Genomic, molecular, and cellular divergence of the human brain

Abstract

While many core biological processes are conserved across species, the human brain has evolved with unique capacities. Current understanding of the neurobiological mechanisms that endow human traits as well as associated vulnerabilities remains limited. However, emerging data have illuminated species divergence in DNA elements and genome organization, in molecular, morphological, and functional features of conserved neural cell types, as well as temporal differences in brain development. Here, we summarize recent data on unique features of the human brain and their complex implications for the study and treatment of brain diseases. We also consider key outstanding questions in the field and discuss the technologies and foundational knowledge that will be required to accelerate understanding of human neurobiology.

Keywords: astrocyte; cortex; evolution; neural development; neuron.

Figure 1.

Levels of genome organization and key differences in organization across species. Illustration of key genomic features. The boxes under each genomic feature indicate areas where species divergence has been investigated. Abbreviations: CTCF, CCCTC-binding factor; RNPII, RNA polymerase II; TF, transcription factor.

Figure 2.

Quantifiable differences between species identified at the whole-brain, circuit, cell, and genomic levels. Approximate evolutionary distance from humans is indicated next to the brackets on the left for chimpanzee, macaque, marmoset, and mouse. Columns 1–6 show estimations of brain mass (with % of human), gyrification index (GI), neuron number (with % of human), postnatal age of peak synaptogenesis, and human sequence homology for coding regions and for all coding and noncoding regions. References: human [91,116,150,151]; chimpanzee [,–153]; macaque [,,,–156]; marmoset [150,151,154,157]; and mouse [24,150,151,158,159]. Figure created with BioRender (biorender.com).

Figure 3.

Timelines of brain development and lifespans. Schematic of gestational timeline (gray bars) and average lifespan (dark-blue bars) for human (global average), chimpanzee, macaque, marmoset, and mouse. Captive lifespans are reported for animal models. The global mean age at the time of diagnosis for autism, schizophrenia, and Alzheimer’s disease is shown in the light-blue bars. Colored bars indicate approximate time windows for key processes during human brain development, including neurogenesis, astrogliogenesis, cortical lamination, synaptogenesis, synaptic pruning, and myelination. Figure created with BioRender (biorender.com).