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Study Uncovers Genes Differentially Expressed in Brains of Humans and Other Primates

NEW YORK (GenomeWeb) – Certain genes are differentially expressed in human brains as compared to those of other primates, a new study has found. They include genes that are involved in the synthesis of a neurotransmitter with a role in cognition and behavior.

Although the human brain is larger than that of other primate and has more neuronal cells, this alone doesn't account for functional and organization differences between brains of people and their nearest relatives.

To look for other evolutionary changes, researchers from Yale School of Medicine and elsewhere sequenced the transcriptomes of nearly 250 tissue samples obtained from various brain regions of humans, chimpanzees, and rhesus macaques. Changes in mRNA and small noncoding RNA levels, they noted, could affect synaptic transmission, electrophysiological properties, and more.

As Yale's Nenad Sestan and his colleagues reported last week in Science, they uncovered differences in global and regional gene expression by species, including of dopamine biosynthesis genes, leading the researchers to conduct additional histological and functional analyses.

"By analyzing brain regions involved in these processes, we show that evolutionary modifications in gene expression and the distribution of neurons associated with neuromodulatory systems may underlie cognitive and behavioral differences between species," the authors wrote in their paper.

The researchers generated transcriptomic profiles of 247 tissues from the hippocampus, cerebellum, amygdala, striatum, and other brain regions from six humans, five chimpanzees, and five rhesus macaques. They annotated those transcripts using a common set of 26,516 orthologous mRNAs.

When they clustered the miRNAs, the researchers found that they clustered primarily by species, though cerebellar mRNA from all species formed a distinct cluster from other brain regions, indicating that the cerebella of the primates studied are more similar to each other than they are to brain regions from the same species.

Still, Sestan and his colleagues noted a number of differences in expression between the species. For instance, they reported that about a quarter of mRNAs and 40 percent of miRNAs were differentially expressed between at least two species in one or more of the brain regions examined.

More than 3,150 mRNAs and 200 miRNAs had human-specific differential expression, and most of these differences occurred in the striatum, followed by the thalamus and primary visual cortex. Only three genes — TWIST1, RP11-364P22.1, and CTB-78F1.1 — were differentially expressed across all neocortical areas examined.

By folding in single-cell RNA sequencing data from the human neocortex, the researchers found that many of the genes that they'd found to have species- or region-specific expression patterns also had cell type-specific expression patterns. When Sestan and his colleagues homed in on genes that encode receptors involved in excitatory, inhibitory, or modulatory signaling, they found that three genes that encode dopamine receptors were downregulated in the striatum of humans.

This led them to focus on the dopamine biosynthesis and signaling genes TH and DDC, both of which they found to be upregulated in the striatum of humans, while TH was downregulated in the neocortex of chimpanzees.

As these species-specific differences in expression patterns could be due to the distribution of neuronal subtypes in primates, Sestan and his colleagues examined the number of TH-expressing interneurons and traced their development. Humans harbored more TH-expressing interneurons than other primates, they found, and the highest TH expression is in the striatum and increases from early fetal development through young adulthood.

Other primates, though, lacked TH-expressing interneurons. Nonhuman primates might have genetic disruptions that affect the migration, differentiation, or survival of the interneurons, or TH could be transiently expressed in the cells, the researchers said.

"Our integrated analysis of the generated data revealed diverse molecular and cellular features of the phylogenetic reorganization of the human brain across multiple levels," they wrote.