Assessment of the gene mosaicism burden in blood and its implications for immune disorders
There are increasing evidences showing the contribution of somatic genetic variants to non-cancer diseases. However, their detection using massive parallel sequencing methods still has important limitations. In addition, the relative importance and dynamics of somatic variation in healthy tissues are not fully understood. We performed high-depth whole-exome sequencing in 16 samples from patients with a previously determined pathogenic somatic variant for a primary immunodeficiency and tested different variant callers detection ability. Subsequently, we explored the load of somatic variants in the whole blood of these individuals and validated it by amplicon-based deep sequencing. Variant callers allowing low frequency read thresholds were able to detect most of the variants, even at very low frequencies in the tissue. The genetic load of somatic coding variants detectable in whole blood is low, ranging from 1 to 2 variants in our dataset, except for one case with 17 variants compatible with clonal haematopoiesis under genetic drift. Because of the ability we demonstrated to detect this type of genetic variation, and its relevant role in disorders such as primary immunodeficiencies, we suggest considering this model of gene mosaicism in future genetic studies and considering revisiting previous massive parallel sequencing data in patients with negative results.
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Springer Nature
2021-06-21
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Online Access: | http://hdl.handle.net/10261/252911 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/501100011033 http://dx.doi.org/10.13039/501100000780 http://dx.doi.org/10.13039/501100002809 http://dx.doi.org/10.13039/100000011 http://dx.doi.org/10.13039/501100004587 |
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There are increasing evidences showing the contribution of somatic genetic variants to non-cancer diseases. However, their detection using massive parallel sequencing methods still has important limitations. In addition, the relative importance and dynamics of somatic variation in healthy tissues are not fully understood. We performed high-depth whole-exome sequencing in 16 samples from patients with a previously determined pathogenic somatic variant for a primary immunodeficiency and tested different variant callers detection ability. Subsequently, we explored the load of somatic variants in the whole blood of these individuals and validated it by amplicon-based deep sequencing. Variant callers allowing low frequency read thresholds were able to detect most of the variants, even at very low frequencies in the tissue. The genetic load of somatic coding variants detectable in whole blood is low, ranging from 1 to 2 variants in our dataset, except for one case with 17 variants compatible with clonal haematopoiesis under genetic drift. Because of the ability we demonstrated to detect this type of genetic variation, and its relevant role in disorders such as primary immunodeficiencies, we suggest considering this model of gene mosaicism in future genetic studies and considering revisiting previous massive parallel sequencing data in patients with negative results. |
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Ministerio de Economía y Competitividad (España) |
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Ministerio de Economía y Competitividad (España) Solís-Moruno, Manuel Mensa-Vilaró, Anna Batlle-Masó, Laura Lobón, Irene Bonet, Núria Marqués-Bonet, Tomàs Arostegui, Juan Ignacio Casals, Ferran |
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Solís-Moruno, Manuel Mensa-Vilaró, Anna Batlle-Masó, Laura Lobón, Irene Bonet, Núria Marqués-Bonet, Tomàs Arostegui, Juan Ignacio Casals, Ferran |
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Solís-Moruno, Manuel Mensa-Vilaró, Anna Batlle-Masó, Laura Lobón, Irene Bonet, Núria Marqués-Bonet, Tomàs Arostegui, Juan Ignacio Casals, Ferran Assessment of the gene mosaicism burden in blood and its implications for immune disorders |
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Solís-Moruno, Manuel |
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Assessment of the gene mosaicism burden in blood and its implications for immune disorders |
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Assessment of the gene mosaicism burden in blood and its implications for immune disorders |
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Assessment of the gene mosaicism burden in blood and its implications for immune disorders |
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Assessment of the gene mosaicism burden in blood and its implications for immune disorders |
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Assessment of the gene mosaicism burden in blood and its implications for immune disorders |
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assessment of the gene mosaicism burden in blood and its implications for immune disorders |
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Springer Nature |
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2021-06-21 |
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http://hdl.handle.net/10261/252911 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/501100011033 http://dx.doi.org/10.13039/501100000780 http://dx.doi.org/10.13039/501100002809 http://dx.doi.org/10.13039/100000011 http://dx.doi.org/10.13039/501100004587 |
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AT solismorunomanuel assessmentofthegenemosaicismburdeninbloodanditsimplicationsforimmunedisorders AT mensavilaroanna assessmentofthegenemosaicismburdeninbloodanditsimplicationsforimmunedisorders AT batllemasolaura assessmentofthegenemosaicismburdeninbloodanditsimplicationsforimmunedisorders AT lobonirene assessmentofthegenemosaicismburdeninbloodanditsimplicationsforimmunedisorders AT bonetnuria assessmentofthegenemosaicismburdeninbloodanditsimplicationsforimmunedisorders AT marquesbonettomas assessmentofthegenemosaicismburdeninbloodanditsimplicationsforimmunedisorders AT arosteguijuanignacio assessmentofthegenemosaicismburdeninbloodanditsimplicationsforimmunedisorders AT casalsferran assessmentofthegenemosaicismburdeninbloodanditsimplicationsforimmunedisorders |
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dig-ibe-es-10261-2529112021-12-28T16:16:13Z Assessment of the gene mosaicism burden in blood and its implications for immune disorders Solís-Moruno, Manuel Mensa-Vilaró, Anna Batlle-Masó, Laura Lobón, Irene Bonet, Núria Marqués-Bonet, Tomàs Arostegui, Juan Ignacio Casals, Ferran Ministerio de Economía y Competitividad (España) Ministerio de Ciencia, Innovación y Universidades (España) Agencia Estatal de Investigación (España) European Commission Generalitat de Catalunya Howard Hughes Medical Institute Fundación "la Caixa" Instituto de Salud Carlos III There are increasing evidences showing the contribution of somatic genetic variants to non-cancer diseases. However, their detection using massive parallel sequencing methods still has important limitations. In addition, the relative importance and dynamics of somatic variation in healthy tissues are not fully understood. We performed high-depth whole-exome sequencing in 16 samples from patients with a previously determined pathogenic somatic variant for a primary immunodeficiency and tested different variant callers detection ability. Subsequently, we explored the load of somatic variants in the whole blood of these individuals and validated it by amplicon-based deep sequencing. Variant callers allowing low frequency read thresholds were able to detect most of the variants, even at very low frequencies in the tissue. The genetic load of somatic coding variants detectable in whole blood is low, ranging from 1 to 2 variants in our dataset, except for one case with 17 variants compatible with clonal haematopoiesis under genetic drift. Because of the ability we demonstrated to detect this type of genetic variation, and its relevant role in disorders such as primary immunodeficiencies, we suggest considering this model of gene mosaicism in future genetic studies and considering revisiting previous massive parallel sequencing data in patients with negative results. This study was funded by grants SAF2015-68472-C2-2-R from the Ministerio de Economía y Competitividad (Spain), RTI2018-096824-B-C22 grant from the Spanish Ministry of Science, Innovation and Universities co-financed by FEDER and by Direcció General de Recerca, Generalitat de Catalunya (2017SGR-702) to F.C. M.S.-M. is supported by the Ministerio de Economía y Competitividad, Spain (Maria de Maetzu grant MDM-2014-0370-16-3). L.B.-M. is supported by a Formació de personal Investigador fellowship from Generalitat de Catalunya (2018_FI_B00072). T.M-B. is supported by BFU2017-86471-P (MINECO/FEDER, UE), U01 MH106874 grant, Howard Hughes International Early Career, Obra Social "La Caixa" and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880). Supported in part by CERCA Programme/Generalitat de Catalunya (JI.A.), SAF2015-68472-C2-1-R grant from the Ministerio de Economía y Competitividad (Spain) co-financed by European Regional Development Fund (ERDF) (JI.A.), RTI2018-096824-B-C21 grant from the Ministerio de Ciencia, Innovación y Universidades (Spain) co-financed by ERDF (JI.A.), AC15/00027 grant from the Instituto de Salud Carlos III / Transnational Research Projects on Rare Diseases (JI.A.). Peer reviewed 2021-10-25T09:02:12Z 2021-10-25T09:02:12Z 2021-06-21 artículo http://purl.org/coar/resource_type/c_6501 Scientific Reports 11: 12940 (2021) http://hdl.handle.net/10261/252911 10.1038/s41598-021-92381-y 2045-2322 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/501100011033 http://dx.doi.org/10.13039/501100000780 http://dx.doi.org/10.13039/501100002809 http://dx.doi.org/10.13039/100000011 http://dx.doi.org/10.13039/501100004587 34155260 en #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/MINECO/Programa Estatal de I+D+I Orientada a los Retos de la Sociedad/SAF2015-68472-C2-2-R info:eu-repo/grantAgreement/AEI/Programa Estatal de I+D+i Orientada a los Retos de la Sociedad/RTI2018-096824-B-C22 info:eu-repo/grantAgreement/MINECO//MDM-2014-0370-16-3 info:eu-repo/grantAgreement/AEI/Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia/BFU2017-86471-P info:eu-repo/grantAgreement/MINECO/Programa Estatal de I+D+I Orientada a los Retos de la Sociedad/SAF2015-68472-C2-1-R info:eu-repo/grantAgreement/AEI/Programa Estatal de I+D+i Orientada a los Retos de la Sociedad/RTI2018-096824-B-C21 Publisher's version https://doi.org/10.1038/s41598-021-92381-y Sí open application/pdf Springer Nature |