Abstract

Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD. However, many technical issues have confounded the phenotypic characterization of such mouse models, including systematically biased genetic backgrounds and weak or absent behavioral phenotypes. To address these issues, we developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion and applied computational approaches to identify hidden variables within neonatal vocalizations that have predictive power for postpubertal dimensions relevant to ASD. After variables of neonatal vocalizations were selected by least absolute shrinkage and selection operator (Lasso), random forest, and Markov model, regression models were constructed to predict postpubertal dimensions relevant to ASD. While the average scores of many standard behavioral assays designed to model dimensions did not differentiate a model of 16p11.2 hemizygous deletion and wild-type littermates, specific call types and call sequences of neonatal vocalizations predicted individual variability of postpubertal reciprocal social interaction and olfactory responses to a social cue in a genotype-specific manner. Deep-phenotyping and computational analyses identified hidden variables within neonatal social communication that are predictive of postpubertal behaviors.

Highlights

  • IntroductionBecause copy number variants (CNVs) are robustly associated with autism spectrum disorder (ASD) and other developmental neuropsychiatric disorders, such genetic variants provide a genetically homogeneous and identifiable

  • As many extraneous variables in testing environments mask or exaggerate phenotypes in mice [22, 23], we developed an independent line of coisogenic mouse model of proximal 16p11.2 hemizygous deletion

  • We developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion through in vitro Cre-mediated recombination of a 378 kb region of the 7qF3 region spanning from Mapk3 to Spn genes (Fig. S1A)

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Summary

Introduction

Because copy number variants (CNVs) are robustly associated with autism spectrum disorder (ASD) and other developmental neuropsychiatric disorders, such genetic variants provide a genetically homogeneous and identifiable. Many CNV mouse models with well-controlled genetic backgrounds (e.g., 1q21.1, 3q29, 15q11.13, maternal 15q11-13, 16p11.2, and 22q11.2) often do not exhibit deficits in social behaviors and other behavioral dimensions relevant to developmental neuropsychiatric disorders, [4,5,6,7,8,9,10,11,12]

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