Genomic evolution reshapes cell-type diversification in the amniote brain

In a study published in Developmental Cell, a team led by Prof. Robert K. Naumann from the Shenzhen Institutes of Advanced Technology of the Chinese Academy of Sciences (CAS), and researchers from BGI Research Hangzhou, Zhengzhou University and the Center for Excellence in Brain Science and Intelligence Technology of CAS, constructed a cross-species single-nucleus RNA-seq atlas of amniote brains comprising over 1.3 million cells, and uncovered conserved and divergent cell-type evolution.

Amniotes, which evolved over 320 million years ago (mya) and include reptiles, birds, and mammals, are among the most abundant and widely distributed terrestrial animals. Amniotes have developed complex brains and cognition through largely unexplored genetic and gene expression mechanisms. 

The cerebral cortex in mammals serves as the neural substrate for advanced cognitive functions and is widely considered the crowning achievement of brain evolution. Surprisingly, birds—despite lacking a structurally homologous cortex—often display complex cognitive capabilities that match or exceed those of primates. Understanding the evolution of brain cell types is key to uncovering both shared and unique features of nervous system organization.

In this study, the researchers used a standardized single-nucleus RNA sequencing (snRNA-seq) platform, generating a comprehensive single-cell atlas which comprises more than one million cells from the telencephalon and cerebellum of several model species, including turtles, zebra finches, pigeons, mice, and macaques.

Global analysis identified that functional divergence or loss of paralogous genes has significantly driven the evolution of brain cell types. Notably, the researchers identified ~3,000 differentially expressed homologous genes between birds and mammals, particularly the paralogous gene pair SLC17A6 and SLC17A7 in cortical excitatory neurons (EXs). These genes showed marked expression differences that correlate with genomic variations across species. 

Researchers found that most telencephalic EXs in birds express SLC17A6, whereas mammals display greater regional heterogeneity, with SLC17A7 predominantly expressed in the neocortex and SLC17A6 in other brain regions. Besides SLC17A6 and SLC17A7, they revealed that numerous other homologous genes contribute to species-specific differences in EXs regulation, highlighting the complex molecular mechanisms that drive functional divergence in brain cell types.

Furthermore, the researchers identified a novel bird-specific Purkinje cell subtype which may underlie the adaptation of the avian cerebellum to specialized behaviors, such as flight and complex vocalizations, indicating functional divergence from the mammalian cerebellum.

The findings of this study underscore the dynamic relationship between genome evolution and ecological adaptation, with genetic variation driving the evolution of specialized cell types across amniote species.