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Genomic approaches for understanding the evolution of the human brain

Nature Neuroscience volume 29, pages 1036–1047 (2026)Cite this article

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Abstract

Human cognitive and social behaviors differ from those of other mammals, but the molecular, cellular and circuit-level changes that underlie these behavioral differences are poorly understood. The recent availability of thousands of mammalian, non-human primate, ancient human and modern human genomes now makes it possible to use quantitative approaches to identify genomic regions with signatures of selection in humans, which, when combined with comparative experimental approaches, can provide precise insights into the phenotypes that were the targets of adaptation across different evolutionary timescales. This Review presents a progress report on a ‘genome-up’ approach to understanding human brain evolution and lays out a framework for further advancement. Additional progress will require cohort expansion to improve the identification of genetic loci under selection, the application of comparative experimental approaches to additional milieus and the functional dissection of specific human-evolved loci.

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Fig. 1: Phenotypic changes along the human evolutionary lineage and available genome resources.
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Fig. 2: Examples of genomic changes between humans and other species and in recent human history.
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Fig. 3: Genomic regions with signatures of selection in humans may be preferentially implicated in conditions that affect cognitive and social behaviors.
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Fig. 4: Challenges for identifying the phenotypic consequences of human-specific variants.
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Fig. 5: Current approaches for identifying the phenotypic consequences of human-specific variants.
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Fig. 6: Proposed ‘genome-up’ approach.
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Acknowledgements

We thank K. Probst for assistance with figure visualization. C.A.W., M.E.G. and D.R. were supported by Allen Family Philanthropies. C.A.W. and D.R. are Howard Hughes Medical Institute Investigators.

Author information

Authors and Affiliations

  1. Allen Discovery Center for Human Brain Evolution, Boston, MA, USA

    Janet H. T. Song, Michael E. Greenberg, David Reich & Christopher A. Walsh

  2. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA

    Janet H. T. Song & Christopher A. Walsh

  3. Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA

    Janet H. T. Song & David Reich

  4. Department of Neurobiology, Harvard Medical School, Boston, MA, USA

    Michael E. Greenberg

  5. Department of Genetics, Harvard Medical School, Boston, MA, USA

    David Reich

  6. Howard Hughes Medical Institute, Boston, MA, USA

    David Reich & Christopher A. Walsh

  7. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    David Reich & Christopher A. Walsh

  8. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Christopher A. Walsh

  9. Department of Neurology, Harvard Medical School, Boston, MA, USA

    Christopher A. Walsh

Authors
  1. Janet H. T. Song
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  2. Michael E. Greenberg
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  3. David Reich
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  4. Christopher A. Walsh
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Contributions

Conceptualization: J.H.T.S., M.E.G., D.R. and C.A.W. Writing, original draft: J.H.T.S. Writing, review and editing: J.H.T.S., M.E.G., D.R. and C.A.W.

Corresponding authors

Correspondence to Janet H. T. Song or Christopher A. Walsh.

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Competing interests

C.A.W. is on the Scientific Advisory Boards of Bioskyrb Genomics (cash, equity) and Mosaica Therapeutics (cash, equity) and is an advisor to Maze Therapeutics (equity) and CAMP4 (cash), but these have no relevance to this work. The remaining authors declare no competing interests.

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Song, J.H.T., Greenberg, M.E., Reich, D. et al. Genomic approaches for understanding the evolution of the human brain. Nat Neurosci 29, 1036–1047 (2026). https://doi.org/10.1038/s41593-026-02277-1

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