SFARI Research Highlights
Highlights of SFARI-funded papers, selected by the SFARI science team.
Epigenetic mechanisms can alter allelic gene expression patterns in the brain, and influence phenotypes and risk for developmental disorders. While genomic imprinting and random X-inactivation are two of the most well-known epigenetic mechanisms, less is known about whether other potential epigenetic mechanisms affect gene expression in the brain. In a new study, SFARI Investigator Christopher Gregg and colleagues developed a genomics strategy and statistical framework for performing genome-wide screens for diverse forms of non-genetic allelic expression effects in both mouse and primate brains. Using this methodology, the researchers uncovered developmental stage and cell-type specific non-genetic allelic effects that were not due to imprinting. Such effects were found to be particularly prevalent in the neonatal mouse brain. Assessments in macaque and postmortem human brains further indicated that such mechanisms can impact genes linked to neurodevelopmental disorders, including the expression of two autism risk genes, DEAF1 and CNTNAP2. These findings suggest that a broad array of epigenetic mechanisms should be considered, in addition to genetic risk variants, as potentially contributing to autism. Moreover, they provide a potential explanation for at least some of the phenotypic heterogeneity associated with autism-associated mutations, in that the impact of a mutation will depend on which allele is affected.
Huang W.C., Ferris E., Cheng T., Hörndli C.S., Gleason K., Tamminga C., Wagner J.D., Boucher K.M., Christian J.L., Gregg C. Diverse non-genetic allele specific expression effects shape genetic architecture at the cellular level in the mammalian brain. Neuron Epub ahead of print (2017) PubMed
Watch a video abstract of this research study below:
SCN2A variants result in opposite effects on sodium channel function in autism and infantile seizures
Mutations in the gene SCN2A, which encodes the neuronal sodium channel NaV1.2, have been linked to both infantile seizures and autism spectrum disorder (ASD). Previous studies indicated that SCN2A variants associated with infantile seizures led to a gain-of-function in NaV1.2 channel activity and increased neuronal excitability; however, how variants associated with ASD affect channel function remains unclear. In the current study, SFARI Investigators Kevin Bender and Stephan Sanders performed functional analyses of 12 de novo SCN2A mutations identified in ASD cases from the Simons Simplex Collection and the Autism Sequencing Consortium. They found that all ASD-associated variants reduced or eliminated channel function in heterologous expression systems. Results from these studies were then incorporated into a computational model of cortical pyramidal neurons. Such a model predicted that all of the ASD variants would impair neuronal excitability at early developmental stages. Thus, the variants associated with ASD have an opposite effect to those associated with infantile seizures. Further investigations into the neurobiological consequences of SCN2A variants, combined with behavioral and neurocognitive studies such as those under investigation as part of the Simons Variation in Individuals Project (Simons VIP), will help to advance our understanding of genotype-phenotype correlations for this gene.
Ben-Shalom R., Keeshen C.M., Berrios K.N., An J.Y., Sanders S.J., Bender K.J. Opposing effects on Nav1.2 function underlie differences between SCN2A variants observed in individuals with autism spectrum disorder or infantile seizures. Biol. Psychiatry Epub ahead of print (2017) Article
Our ability to perform social interactions is driven by a social brain network, of which the amygdala is a key component. Social interaction difficulties are a core symptom in autism spectrum disorder (ASD) and a number of studies have found functional alterations in the amygdala in individuals with ASD. While intra-communication between amygdala subregions and inter-communication with connected brain regions regulates a variety of behaviors, the precise nature of these connections in the context of social learning has remained unclear. SFARI Investigator Amiel Rosenkranz and colleagues have now demonstrated in rats that interactions between two key regions of the amygdala, the lateral amygdala (LA) and the posterior medial amygdala (MeA), are important. Specifically, the LA-MeA circuit functions as a link between social cue comprehension and the subsequent use of this information to guide appropriate behavioral responses. The researchers also found that this circuit was disrupted in a rat model of ASD (NRXN1 knockout). Importantly, activation of the MeA alleviated some of the social behavioral deficits in this model. These findings argue for the importance of this circuitry in social learning and suggest that targeted augmentation of this circuit could be explored as a potential therapeutic intervention for improving social interaction difficulties in ASD.
Twining R.C., Vantrease J.E., Love S., Padival M., Rosenkranz J.A. An intra-amygdala circuit specifically regulates social fear learning. Nat. Neurosci. (2017) PubMed
Interactions between genes, referred to as epistasis, have been shown to play a large role in the variation in complex traits in model organisms. Yet human genome-wide association studies (GWAS) have had limited success in identifying genetic interactions. SFARI Investigator Lauren Weiss and colleagues investigated whether analyses of a known autism spectrum disorder (ASD)-associated signaling pathway, the Ras/MAPK pathway, might provide insights into genetic epistasis in idiopathic ASD. Weiss’s team generated an ASD GWAS dataset from available cohorts, including the Simons Simplex Collection, and found that common single nucleotide polymorphisms (SNPs) in RAS/MAPK genes are significantly enriched for association with ASD. They then performed a genome-wide screen for interactors with Ras/MAPK gene SNPs and found 19 unique epistatic pairs that met criteria for significance in ASD cases compared with controls. They also performed a modifier screen based on quantifiable measures of a social responsiveness trait in individuals with rare RASopathies – Mendelian disorders of the Ras/MAPK pathway. They went on to show that the expression of GPR141, one of the genes located in one of the identified epistatic loci, was reduced in RASopathy neural cell lines. This study highlights that a reverse pathway genetic approach, focusing on key biological pathways, can be applied to study epistasis in ASD.
Mitra I., Lavillaureix A., Yeh E., Traglia M., Tsang K., Bearden C.E., Rauen K.A., Weiss L.A. Reverse pathway genetic approach identifies epistasis in autism spectrum disorders. PLOS Genet. 13, e1006516 (2017) PubMed