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Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice / R. T. MOLENHUIS in Molecular Autism, 9 (2018)
[article]
Titre : Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice Type de document : Texte imprimé et/ou numérique Auteurs : R. T. MOLENHUIS, Auteur ; Hilgo BRUINING, Auteur ; M. J. V. BRANDT, Auteur ; P. E. VAN SOLDT, Auteur ; H. J. ABU-TOAMIH ATAMNI, Auteur ; J. P. H. BURBACH, Auteur ; F. A. IRAQI, Auteur ; R. F. MOTT, Auteur ; M. J. H. KAS, Auteur Article en page(s) : 63 p. Langues : Anglais (eng) Mots-clés : Animals Autism Spectrum Disorder/*genetics Genetics, Behavioral/*methods/standards Genome-Wide Association Study/*methods/standards Male Mice Mice, Inbred C57BL Multifactorial Inheritance Quantitative Trait Loci Reference Standards *Animal models *Autism *Behavioral neuroscience *Genetic reference population *Histamine 3 receptor *Neurodevelopmental disorders *Quantitative genetics *Repetitive behavior Care and Use Committee of Tel Aviv University.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Animal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background. Recent human genetic studies however indicate that a clinical diagnosis with ASDAutism Spectrum Disorder (ASD) is almost always associated with multiple genetic fore- and background changes. The translational value of animal model studies would be greatly enhanced if genetic insults could be studied in a more quantitative framework across genetic backgrounds. Methods: We used the Collaborative Cross (CC), a novel mouse genetic reference population, to investigate the quantitative genetic architecture of mouse behavioral phenotypes commonly used in animal models for NDD. Results: Classical tests of social recognition and grooming phenotypes appeared insufficient for quantitative studies due to genetic dilution and limited heritability. In contrast, digging, locomotor activity, and stereotyped exploratory patterns were characterized by continuous distribution across our CC sample and also mapped to quantitative trait loci containing genes associated with corresponding phenotypes in human populations. Conclusions: These findings show that the CC can move animal model studies beyond comparative single gene-single background designs, and point out which type of behavioral phenotypes are most suitable to quantify the effect of developmental etiologies across multiple genetic backgrounds. En ligne : https://dx.doi.org/10.1186/s13229-018-0252-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389
in Molecular Autism > 9 (2018) . - 63 p.[article] Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice [Texte imprimé et/ou numérique] / R. T. MOLENHUIS, Auteur ; Hilgo BRUINING, Auteur ; M. J. V. BRANDT, Auteur ; P. E. VAN SOLDT, Auteur ; H. J. ABU-TOAMIH ATAMNI, Auteur ; J. P. H. BURBACH, Auteur ; F. A. IRAQI, Auteur ; R. F. MOTT, Auteur ; M. J. H. KAS, Auteur . - 63 p.
Langues : Anglais (eng)
in Molecular Autism > 9 (2018) . - 63 p.
Mots-clés : Animals Autism Spectrum Disorder/*genetics Genetics, Behavioral/*methods/standards Genome-Wide Association Study/*methods/standards Male Mice Mice, Inbred C57BL Multifactorial Inheritance Quantitative Trait Loci Reference Standards *Animal models *Autism *Behavioral neuroscience *Genetic reference population *Histamine 3 receptor *Neurodevelopmental disorders *Quantitative genetics *Repetitive behavior Care and Use Committee of Tel Aviv University.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Animal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background. Recent human genetic studies however indicate that a clinical diagnosis with ASDAutism Spectrum Disorder (ASD) is almost always associated with multiple genetic fore- and background changes. The translational value of animal model studies would be greatly enhanced if genetic insults could be studied in a more quantitative framework across genetic backgrounds. Methods: We used the Collaborative Cross (CC), a novel mouse genetic reference population, to investigate the quantitative genetic architecture of mouse behavioral phenotypes commonly used in animal models for NDD. Results: Classical tests of social recognition and grooming phenotypes appeared insufficient for quantitative studies due to genetic dilution and limited heritability. In contrast, digging, locomotor activity, and stereotyped exploratory patterns were characterized by continuous distribution across our CC sample and also mapped to quantitative trait loci containing genes associated with corresponding phenotypes in human populations. Conclusions: These findings show that the CC can move animal model studies beyond comparative single gene-single background designs, and point out which type of behavioral phenotypes are most suitable to quantify the effect of developmental etiologies across multiple genetic backgrounds. En ligne : https://dx.doi.org/10.1186/s13229-018-0252-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model in Molecular Autism, 9 (2018)
[article]
Titre : Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Type de document : Texte imprimé et/ou numérique Article en page(s) : 64 p. Langues : Anglais (eng) Mots-clés : Adult Autism Spectrum Disorder/*genetics Child Female Humans Male *Models, Genetic *Multifactorial Inheritance *Mutation Pedigree Quantitative Trait Loci *Autism spectrum disorders *De novo mutations *Genotype-phenotype relationship *Multifactorial model *Multiple hit *Targeted sequencing Institutional Review Board of the School of Life Sciences at Central South University (CSU), Changsha, Hunan, China. Informed consent was obtained from the parents or legal guardians of all study participants.Written informed consent for publication was obtained from the parents or legal guardians.EEE is on the scientific advisory board (SAB) of DNAnexus, Inc.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results: We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk. En ligne : https://dx.doi.org/10.1186/s13229-018-0247-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389
in Molecular Autism > 9 (2018) . - 64 p.[article] Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model [Texte imprimé et/ou numérique] . - 64 p.
Langues : Anglais (eng)
in Molecular Autism > 9 (2018) . - 64 p.
Mots-clés : Adult Autism Spectrum Disorder/*genetics Child Female Humans Male *Models, Genetic *Multifactorial Inheritance *Mutation Pedigree Quantitative Trait Loci *Autism spectrum disorders *De novo mutations *Genotype-phenotype relationship *Multifactorial model *Multiple hit *Targeted sequencing Institutional Review Board of the School of Life Sciences at Central South University (CSU), Changsha, Hunan, China. Informed consent was obtained from the parents or legal guardians of all study participants.Written informed consent for publication was obtained from the parents or legal guardians.EEE is on the scientific advisory board (SAB) of DNAnexus, Inc.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype-phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods: We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results: We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions: We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk. En ligne : https://dx.doi.org/10.1186/s13229-018-0247-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389