Biology subjects

del Rosario, R.

Publications and source records attributed to del Rosario, R..

3 recordsLinked to original sources

bioRxiv2025

Next-generation enhancer AAVs for selective interspecies targeting of midbrain dopaminergic neurons

Using single-nucleus multiomic profiling of the marmoset midbrain, we develop and benchmark enhancer-AAVs to selectively access dopamine (DA) neurons in wild-type animals without combinatorial systems. In vivo candidate screenings identified one highly specific DA enhancer, cjDAE8, in both mice and marmosets. To overcome low-level off-target (leaky) expression, a common limitation for enhancer AAVs, we engineered next-generation AAV backbones that strengthen expression while minimizing leakiness. Quantitative histology comparing natural versus antibody-amplified fluorescence defined AAV doses to achieve high labeling efficiency with greater than 90-95% DA-neuron specificity across species and injection routes. We further demonstrate applications of DA-enhancer-AAVs for (i) retrograde targeting of projection-defined DA populations in marmoset, (ii) fiber-photometric recording of divergent DA-axonal dynamics in striatal subregions, and (iii) optogenetic VTA-DA self-stimulation in mice. Our results establish a resource for cross-species DA targeting and two practical guidelines: backbone context critically shapes enhancer performance, and antibody-amplified readouts rigorously assess specificity.

neuroscience↗

bioRxiv2023

Structurally divergent and recurrently mutated regions of primate genomes

To better understand the pattern of primate genome structural variation, we sequenced and assembled using multiple long-read sequencing technologies the genomes of eight nonhuman primate species, including New World monkeys (owl monkey and marmoset), Old World monkey (macaque), Asian apes (orangutan and gibbon), and African ape lineages (gorilla, bonobo, and chimpanzee). Compared to the human genome, we identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. Across 50 million years of primate evolution, we estimate that 819.47 Mbp or ~27% of the genome has been affected by SVs based on analysis of these primate lineages. We identify 1,607 structurally divergent regions (SDRs) wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (CARDs, ABCD7, OLAH) and new lineage-specific genes are generated (e.g., CKAP2, NEK5) and have become targets of rapid chromosomal diversification and positive selection (e.g., RGPDs). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species for the first time.

genomics↗

bioRxiv2019

Innovations in Primate Interneuron Repertoire

Primates and rodents, which descended from a common ancestor more than 90 million years ago, exhibit profound differences in behavior and cognitive capacity. Modifications, specializations, and innovations to brain cell types may have occurred along each lineage. We used Drop-seq to profile RNA expression in more than 184,000 individual telencephalic interneurons from humans, macaques, marmosets, and mice. Conserved interneuron types varied significantly in abundance and RNA expression between mice and primates, but varied much more modestly among primates. In adult primates, the expression patterns of dozens of genes exhibited spatial expression gradients among neocortical interneurons, suggesting that adult neocortical interneurons are imprinted by their local cortical context. In addition, we found that an interneuron type previously associated with the mouse hippocampus--the \"ivy cell\", which has neurogliaform characteristics--has become abundant across the neocortex of humans, macaques, and marmosets. The most striking innovation was subcortical: we identified an abundant striatal interneuron type in primates that had no molecularly homologous cell population in mouse striatum, cortex, thalamus, or hippocampus. These interneurons, which expressed a unique combination of transcription factors, receptors, and neuropeptides, including the neuropeptide TAC3, constituted almost 30% of striatal interneurons in marmosets and humans. Understanding how gene and cell-type attributes changed or persisted over the evolutionary divergence of primates and rodents will guide the choice of models for human brain disorders and mutations and help to identify the cellular substrates of expanded cognition in humans and other primates.

neuroscience↗