Did MicroRNAs Orchestrate the Human Brain Boom?

Humankind may owe its outsized intelligence to our microRNAs. The activity of these tiny gene regulators during brain development distinguishes us from our furrier, less brilliant primate cousins, according to a paper in the December 6 PLoS Biology. This is one mechanism by which humankind could have gone from tree-swinging to rocket-building in a mere six million years, an evolutionary eye blink, suggest the authors, led by Philipp Khaitovich of the Chinese Academy of Sciences in Shanghai and Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. The team compared patterns of messenger and microRNA (miRNA) expression among humans, chimpanzees, and rhesus macaques. Human miRNAs stood out as playing a greater regulatory role.

“We wanted to find out what makes the human brain so different, why human babies can learn all the things they do as they develop,” said Khaitovich, noting that a chimp or macaque, even if placed in the same stimulating environment as a human toddler, would not sponge up all the knowledge that human children do. The group focused on two areas of the brain: the prefrontal cortex, believed to be the seat of human-specific abilities such as abstract thinking and future planning; and the cerebellum, which is thought to control aspects of movement, memory, and human language. They collected tissue samples from 33 people, aged newborn to 98; 14 chimps aged newborn to 44; and 34 macaques aged newborn to 28. All of the people and animals had died suddenly, for reasons unrelated to disease or the study.

Given the short time span between today and our last common primate ancestor, it is unlikely that many new genes emerged during human evolution, Khaitovich said. With the same complement of genetic options, the team guessed that humans differ from other species in how they use that genetic material. The genes are like players in an orchestra; depending on who plays what when, a different symphony is born. To test their idea, the researchers used microarrays to measure expression of messenger RNA in the cortex and cerebellum—basically, figuring out the musical score for each species’ brain development.

Joint first authors Mehmet Somel and Xiling Liu of the Chinese Academy of Sciences found that some genes were expressed at more or less the same level throughout life in humans, chimps, and macaques. Other mRNAs varied with development, but had consistent patterns across the three species. Khaitovich and colleagues focused on a third group comprising several hundred genes with lifetime patterns of expression unique to humans. “It is really the developmental processes that most dramatically changed in humans compared to chimpanzees and macaques,” Khaitovich said.

How did humans change their tune while keeping the same orchestra? It turns out that our conductors are different. Somel, now at the University of California, Berkeley, and colleagues discovered an enrichment for microRNA and transcription factor binding sites among the human-specific developmentally patterned genes. The abundance hints at much finer control of gene activation. That could explain how people got so smart so quickly, Khaitovich said.

The team focused on the microRNA connection. They found that some microRNAs showed human-specific developmental patterning. In addition, the team identified 39 microRNAs that were likely to bind the genes whose expression was altered during human development. Although other primates may have the same or similar microRNAs, they do not regulate gene expression in the same pattern as they do in humans.

To validate their results, Somel and colleagues tested a few of those microRNAs in cultured human neuroblastoma cell lines, and confirmed that the microRNAs regulated their predicted target genes. Notably, at least two of the human brain-patterning microRNAs regulate genes involved in calcium signaling, which is key for neural plasticity. Next, the team would like to alter some of these microRNAs in mice, Khaitovich said. Copying the evolutionary changes that happened in humans might make the rodents more clever, he suggested.

MicroRNA expression is just one possible explanation for human smarts. Gene sequence differences in coding and regulatory genes (Carroll, 2003; King and Wilson, 1975), alterations in the transcriptome (Xu et al., 2010) and in noncoding RNAs (Babbitt et al., 2010), increased transcript and protein levels (see ARF related news story and Cáceres et al., 2003), and metabolic changes (Fu et al., 2011) have also been suggested. All are correct, said Peter Nelson of the University of Kentucky in Lexington, and helped lead to the human brain being so much more complicated than that of a monkey or a mouse. “The human brain is not just a bigger brain; it is quite different at the molecular level,” agreed Todd Preuss of Emory University in Atlanta, Georgia. Understanding the evolution of humankind’s cognitive abilities—as Preuss put it, “the strangeness of human beings”—could help scientists comprehend human-specific diseases such as schizophrenia, autism, and Alzheimer’s, he suggested. Neither Preuss nor Nelson was part of the PLoS study team.—Amber Dance

Comments

  1. In this somewhat “hard-core” transcriptomics study, the authors propose that human-specific gene expression changes that occur during brain development (in what the authors define as “type III” genes) are regulated mainly by transregulatory elements, and, in particular, non-protein-coding microRNAs (miRNAs or miRs). MicroRNAs, a large and abundant class of regulatory RNAs, function in gene silencing and are important for neuronal function and survival. The authors also identified miRNAs that correlated negatively with a subset of type III neuronal genes. Among these, they focused on three: miR-92a, miR-454, and miR-320b, which are highly conserved among humans, chimpanzees, and macaques. When overexpressed in human neuroblastoma cells, candidate miRNAs could indeed regulate predicted target genes.

    Notably, two out of three candidate miRNAs could regulate genes associated with calcium signaling, known to be important for synaptic plasticity and memory formation. Importantly, the authors could show that miR-320b is expressed in neuronal cells in humans and in macaques in vivo, although expression levels seemed quite low, which is line with deep-sequencing data in humans (miRBase.org). It should be noted that humans, like the macaque and the chimp, express mainly the 3’ arm (-3p) of miR-92a and miR-454 precursors. Unfortunately, it is not clear which miRNA sequence (either 3p or 5p) was used in the functional analyses described in the study. This is important, as 3’ and 5’ arms of the same miRNA have different sequences, and thus could target different genes.

    Certainly, this study opens the door to various validation and functional studies, and provides good candidates for future studies aimed at understanding the role of miRNAs in age-related neurodegenerative disorders.

    View all comments by Sébastien S. Hébert

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References

News Citations

  1. It's All in the Dose: Protein Levels, Not Structures, May Separate Us from Chimps

Paper Citations

  1. Carroll SB. Genetics and the making of Homo sapiens. Nature. 2003 Apr 24;422(6934):849-57. PubMed.
  2. King MC, Wilson AC. Evolution at two levels in humans and chimpanzees. Science. 1975 Apr 11;188(4184):107-16. PubMed.
  3. Xu AG, He L, Li Z, Xu Y, Li M, Fu X, Yan Z, Yuan Y, Menzel C, Li N, Somel M, Hu H, Chen W, Pääbo S, Khaitovich P. Intergenic and repeat transcription in human, chimpanzee and macaque brains measured by RNA-Seq. PLoS Comput Biol. 2010;6:e1000843. PubMed.
  4. Babbitt CC, Fedrigo O, Pfefferle AD, Boyle AP, Horvath JE, Furey TS, Wray GA. Both noncoding and protein-coding RNAs contribute to gene expression evolution in the primate brain. Genome Biol Evol. 2010;2:67-79. PubMed.
  5. Cáceres M, Lachuer J, Zapala MA, Redmond JC, Kudo L, Geschwind DH, Lockhart DJ, Preuss TM, Barlow C. Elevated gene expression levels distinguish human from non-human primate brains. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13030-5. PubMed.
  6. Fu X, Giavalisco P, Liu X, Catchpole G, Fu N, Ning ZB, Guo S, Yan Z, Somel M, Pääbo S, Zeng R, Willmitzer L, Khaitovich P. Rapid metabolic evolution in human prefrontal cortex. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6181-6. PubMed.

Further Reading

Papers

  1. Nelson PT, Keller JN. RNA in brain disease: no longer just "the messenger in the middle". J Neuropathol Exp Neurol. 2007 Jun;66(6):461-8. PubMed.
  2. Khaitovich P, Muetzel B, She X, Lachmann M, Hellmann I, Dietzsch J, Steigele S, Do HH, Weiss G, Enard W, Heissig F, Arendt T, Nieselt-Struwe K, Eichler EE, Pääbo S. Regional patterns of gene expression in human and chimpanzee brains. Genome Res. 2004 Aug;14(8):1462-73. PubMed.
  3. Fraser HB, Khaitovich P, Plotkin JB, Pääbo S, Eisen MB. Aging and gene expression in the primate brain. PLoS Biol. 2005 Sep;3(9):e274. PubMed.
  4. Hu HY, Guo S, Xi J, Yan Z, Fu N, Zhang X, Menzel C, Liang H, Yang H, Zhao M, Zeng R, Chen W, Pääbo S, Khaitovich P. MicroRNA expression and regulation in human, chimpanzee, and macaque brains. PLoS Genet. 2011 Oct;7(10):e1002327. PubMed.
  5. Heimberg AM, Sempere LF, Moy VN, Donoghue PC, Peterson KJ. MicroRNAs and the advent of vertebrate morphological complexity. Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2946-50. PubMed.

Primary Papers

  1. Somel M, Liu X, Tang L, Yan Z, Hu H, Guo S, Jiang X, Zhang X, Xu G, Xie G, Li N, Hu Y, Chen W, Pääbo S, Khaitovich P. MicroRNA-Driven Developmental Remodeling in the Brain Distinguishes Humans from Other Primates. PLoS Biol. 2011 Dec;9(12):e1001214. PubMed.

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