Cargando…

Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Molenhuis, Remco T., Bruining, Hilgo, Brandt, Myrna J. V., van Soldt, Petra E., Abu-Toamih Atamni, Hanifa J., Burbach, J. Peter H., Iraqi, Fuad A., Mott, Richard F., Kas, Martien J. H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293525/
https://www.ncbi.nlm.nih.gov/pubmed/30559955
http://dx.doi.org/10.1186/s13229-018-0252-2
_version_ 1783380552020131840
author Molenhuis, Remco T.
Bruining, Hilgo
Brandt, Myrna J. V.
van Soldt, Petra E.
Abu-Toamih Atamni, Hanifa J.
Burbach, J. Peter H.
Iraqi, Fuad A.
Mott, Richard F.
Kas, Martien J. H.
author_facet Molenhuis, Remco T.
Bruining, Hilgo
Brandt, Myrna J. V.
van Soldt, Petra E.
Abu-Toamih Atamni, Hanifa J.
Burbach, J. Peter H.
Iraqi, Fuad A.
Mott, Richard F.
Kas, Martien J. H.
author_sort Molenhuis, Remco T.
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13229-018-0252-2) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-6293525
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-62935252018-12-17 Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice Molenhuis, Remco T. Bruining, Hilgo Brandt, Myrna J. V. van Soldt, Petra E. Abu-Toamih Atamni, Hanifa J. Burbach, J. Peter H. Iraqi, Fuad A. Mott, Richard F. Kas, Martien J. H. Mol Autism Research 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13229-018-0252-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-12-13 /pmc/articles/PMC6293525/ /pubmed/30559955 http://dx.doi.org/10.1186/s13229-018-0252-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Molenhuis, Remco T.
Bruining, Hilgo
Brandt, Myrna J. V.
van Soldt, Petra E.
Abu-Toamih Atamni, Hanifa J.
Burbach, J. Peter H.
Iraqi, Fuad A.
Mott, Richard F.
Kas, Martien J. H.
Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice
title Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice
title_full Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice
title_fullStr Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice
title_full_unstemmed Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice
title_short Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice
title_sort modeling the quantitative nature of neurodevelopmental disorders using collaborative cross mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293525/
https://www.ncbi.nlm.nih.gov/pubmed/30559955
http://dx.doi.org/10.1186/s13229-018-0252-2
work_keys_str_mv AT molenhuisremcot modelingthequantitativenatureofneurodevelopmentaldisordersusingcollaborativecrossmice
AT bruininghilgo modelingthequantitativenatureofneurodevelopmentaldisordersusingcollaborativecrossmice
AT brandtmyrnajv modelingthequantitativenatureofneurodevelopmentaldisordersusingcollaborativecrossmice
AT vansoldtpetrae modelingthequantitativenatureofneurodevelopmentaldisordersusingcollaborativecrossmice
AT abutoamihatamnihanifaj modelingthequantitativenatureofneurodevelopmentaldisordersusingcollaborativecrossmice
AT burbachjpeterh modelingthequantitativenatureofneurodevelopmentaldisordersusingcollaborativecrossmice
AT iraqifuada modelingthequantitativenatureofneurodevelopmentaldisordersusingcollaborativecrossmice
AT mottrichardf modelingthequantitativenatureofneurodevelopmentaldisordersusingcollaborativecrossmice
AT kasmartienjh modelingthequantitativenatureofneurodevelopmentaldisordersusingcollaborativecrossmice