Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice

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 b...

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Bibliographic Details
Published in:	Molecular autism Vol. 9; no. 1; p. 63
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 13-12-2018 BioMed Central BMC
Subjects:	Animal models Animals Attention deficit hyperactivity disorder Autism Autism Spectrum Disorder - genetics Behavioral neuroscience Diagnosis Gene mutation Genetic aspects Genetic reference population Genetics, Behavioral - methods Genetics, Behavioral - standards Genome-Wide Association Study - methods Genome-Wide Association Study - standards Male Mice Mice, Inbred C57BL Multifactorial Inheritance Mutation Neurodevelopmental disorders Pervasive developmental disorders Quantitative genetics Quantitative Trait Loci Reference Standards Risk factors Rodents Studies Quantitative genetics Autism Animal models Genetic reference population Neurodevelopmental disorders Behavioral neuroscience Repetitive behavior Histamine 3 receptor
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Summary:	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. 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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2040-2392 2040-2392
DOI:	10.1186/s13229-018-0252-2