon1, and up to ∼5% of other genes when intronic ERV polymorphisms are present. Analysis of expression quantitative trait loci (eQTLs) in recombinant BxD mouse strains demonstrated very strong genetic associations between the polymorphic ERV in cis and disrupted transcript levels. Premature polyadenylation is triggered at genomic distances up to >12.5 kb upstream of the ERV, both in cis and between alleles. The parent of origin of the ERV is associated with variable expression of nonterminated transcripts and differential DNA methylation at its 5′-long terminal repeat. This study defines an unexpectedly strong functional impact of ERVs in disrupting gene transcription at a distance and demonstrates that ongoing retrotransposition can contribute significantly to natural phenotypic diversity.
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spelling pubmed-33374332012-11-01 Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance Li, Jingfeng Akagi, Keiko Hu, Yongjun Trivett, Anna L. Hlynialuk, Christopher J.W. Swing, Deborah A. Volfovsky, Natalia Morgan, Tamara C. Golubeva, Yelena Stephens, Robert M. Smith, David E. Symer, David E. Genome Res Research Endogenous retrotransposons have caused extensive genomic variation within mammalian species, but the functional implications of such mobilization are mostly unknown. We mapped thousands of endogenous retrovirus (ERV) germline integrants in highly divergent, previously unsequenced mouse lineages, facilitating a comparison of gene expression in the presence or absence of local insertions. Polymorphic ERVs occur relatively infrequently in gene introns and are particularly depleted from genes involved in embryogenesis or that are highly expressed in embryonic stem cells. Their genomic distribution implies ongoing negative selection due to deleterious effects on gene expression and function. A polymorphic, intronic ERV at Slc15a2 triggers up to 49-fold increases in premature transcriptional termination and up to 39-fold reductions in full-length transcripts in adult mouse tissues, thereby disrupting protein expression and functional activity. Prematurely truncated transcripts also occur at Polr1a, Spon1, and up to ∼5% of other genes when intronic ERV polymorphisms are present. Analysis of expression quantitative trait loci (eQTLs) in recombinant BxD mouse strains demonstrated very strong genetic associations between the polymorphic ERV in cis and disrupted transcript levels. Premature polyadenylation is triggered at genomic distances up to >12.5 kb upstream of the ERV, both in cis and between alleles. The parent of origin of the ERV is associated with variable expression of nonterminated transcripts and differential DNA methylation at its 5′-long terminal repeat. This study defines an unexpectedly strong functional impact of ERVs in disrupting gene transcription at a distance and demonstrates that ongoing retrotransposition can contribute significantly to natural phenotypic diversity. Cold Spring Harbor Laboratory Press 2012-05 /pmc/articles/PMC3337433/ /pubmed/22367191 http://dx.doi.org/10.1101/gr.130740.111 Text en © 2012, Published by Cold Spring Harbor Laboratory Press This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.
spellingShingle Research
Li, Jingfeng
Akagi, Keiko
Hu, Yongjun
Trivett, Anna L.
Hlynialuk, Christopher J.W.
Swing, Deborah A.
Volfovsky, Natalia
Morgan, Tamara C.
Golubeva, Yelena
Stephens, Robert M.
Smith, David E.
Symer, David E.
Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance
title Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance
title_full Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance
title_fullStr Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance
title_full_unstemmed Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance
title_short Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance
title_sort mouse endogenous retroviruses can trigger premature transcriptional termination at a distance
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337433/
https://www.ncbi.nlm.nih.gov/pubmed/22367191
http://dx.doi.org/10.1101/gr.130740.111
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