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  • Review Article
  • Published:

Human brain evolution: transcripts, metabolites and their regulators

Nature Reviews Neuroscience volume 14, pages 112–127 (2013)Cite this article

Subjects

Key Points

  • Studies investigating species-specific molecular phenotypes, such as gene expression or metabolome concentrations, can link genetic and phenotypic differences among species.

  • Human brain evolution may be divided into an early phase that is shared among Homo species and included a gradual increase in cranial volume and possibly increased communication skills, and a recent and rapid evolutionary phase that is possibly specific to the Homo sapiens species. This recent phase is characterized by a remodelling of brain development that enhanced human infant abilities for social learning.

  • Studies investigating human-specific changes that occur during postnatal brain development and that accompany human cognitive phenotype formation may provide more insights into the molecular mechanisms of human cognitive evolution than studies investigating human-specific features in adults only.

  • One recent insight emerging from comparative developmental studies is that the extended period of human cortical synaptogenesis that had been identified using synaptic density measurements in higher-order associative brain areas (such as the prefrontal cortex in the human–macaque comparison) is specific to humans. The pace of cortical synaptogenesis in chimpanzee brains is more similar to that of macaques than of humans.

  • Differences in the rates of cortical synaptogenesis between the prefrontal cortex of humans and non-human primates can be observed at the gene expression and metabolite concentration levels and might be driven by one or several mutations affecting a few transcriptional or epigenetic regulators. These mutations might have occurred after the separation of the human and the Neanderthal lineages ∼400,000 years ago.

  • Population genetics analyses show that the total number of genetic mutations underlying human brain evolution after the separation of the human and the Neanderthal lineages is likely to be small, possibly less than a dozen.

  • Many more human-specific changes that are as yet unknown might be revealed by studies that integrate different levels of biological data — epigenome, transcriptome, proteome and metabolome — from specific brain structures, separate cortical layers and individual cell types. Although rapid technological developments have provided us with the tools to conduct such studies, the low availability of well-characterized, good-quality brain samples, especially from non-human primates, remains the major stumbling block to future research efforts.

Abstract

What evolutionary events led to the emergence of human cognition? Although the genetic differences separating modern humans from both non-human primates (for example, chimpanzees) and archaic hominins (Neanderthals and Denisovans) are known, linking human-specific mutations to the cognitive phenotype remains a challenge. One strategy is to focus on human-specific changes at the level of intermediate phenotypes, such as gene expression and metabolism, in conjunction with evolutionary changes in gene regulation involving transcription factors, microRNA and proximal regulatory elements. In this Review we show how this strategy has yielded some of the first hints about the mechanisms of human cognition.

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Figure 1: A schematic representation of the complete molecular roadmap for deciphering human brain evolution.
Figure 2: Expression divergence patterns in the prefrontal cortex.
Figure 3: Schematic representation of potential contributors to the emergence of novel cognitive phenotypes.

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Acknowledgements

We thank F. Kaya, N. Singh, E.-H. Sanchez, R. Nielsen, K. Bozek and J. Boyd-Kirkup for suggestions and help in preparation of this manuscript. The authors' studies are supported by the Ministry of Science and Technology of the People's Republic of China (grant number S2012GR0368), Chinese Academy of Sciences (grant numbers KSCX2-EW-R-02-02, KSCX2-EW-J-15-03 and KSCX2-EW-J-15-02), National Natural Science Foundation of China (grant number 31171232) and the Max Planck-Society. M. S. is funded by a fellowship from the European Molecular Biology Organization (EMBO ALTF 1475–2010).

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  1. CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, 320 Yue Yang Road, Shanghai, 200031, China

    Mehmet Somel, Xiling Liu & Philipp Khaitovich

  2. Department of Integrative Biology, University of California Berkeley, Berkeley, 94820, California, USA

    Mehmet Somel

  3. Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, Leipzig, 04103, Germany

    Philipp Khaitovich

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Glossary

Neuropile

A synaptically dense region between the neuronal and glial cell bodies, composed of dendrites, axons, synapses, glial cell processes and microvasculature.

Hominid

A member of the family Hominidae (the great apes), including the subfamily Homininae (humans, gorillas and chimpanzees) and the subfamily Ponginae (orang-utans).

Hominin

Member of the tribe Hominini, including all species that evolved since the last common ancestor between humans and chimpanzees, and which were more closely related to humans than to chimpanzees, including the genera Ardipithecus, Australopithecus, Paranthropus and Homo.

Neanderthals

An extinct species of the genus Homo, which inhabited Europe and parts of western Asia between 400,000 and 30,000 years ago. Notably, they had very similar morphology to modern humans, slightly bigger brains, and interbred with Eurasian modern humans for some period.

Denisovans

A recently discovered extinct Homo species identified by genome sequencing of a finger bone from Siberia. Denisovans were more closely related to Neanderthals than to modern humans.

mRNAs

Transcripts encoding sequences of protein-coding genes. mRNAs serve as messengers between genomic DNA and the protein translation machinery of the cell.

Non-coding RNAs

(ncRNAs). Transcripts that do not encode proteins but have regulatory, structural and catalytic roles in cells.

Broca's area

A region of the brain within the inferior frontal gyrus that is associated with speech in humans and manual gestures in other primates. The region tends to be larger in the left hemisphere.

Heterochrony

An evolutionary phenomenon involving changes in the rate and timing of development.

Synaptogenesis

The formation of synapses between neurons. In the human cerebrum, synaptogenesis is especially intense starting from 30 weeks of pregnancy until 15 months of age.

Synaptic elimination

Also called synaptic pruning, this is the developmental process whereby immature synapses — that is, those not subject to activity-dependent strengthening — are removed. At least half of the synapses generated in the infant cortex are eventually eliminated.

Neoteny

A type of evolutionary change in timing — that is, heterochrony — brought about by a retardation of somatic development, resulting in adult features characteristic of the juvenile state of ancestors.

Hominoid

Member of the superfamily Hominoidea, which contains two families of extant species — the family Hominidae (the great apes, including humans, orang-utans, gorillas, chimpanzees and bonobos) and the family Hylobatidae (lesser apes, including gibbons).

Transcription factors

Proteins activating or repressing the expression of genes by binding to particular DNA sequence motifs proximal to a gene's transcription start site.

MicroRNAs

(miRNAs). miRNAs are commonly single-stranded RNA molecules of 20–23 nucleotides in length, generated endogenously from a single-stranded hairpin precursor. They act as post-transcriptional inhibitors in association with the RNA-induced silencing complex (RISC).

Cis-elements

DNA sequences, such as a transcription binding site, directly affecting the expression of a gene within the same chromosomal region.

Trans-regulator

An RNA or protein that regulates the expression of another, so-called target gene. Unlike a cis-element, it does not necessarily reside in the same chromosomal region as the target gene.

Neutral mutation

A mutation that has no effect on evolutionary fitness: that is, it is neither positively nor negatively selected, so its frequency changes only as a result of genetic drift.

Genetic drift

Random sampling effects, such as random variance in the number of offspring among individuals, that can increase or decrease a mutation's frequency in a population across generations. Such events can cause the loss or, more rarely, fixation of a neutral or nearly neutral mutation.

Zinc finger proteins

A family of proteins containing a zinc finger motif, where zinc ions take part in stabilizing the structure, and which usually function in DNA or RNA binding. The largest family of mammalian transcription factors consists of zinc finger proteins.

RNA editing

A molecular process in which the information content in an RNA molecule is altered through a chemical change in the base make-up at the post-transcriptional level.

RNA-binding proteins

Proteins that bind to RNAs through an RNA-binding motif. The binding may regulate the translation of RNA or induce post-transcriptional changes, such as RNA splicing and editing.

PIWI-interacting RNA

(piRNA). A class of small non-coding RNA molecules of 26–31 nucleotides in length with a bias for a 5′ uridine, which is abundant in the germ line and has been implicated in the maintenance of genomic integrity by both epigenetic and post-transcriptional silencing of transposable elements and other genetic elements.

Large intergenic non-coding RNA

(lincRNA). Non-protein coding transcripts of more than 200 nucleotides in length, which are characterized by the complexity and diversity of their sequences. lincRNAs have emerged as key molecules involved in the control of transcriptional and post-transcriptional gene regulatory pathways.

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Somel, M., Liu, X. & Khaitovich, P. Human brain evolution: transcripts, metabolites and their regulators. Nat Rev Neurosci 14, 112–127 (2013). https://doi.org/10.1038/nrn3372

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