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Human-specific duplicated genes contributed to phenotypic innovations during the origin of our own species, such as an enlarged brain and highly developed cognitive abilities. While prior studies on transgenic mice carrying the human-specific SRGAP2C gene have shown enhanced brain connectivity, the relevance to humans remains unclear due to the significant evolutionary gap between humans and rodents. In this study, to investigate the phenotypic outcome and underlying genetic mechanism of SRGAP2C , we generated transgenic cynomolgus macaques (Macaca fascicularis) carrying the human-specific SRGAP2C gene. Longitudinal MRI imaging revealed delayed brain development with region-specific volume changes, accompanied by altered myelination levels in the temporal and occipital regions. On a cellular level, the transgenic monkeys exhibited increased deep-layer neurons during fetal neurogenesis and delayed synaptic maturation in adolescence. Moreover, transcriptome analysis detected neotenic expression in molecular pathways related to neuron ensheathment, synaptic connections, extracellular matrix and energy metabolism. Cognitively, the transgenic monkeys demonstrated improved motor planning and execution skills. Together, our findings provide new insights into the mechanisms by which the newly evolved gene shapes the unique development and circuitry of the human brain. [ABSTRACT FROM AUTHOR]

The adaptation of Tibetans to high-altitude environments has been studied extensively. However, the direct assessment of evolutionary adaptation, i.e., the reproductive fitness of Tibetans and its genetic basis, remains elusive. Here, we conduct systematic phenotyping and genome-wide association analysis of 2,252 mother-newborn pairs of indigenous Tibetans, covering 12 reproductive traits and 76 maternal physiological traits. Compared with the lowland immigrants living at high altitudes, indigenous Tibetans show better reproductive outcomes, reflected by their lower abortion rate, higher birth weight, and better fetal development. The results of genome-wide association analyses indicate a polygenic adaptation of reproduction in Tibetans, attributed to the genomic backgrounds of both the mothers and the newborns. Furthermore, the EPAS1 -edited mice display higher reproductive fitness under chronic hypoxia, mirroring the situation in Tibetans. Collectively, these results shed new light on the phenotypic pattern and the genetic mechanism of human reproductive fitness in extreme environments. [Display omitted] • Deep phenotyping and genetic association of 2,252 mother-newborn pairs of Tibetans • Tibetans have higher reproductive fitness than lowland immigrants at high altitudes • GWAS results indicate a polygenic adaptation of reproduction in Tibetans • EPAS1 -edited mice display a higher reproductive fitness under chronic hypoxia He et al. conduct systematic phenotyping and genome-wide association analysis of reproductive fitness in 2,252 mother-newborn pairs of indigenous Tibetans, and they demonstrate that native Tibetans possess a high reproductive fitness at high altitude resulting from the mechanism of polygenic adaptation. [ABSTRACT FROM AUTHOR]

Elucidating the regulatory mechanisms of human brain evolution is essential to understanding human cognition and mental disorders. We generated multi-omics profiles and constructed a high-resolution map of 3D genome architecture of rhesus macaque during corticogenesis. By comparing the 3D genomes of human, macaque, and mouse brains, we identified many human-specific chromatin structure changes, including 499 topologically associating domains (TADs) and 1,266 chromatin loops. The human-specific loops are significantly enriched in enhancer-enhancer interactions, and the regulated genes show human-specific expression changes in the subplate, a transient zone of the developing brain critical for neural circuit formation and plasticity. Notably, many human-specific sequence changes are located in the human-specific TAD boundaries and loop anchors, which may generate new transcription factor binding sites and chromatin structures in human. Collectively, the presented data highlight the value of comparative 3D genome analyses in dissecting the regulatory mechanisms of brain development and evolution. • Construction of a high-resolution Hi-C map of macaque fetal brain • Cross-species 3D genome analyses uncover human-specific chromatin structures • The subplate lamina shows human-specific regulatory changes during corticogenesis • The human-specific loop regulating EPHA7 affects neuron dendrite development High-resolution map of developing rhesus macaque brain genome architecture during corticogenesis reveals human-specific chromatin structure and regulatory changes that impact dendrite development. [ABSTRACT FROM AUTHOR]