title: MicroRNA-driven developmental remodeling in the brain distinguishes humans from other primates.
abstract: While multiple studies have reported the accelerated evolution of brain gene expression in the human lineage, the mechanisms underlying such changes are unknown. Here, we address this issue from a developmental perspective, by analyzing mRNA and microRNA (miRNA) expression in two brain regions within macaques, chimpanzees, and humans throughout their lifespan. We find that constitutive gene expression divergence (species differences independent of age) is comparable between humans and chimpanzees. However, humans display a 3-5 times faster evolutionary rate in divergence of developmental patterns, compared to chimpanzees. Such accelerated evolution of human brain developmental patterns (i) cannot be explained by life-history changes among species, (ii) is twice as pronounced in the prefrontal cortex than the cerebellum, (iii) preferentially affects neuron-related genes, and (iv) unlike constitutive divergence does not depend on cis-regulatory changes, but might be driven by human-specific changes in expression of trans-acting regulators. We show that developmental profiles of miRNAs, as well as their target genes, show the fastest rates of human-specific evolutionary change, and using a combination of computational and experimental methods, we identify miR-92a, miR-454, and miR-320b as possible regulators of human-specific neural development. Our results suggest that different mechanisms underlie adaptive and neutral transcriptome divergence, and that changes in the expression of a few key regulators may have been a major driving force behind rapid evolution of the human brain.
authors.affiliation: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Somel
authors.forename: Xiling
authors.initials: X
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Tang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yan
authors.forename: Haiyang
authors.initials: H
authors.lastname: Hu
authors.forename: Song
authors.initials: S
authors.lastname: Guo
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Guohua
authors.initials: G
authors.lastname: Xu
authors.forename: Gangcai
authors.initials: G
authors.lastname: Xie
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Svante
authors.initials: S
authors.lastname: Pääbo
authors.forename: Philipp
authors.initials: P
authors.lastname: Khaitovich
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007231:Infant, Newborn; D008253:Macaca mulatta; D035683:MicroRNAs / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D002679:Pan troglodytes; D017397:Prefrontal Cortex / Q000254:growth & development / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013045:Species Specificity; D014015:Tissue Banks; D055815:Young Adult
chemical_list: D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger