1Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
2Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Mol Autism. 2018 Dec 13;9:63. doi: 10.1186/s13229-018-0252-2. eCollection 2018.
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.
神经发育障碍（NDD）的动物模型通常依赖于固定遗传背景下的单一基因突变。然而，最近的人类遗传学研究表明，具有 ASDAutism Spectrum Disorder（ASD）临床诊断的个体几乎总是与多种遗传前因和背景变化相关。如果可以在更广泛的遗传背景下研究遗传损伤，那么动物模型研究的转化价值将会大大提高。
我们使用了新型的小鼠遗传参考群体——合作交叉（CC），来研究在神经发育障碍动物模型中常用的小鼠行为表型的定量遗传结构。
由于遗传稀释和遗传力有限，经典的社会识别和梳理行为表型测试对于定量研究来说显得不够充分。相比之下，挖掘、运动活动和刻板的探索模式具有连续分布的特点，并且可以映射到包含与人类群体中相应表型相关基因的数量性状基因座上。
这些发现表明 CC 可以将动物模型研究从比较的单一基因-单一背景设计推进到多个遗传背景下的发育病因的效果进行定量研究，同时指出哪种类型的行为表型最适合进行定量研究。
