Characterization and visualization of tandem repeats at genome scale.

Tandem repeat (TR) variation is associated with gene expression changes and numerous rare monogenic diseases. Although long-read sequencing provides accurate full-length sequences and methylation of TRs, there is still a need for computational methods to profile TRs across the genome. Here we introduce the Tandem Repeat Genotyping Tool (TRGT) and an accompanying TR database. TRGT determines the consensus sequences and methylation levels of specified TRs from PacBio HiFi sequencing data. It also reports reads that support each repeat allele. These reads can be subsequently visualized with a companion TR visualization tool. Assessing 937,122 TRs, TRGT showed a Mendelian concordance of 98.38%, allowing a single repeat unit difference. In six samples with known repeat expansions, TRGT detected all expansions while also identifying methylation signals and mosaicism and providing finer repeat length resolution than existing methods. Additionally, we released a database with allele sequences and methylation levels for 937,122 TRs across 100 genomes.

Excitatory neuron-specific suppression of the integrated stress response contributes to autism-related phenotypes in fragile X syndrome.

Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory, but not inhibitory, neurons in a mouse model of fragile X syndrome (FXS; Fmr1-/y). We further show that the decrease in p-eIF2α is mediated via activation of mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, restoration of p-eIF2α solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis, and core phenotypes reminiscent of autism in a mouse model of FXS.

Perirhinal damage produces modality-dependent deficits in fear learning.

The perirhinal cortex (PER) receives multimodal and unimodal sensory information from all modalities. In addition, the PER is anatomically connected with several brain regions that support fear learning. Several studies suggest that the PER is involved in fear conditioning to discontinuous auditory cues but not to continuous auditory cues. To date, studies examining the role of the PER in fear conditioning has largely focused on auditory and contextual stimuli. The present study assessed whether the role of the PER in fear conditioning would extend to visual modalities. Rodents were randomly assigned to one of four conditioned stimuli, which consisted of either a tone or a light stimulus that was either continuous or discontinuous. Pre-training excitotoxic lesions to the PER significantly reduced freezing to auditory and visual cues during the acquisition phase regardless of stimulus continuity. During subsequent testing, perirhinal lesions produced significant decreases in freezing levels to both continuous and discontinuous tones but not to either of the light CS groups. These results suggest that the PER is involved in the acquisition of fear across multiple cue modalities. However, the PER may have a more limited role in the retrieval of the fear memory dependent upon the cue modality.