UC Davis

A large proportion of genetic variation underlying differences in behavioral traits and neurodevelopmental disorders remains unknown despite considerable effort. Much work has focused on protein-coding regions, which comprise ~1.5% of primate genomes, compared to functional noncoding elements comprising ~40%. Transcriptional analyses of the developing brain in distantly related primates, such as humans and rhesus macaques, show that spatiotemporal expression patterns are largely conserved across lineages, with minor differences likely contributing to species’ divergence. To delve into genomic mechanisms underlying gene regulation in the developing primate brain, we have generated transcriptional genomic datasets (3’ Tag-Seq (n=3) and single-cell RNA-seq (n=1)) from diverse regions of fetal macaque brains (60 days gestation, late first/early second trimester) representing a time of early neurogenesis. The 3’ Tag-Seq expression levels show correlation with previously published data of the same time point and comparable brain regions and highlights genes important in region-specific development. The single-cell RNA-seq data has revealed a number of different cell types, the majority of which are neuronal in all brain regions with the exception of the cerebellum.We then queried the 3D genome organization of two different brain regions using a targeted protein mediated approach called Proximity Ligation-Assisted ChIP-Seq (PLAC-Seq) to identify DNA interactions within chromatin enriched at active promoters in macaque neural tissue. Our data generated from samples from the prefrontal cortex and cerebellum (n=3, 60 days gestation) shows low enrichment for the H3K4me3 antibody. Despite this low enrichment, we were able to identify 32,959 and 13,814 significant chromatin interactions for prefrontal cortex and cerebellum, respectively. The identified significant interactions in the prefrontal cortex were connected to over half of the genes implicated in ASD from two separate datasets, while significant interactions in the cerebellum connected to about a third of those genes, providing putative cis regulatory elements driving regulation of these disease-associated genes in diverse brain regions.