Decoding the Molecular Evolution of Human Cognition Using Comparative Genomics

Abstract

Identification of genetic and molecular factors responsible for the specialized cognitive abilities of humans is expected to provide important insights into the mechanisms responsible for disorders of cognition such as autism, schizophrenia and Alzheimer's disease. Here, we discuss the use of comparative genomics for identifying salient genes and gene networks that may underlie cognition. We focus on the comparison of human and non-human primate brain gene expression and the utility of building gene coexpression networks for prioritizing hundreds of genes that differ in expression among the species queried. We also discuss the importance of and methods for functional studies of the individual genes identified. Together, this integration of comparative genomics with cellular and animal models should provide improved systems for developing effective therapeutics for disorders of cognition.

Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development

“…In addition, neuron-specific knockdown of all SUMO-1/2/3 in RNAi transgenic mice leads to anxiety-like behavior, and impairs episodic and fear memories (74). Many genes implicated in ASD encode synaptic proteins important for regulating synaptic homeostasis involved in cognition (3, 75, 76). Sumoylation of ASD genes (e.g.…”

“…The transcription factor FOXP2 has been implicated in human brain evolution, language, cognition, vocal-motor integration, and neural development in the central nervous system (CNS) through orchestration of transcriptional cascades that also tend to be at risk in several neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia (1–3). Previous work using humanized Foxp2 mouse models has suggested that humanized Foxp2 alters cortico-striatal function (4–6), but the cerebellum appears to be a key brain region for FOXP2 function as patients with mutations in FOXP2 demonstrate significant grey matter reduction in the cerebellum as evidenced by MRI (7), and genetic disruption of Foxp2 in mice results in decreased cerebellar size (8–11).…”

Insights into the Neural and Genetic Basis of Vocal Communication

“…In particular, Purkinje neurons, which are the sole motor output of the cerebellum, appear to be particularly vulnerable in ASD and relevant to vocal production. Of note, FOXP2 expression in the cerebellum is limited to the Purkinje neurons and mouse models of Foxp2 exhibit striking cerebellar defects as well as altered vocal behavior (see references in (Usui et al, 2014)). The ASD-related gene Tsc1 has also been specifically deleted in Purkinje neurons in mice leading to ASD-relevant behaviors including changes in vocalizations (Tsai et al, 2012).…”

Genomic Strategies for Understanding the Pathophysiology of Autism Spectrum Disorder

“…FOXP1 is also frequently reported to be involved in social communication, cortical development, spatial learning, synaptic plasticity, and the regulation of ASD-associated gene expression (Araujo et al, 2015(Araujo et al, , 2017Usui et al, 2017a). FOXP2 regulates vocal communication, cortical development, behavioral flexibility, and ASD-associated gene expression (Usui et al, 2014(Usui et al, , 2017bCo et al, 2020). Collectively, predicting gene ontology of the SFARI genes implicates the majority of them in brain development (Figure 1), with most of them being synapseassociated genes (de la Torre- Ubieta et al, 2016).…”