Animal Model of Genetics and Social Behavior in Autism Spectrum Disorders

描述（由申请人提供）：自闭症谱系障碍（ASD）阻碍了美国每110名儿童中就有1名儿童的社交和沟通能力。有证据表明，ASD中社会行为的个体差异，以及在典型的发展中人群中，来自遗传倾向和个人经验的组合，但潜在的生物学机制仍然知之甚少。由于缺乏合适的动物模型，研究进展滞后，在这种动物模型中，潜在遗传学和个体经验的自然变异会产生社会行为的异质性，这种异质性与人类在性质上相似，如果不是同源的话。开发具有与人类同源的自然社会变化的动物模型将使我们能够更有效地针对直接影响ASD中介导行为受损的神经回路的干预措施。为了解决这一差距，我们将开发一个完全实现的遗传贡献的生物模型， 社会行为表型通过表征生活在自然环境中的大量动物的社会行为和认知及其遗传基础，以最小的外部干预。我们将使用观察技术和实地实验来定量定义男性和女性的社会气质和社会认知表型的异质性。在我们的分层方法中，我们将使用标准实验室任务的模拟物，通过对自然行为和社会认知的深入观察来评估社会气质。我们还将使用分层方法测定遗传变异。我们将首先使用一种先验的方法，检测先前与社会行为有关的基因多态性，以及尚未在猕猴中评估的相同或相关途径中的多态性。遗传变异将包括重复长度多态性（VNTR）以及单核苷酸多态性（SNP），并将用于鉴定社会表型的遗传生物标志物。与此同时，我们将使用数据驱动的自下而上的方法，通过对50个根据血统和社会气质确定的关键个体进行全基因组测序，来识别与社会行为和认知相关的新基因组变异。通过选定个体的全基因组测序鉴定出的变异体将在整个人群中进行分析，以评估与社会行为的统计相关性。计算技术将用于开发表型和基因型变异之间关系的生物学意义的措施。生物信息学软件和基础设施，以前开发和广泛验证了我们的小组在人群中的基因组变异的分析，将适应于识别和注释猕猴种群中的基因组变异，并确定与社会行为的具体措施相关的变异。这些数据将与生活史和谱系数据相结合，以生成基因型和社会表型对生物学成功影响的预测模型。

DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) handicaps the social and communicative abilities of 1 out of every 110 children in the United States. Evidence suggests that individual variation in social behavior in ASD, as well as within the typically developing human population, arises from a combination of genetic predispositions and individual experience, yet the underlying biological mechanisms remain poorly understood. Progress lags due to the lack of a suitable animal model in which natural variation in both underlying genetics and individual experience generates heterogeneity in social behavior that is qualitatively similar, if not homologous, to that in humans. Development of an animal model with natural social variation homologous to that of humans will permit us to more effectively target interventions that directly impact the neural circuits mediating behaviors impaired in ASD. To address this gap, we will develop a fully-realized biological model of the genetic contributions to social behavior phenotype by characterizing social behavior and cognition and their genetic foundations in a large population of animals living in naturalistic circumstances with minimal external intervention. We will use observational techniques and field experiments to quantitatively define heterogeneity in social temperament and social cognition phenotypes in males and females. In our stratified approach, we will assess social temperament using intensive observation of natural behavior and social cognition using analogs of standard laboratory tasks. We will also assay genetic variation using a stratified approach. We will first use an a priori approach that assays gene polymorphisms previously implicated in social behavior, as well as polymorphisms in the same or related pathways that have yet to be assessed in macaques. Genetic variation will include repeat length polymorphisms (VNTRs) as well as single nucleotide polymorphisms (SNPs) and will be used to identify genetic biomarkers for social phenotypes. In parallel, we will use a data-driven, bottom-up approach to identify new genomic variants linked to social behavior and cognition, by conducting full genome sequencing on 50 key individuals identified by pedigree and social temperament. Variants identified by whole-genome sequencing of selected individuals then will be assayed across the entire population to assess statistical correlations with social behaviors. Computational techniques will be used to develop biologically-meaningful measures of the relationships between phenotypic and genotypic variation. Bioinformatics software and infrastructure, previously developed and extensively validated by our group for analysis of genomic variants in human populations, will be adapted to identify and annotate genomic variations in the macaque population, and to identify variants correlated with specific measures of social behavior. These data will be combined with life history and pedigree data to generate predictive models of the impact of genotype and social phenotype on biological success.