Donna Werling, PhD – Slide of the Week

Donna Werling, PhD - Slide of the Week

Title: Genes elevated in the autistic brain have male-biased expression during neurotypical development

Legend: The complete legend, a simplified legend, or both Sex-differential expression of ASD-dysregulated module genes across developmental time. The average log2 fold
differences (solid black curves) observed in frontal and temporal neocortex samples from the BrainSpan resource for protein-coding genes belonging to the 6 ASD-downregulated (top) or upregulated (bottom) modules identified by Parikshak et al. are displayed at each of 8 developmental windows (gray dashed vertical lines). Red-blue shading displays the 99% confidence interval around the mean log2 fold difference for each gene set. The median and interquartile range of the log2 fold difference for all 17,222 protein-coding genes expressed in the frontal and temporal cortex samples are displayed in gray behind each modules’ sex-differential expression. ASD, autism  spectrum disorder; FD, fold difference; Fem, female.

Citation: Lee T. Kissel & Donna M. Werling. Neural transcriptomic analysis of sex differences in autism spectrum disorder: Current insights and future directions. Biological Psychiatry, (2020). Epub ahead of print. PMID: 33551190.

Abstract: Autism spectrum disorder (ASD) is consistently diagnosed 3 to 5 times more frequently in males than females, a dramatically sex-biased prevalence that suggests the involvement of sex-differential biological factors in modulating risk. The genomic scale of transcriptomic analyses of human brain tissue can provide an unbiased approach for identifying genes and associated functional processes at the intersection of sex-differential and ASD-impacted neurobiology. Several studies characterizing gene expression changes in the ASD brain have been published in recent years with increasing sample size and cellular resolution. These studies report several convergent patterns across data sets and genetically heterogeneous samples in the ASD brain, including elevated expression of gene sets associated with glial and immune function, and reduced expression of gene sets associated with neuronal and synaptic functions. Assessment of neurotypical cortex tissue has reported parallel patterns by sex, with male-elevated expression of overlapping sets of glial/immune-related genes and female-biased expression of neuron-associated genes, suggesting potential roles for these cell types in sex-differential ASD risk mechanisms. However, validating and further exploring these mechanisms is challenged by the available data, as existing studies of ASD brain include a limited number of female ASD donors and focus predominantly on cortex regions not known to show pronounced sex-differential morphology or function. With this review, we summarize convergent findings from several landmark studies of the transcriptome in ASD brain and their relationship to sex-differential gene expression, and we discuss limitations and remaining questions regarding transcriptomic analysis of sex differences in ASD.

About the Lab: Donna Werling is interested in characterizing sex-differential risk mechanisms in autism spectrum disorder (ASD). During her doctoral work in the laboratory of Dan Geschwind at the University of California, Los Angeles, Werling used functional genomics, human genetics and bioinformatics approaches to understand the relationship between sex and genetic risk in ASD.

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