Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice

Abstract

BackgroundAnimal 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.MethodsWe 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.ResultsClassical 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.ConclusionsThese 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 materialThe online version of this article (10.1186/s13229-018-0252-2) contains supplementary material, which is available to authorized users.

Designing a QTL Mapping Study for Implementation in the Realized Collaborative Cross Genetic Reference Population

“…Full details of CC lines and their power of mapping QTL with host susceptibility to complex traits are presented in various publications (Abu‐Toamih Atamni, Mott et al., ; Abu‐Toamih Atamni, Botzman et al., ; Abu‐Toamih Atamni et al. ; Aylor et al., ; Durrant et al., ; Iraqi et al., ; Iraqi, Churchill, & Mott, ; Levy et al., ; Lorè, Iraqi, & Bragonzi, ; Molenhuis et al., ; Nashef et al., ; Philip et al., ; Vered et al., ; Welsh et al., ). The CC mouse model is the focal point in our research, having exclusive access to the CC lines produced at our laboratory at Tel Aviv University (TAU).…”

“…The updated genotype status of the population was presented recently (Iraqi et al., ), while numerous studies show the diversity of the phenotypic response of the CC lines to complex disease and the power of this resource for mapping QTL associated with this trait to small genomic intervals less than 0.5 centimorgans (CM), which contain only a few genes (Abu‐Toamih Atamni, Mott et al., ; Abu‐Toamih Atamni, Botzman et al., ; Abu‐Toamih Atamni et al. ; Abu‐Toamih Atamni, Botzman, Mott, Gat‐Viks, & Iraqi, ; Durrant et al., ; Levy et al., ; Molenhuis et al., ; Nashef et al., ; Vered et al., ). Herein, we present our various protocols and methods, using the CC mouse resource for dissecting the genetic architecture underlying the phenotypic variation of complex traits.…”

Using a mouse model to gain insights into developmental coordination disorder

“…Additionally, desired gene mutations can be obtained through direct techniques such as transgenesis . These manipulations allow the investigator to study one gene at a time and the gene's role in the disease mechanism . While these models provide insights into the biology of neurodevelopmental disorders and have impacted the field of intervention development, recent human genetic studies indicate that disorders such as ASD are not often due to single gene mutations .…”

“…These manipulations allow the investigator to study one gene at a time and the gene's role in the disease mechanism . While these models provide insights into the biology of neurodevelopmental disorders and have impacted the field of intervention development, recent human genetic studies indicate that disorders such as ASD are not often due to single gene mutations . Multiple genetic variants may be responsible for such disorders, thereby adding additional complexity to the genotype‐phenotype relationship observed in single mouse genetic models .…”

“…While these models provide insights into the biology of neurodevelopmental disorders and have impacted the field of intervention development, recent human genetic studies indicate that disorders such as ASD are not often due to single gene mutations . Multiple genetic variants may be responsible for such disorders, thereby adding additional complexity to the genotype‐phenotype relationship observed in single mouse genetic models . Another approach is to find a genotype‐to‐phenotype link using natural variations in inbred strains of mice .…”