Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice

Remco T Molenhuis,Richard F Mott,Fuad A Iraqi,J Peter H Burbach,Petra E Van Soldt,Myrna J V Brandt,Martien J H Kas,Hanifa J Abu-Toamih Atamni,Hilgo Bruining

doi:10.1186/s13229-018-0252-2

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 Autism 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.

Highlights

Animal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background
These included 37 Collaborative Cross (CC) lines originating from the International Livestock Research Institute (ILRI) in Kenya and relocated to Tel Aviv University (Israel) in 2006, 10 CC lines originating from Geniad Ltd. in Western Australia (CC-GND), and six CC lines originating from the Oak Ridge National Laboratory (ORNL) in Tennessee that were subsequently relocated to the University of North Carolina in 2009 (CC-UNC)
We identified the human orthologs of genes within each mouse behavioral Quantitative Trait Loci (QTLs) and ranked these genes on the basis of a recently developed genome-wide prediction algorithm to prioritize genes for Autism Spectrum Disorder (ASD) based on prior genetic evidence and functional interaction networks [40]

Summary

Introduction

Animal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background. Recent studies show that genetic risk factors for neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) segregate in the general population They influence continua of behavioral and developmental traits [1,2,3,4]. Recent human genetic studies indicate that ASD is most often not due to single genetic mutations, but rather occurs due to multiple genetic variants—even in individuals in which a contributing rare genetic mutation has been identified [4] Another complexity is that genotype-phenotype relationships observed in a single mouse genetic background are often not generalizable to other backgrounds, thereby limiting (2018) 9:63 their translational value [9]. Animal model strategies should enable to evaluate the clinical impact of etiological factors on continuous behavioral traits across diverse genetic backgrounds

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Discussion

Conclusion