Abstract
Brain size and cognitive skills are the most dramatically changed traits in humans during evolution and yet the genetic mechanisms underlying these human-specific changes remain elusive. Here, we successfully generated 11 transgenic rhesus monkeys (8 first-generation and 3 second-generation) carrying human copies of MCPH1, an important gene for brain development and brain evolution. Brain-image and tissue-section analyses indicated an altered pattern of neural-cell differentiation, resulting in a delayed neuronal maturation and neural-fiber myelination of the transgenic monkeys, similar to the known evolutionary change of developmental delay (neoteny) in humans. Further brain-transcriptome and tissue-section analyses of major developmental stages showed a marked human-like expression delay of neuron differentiation and synaptic-signaling genes, providing a molecular explanation for the observed brain-developmental delay of the transgenic monkeys. More importantly, the transgenic monkeys exhibited better short-term memory and shorter reaction time compared with the wild-type controls in the delayed-matching-to-sample task. The presented data represent the first attempt to experimentally interrogate the genetic basis of human brain origin using a transgenic monkey model and it values the use of non-human primates in understanding unique human traits.
Highlights
Expansion in brain size and improvement in cognitive skills are among the most fundamental evolutionary changes that set humans apart from other primates
To mimic the human-specific genetic changes, using lentivirus transfection, we introduced the human MCPH1 copies into the rhesus monkey genome so that the transgenic (TG) monkeys have an overexpression of human MCPH1
To further dissect the impact of the human MCPH1 copies (huMCPH1) copies on brain development, we generated three F1 TG monkeys by IVF using the sperms of TG 01 that we proved were carrying the huMCPH1 copies in the germ line (Supplementary Fig. 12)
Summary
Expansion in brain size and improvement in cognitive skills are among the most fundamental evolutionary changes that set humans apart from other primates. Our previous in vitro experiments showed that these human-specific protein-sequence changes could alter the regulation of MCPH1 on its downstream genes [18]. Current evidence suggests that the human-specific protein-sequence changes, and gene-expression alteration of MCPH1 may contribute to human brain development and function. MCPH1 loss of function causes abnormal brain development, resulting in a reduced brain size in human and animals, the functional consequence of the human-specific seqence and expression changes remains to be understood. The 5’ non-coding sequence (∼5 kb) of MCPH1 likely contains regulatory elements for gene-expression regulation and it has 88.7% similarity between human and rhesus monkey, while it is only 40.4% between human and mouse. A rhesus monkey model is promising to study the functional impact of the human-specific changes (protein sequence and gene expression) on human brain evolution. Our preliminary cognitive test detected an improved short-term memory in the TG monkeys
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