Analysis of miRNA rare variants in amyotrophic lateral sclerosis and in silico prediction of their biological effects
Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and/or lower motor neurons and characterized by complex etiology. Familial cases show high genetic heterogeneity and sporadic cases (90%) are associated with several genetic and environmental risk factors....
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.1055313/full |
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| author | Alberto Brusati Alberto Brusati Antonia Ratti Antonia Ratti Viviana Pensato Silvia Peverelli Davide Gentilini Davide Gentilini Eleonora Dalla Bella Marta Nice Sorce Megi Meneri Megi Meneri Delia Gagliardi Stefania Corti Stefania Corti Cinzia Gellera Giuseppe Lauria Pinter Giuseppe Lauria Pinter Nicola Ticozzi Nicola Ticozzi Vincenzo Silani Vincenzo Silani |
| author_facet | Alberto Brusati Alberto Brusati Antonia Ratti Antonia Ratti Viviana Pensato Silvia Peverelli Davide Gentilini Davide Gentilini Eleonora Dalla Bella Marta Nice Sorce Megi Meneri Megi Meneri Delia Gagliardi Stefania Corti Stefania Corti Cinzia Gellera Giuseppe Lauria Pinter Giuseppe Lauria Pinter Nicola Ticozzi Nicola Ticozzi Vincenzo Silani Vincenzo Silani |
| author_sort | Alberto Brusati |
| collection | DOAJ |
| description | Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and/or lower motor neurons and characterized by complex etiology. Familial cases show high genetic heterogeneity and sporadic cases (90%) are associated with several genetic and environmental risk factors. Among the genetic risk factors, the contribution of non-coding elements, such as microRNAs (miRNAs), to ALS disease susceptibility remains largely unexplored.Aim: This work aims to identify rare variants in miRNA genes in sporadic ALS (sALS) patients which may cause a defective miRNA maturation or altered target gene recognition by changing miRNA secondary structure or seed sequence, respectively.Methods: Rare variants located in miRNA loci with a minor allele frequency (MAF) < 0.01 were extracted from whole genome sequencing (WGS) data of 100 sALS patients. The secondary pre-miRNA structures were predicted using MiRVas to evaluate the impact of the variants on RNA folding process. Human TargetScan was used to retrieve all the potential target genes of miRNAs with variants in the seed region. Over Representation Analysis (ORA) was conducted to compare the lists of target genes for the reference and mutated miRNAs in the seed sequence.Results: Our analysis identified 86 rare variants in 77 distinct miRNAs and distributed in different parts of the miRNA precursors. The presence of these variants changed miRNA secondary structures in ∼70% of MiRVas predictions. By focusing on the 6 rare variants mapping within the seed sequence, the predicted target genes increased in number compared to the reference miRNA and included novel targets in a proportion ranging from 30 to 82%. Interestingly, ORA revealed significant changes in gene set enrichment only for mutated miR-509-1 and miR-941-3 for which the Gene Ontology term related to “nervous system development” was absent and present, respectively, compared to target lists of the reference miRNA.Conclusion: We here developed a workflow to study miRNA rare variants from WGS data and to predict their biological effects on miRNA folding, maturation and target gene recognition. Although this in silico approach certainly needs functional validation in vitro and in vivo, it may help define the role of miRNA variability in ALS and complex diseases. |
| first_indexed | 2024-04-13T06:08:38Z |
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| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-13T06:08:38Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-2bbf59dadc1c41bdad2d245deacfabd82022-12-22T02:59:09ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-12-011310.3389/fgene.2022.10553131055313Analysis of miRNA rare variants in amyotrophic lateral sclerosis and in silico prediction of their biological effectsAlberto Brusati0Alberto Brusati1Antonia Ratti2Antonia Ratti3Viviana Pensato4Silvia Peverelli5Davide Gentilini6Davide Gentilini7Eleonora Dalla Bella8Marta Nice Sorce9Megi Meneri10Megi Meneri11Delia Gagliardi12Stefania Corti13Stefania Corti14Cinzia Gellera15Giuseppe Lauria Pinter16Giuseppe Lauria Pinter17Nicola Ticozzi18Nicola Ticozzi19Vincenzo Silani20Vincenzo Silani21Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment Brain and Behavioral Sciences, University of Pavia, Pavia, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment Medical Biotechnology and Translational Medicine, University of Milan, Milan, ItalyFondazione IRCCS Istituto Neurologico Carlo Besta, Milano, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment Brain and Behavioral Sciences, University of Pavia, Pavia, ItalyBioinformatics and Statistical Genomics Unit,IRCCS Istituto Auxologico Italiano,Milan,ItalyFondazione IRCCS Istituto Neurologico Carlo Besta, Milano, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyFondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, ItalyDepartment of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, Milan, ItalyFondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, ItalyFondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, ItalyDepartment of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, Milan, ItalyFondazione IRCCS Istituto Neurologico Carlo Besta, Milano, ItalyDepartment Medical Biotechnology and Translational Medicine, University of Milan, Milan, ItalyFondazione IRCCS Istituto Neurologico Carlo Besta, Milano, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, Milan, ItalyDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, ItalyDepartment of Pathophysiology and Transplantation, Dino Ferrari Center, University of Milan, Milan, ItalyBackground: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and/or lower motor neurons and characterized by complex etiology. Familial cases show high genetic heterogeneity and sporadic cases (90%) are associated with several genetic and environmental risk factors. Among the genetic risk factors, the contribution of non-coding elements, such as microRNAs (miRNAs), to ALS disease susceptibility remains largely unexplored.Aim: This work aims to identify rare variants in miRNA genes in sporadic ALS (sALS) patients which may cause a defective miRNA maturation or altered target gene recognition by changing miRNA secondary structure or seed sequence, respectively.Methods: Rare variants located in miRNA loci with a minor allele frequency (MAF) < 0.01 were extracted from whole genome sequencing (WGS) data of 100 sALS patients. The secondary pre-miRNA structures were predicted using MiRVas to evaluate the impact of the variants on RNA folding process. Human TargetScan was used to retrieve all the potential target genes of miRNAs with variants in the seed region. Over Representation Analysis (ORA) was conducted to compare the lists of target genes for the reference and mutated miRNAs in the seed sequence.Results: Our analysis identified 86 rare variants in 77 distinct miRNAs and distributed in different parts of the miRNA precursors. The presence of these variants changed miRNA secondary structures in ∼70% of MiRVas predictions. By focusing on the 6 rare variants mapping within the seed sequence, the predicted target genes increased in number compared to the reference miRNA and included novel targets in a proportion ranging from 30 to 82%. Interestingly, ORA revealed significant changes in gene set enrichment only for mutated miR-509-1 and miR-941-3 for which the Gene Ontology term related to “nervous system development” was absent and present, respectively, compared to target lists of the reference miRNA.Conclusion: We here developed a workflow to study miRNA rare variants from WGS data and to predict their biological effects on miRNA folding, maturation and target gene recognition. Although this in silico approach certainly needs functional validation in vitro and in vivo, it may help define the role of miRNA variability in ALS and complex diseases.https://www.frontiersin.org/articles/10.3389/fgene.2022.1055313/fullALSmiRNAWGSrare variantsbioinformatics |
| spellingShingle | Alberto Brusati Alberto Brusati Antonia Ratti Antonia Ratti Viviana Pensato Silvia Peverelli Davide Gentilini Davide Gentilini Eleonora Dalla Bella Marta Nice Sorce Megi Meneri Megi Meneri Delia Gagliardi Stefania Corti Stefania Corti Cinzia Gellera Giuseppe Lauria Pinter Giuseppe Lauria Pinter Nicola Ticozzi Nicola Ticozzi Vincenzo Silani Vincenzo Silani Analysis of miRNA rare variants in amyotrophic lateral sclerosis and in silico prediction of their biological effects Frontiers in Genetics ALS miRNA WGS rare variants bioinformatics |
| title | Analysis of miRNA rare variants in amyotrophic lateral sclerosis and in silico prediction of their biological effects |
| title_full | Analysis of miRNA rare variants in amyotrophic lateral sclerosis and in silico prediction of their biological effects |
| title_fullStr | Analysis of miRNA rare variants in amyotrophic lateral sclerosis and in silico prediction of their biological effects |
| title_full_unstemmed | Analysis of miRNA rare variants in amyotrophic lateral sclerosis and in silico prediction of their biological effects |
| title_short | Analysis of miRNA rare variants in amyotrophic lateral sclerosis and in silico prediction of their biological effects |
| title_sort | analysis of mirna rare variants in amyotrophic lateral sclerosis and in silico prediction of their biological effects |
| topic | ALS miRNA WGS rare variants bioinformatics |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.1055313/full |
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