3D Genome of macaque fetal brain reveals evolutionary innovations during primate corticogenesis.

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.

Sex-biased regulatory changes in the placenta of native highlanders contribute to adaptive fetal development.

Compared with lowlander migrants, native Tibetans have a higher reproductive success at high altitude though the underlying mechanism remains unclear. Here, we compared the transcriptome and histology of full-term placentas between native Tibetans and Han migrants. We found that the placental trophoblast shows the largest expression divergence between Tibetans and Han, and Tibetans show decreased immune response and endoplasmic reticulum stress. Remarkably, we detected a sex-biased expression divergence, where the male-infant placentas show a greater between-population difference than the female-infant placentas. The umbilical cord plays a key role in the sex-biased expression divergence, which is associated with the higher birth weight of the male newborns of Tibetans. We also identified adaptive histological changes in the male-infant placentas of Tibetans, including larger umbilical artery wall and umbilical artery intima and media, and fewer syncytial knots. These findings provide valuable insights into the sex-biased adaptation of human populations, with significant implications for medical and genetic studies of human reproduction.

Brain developmental and cortical connectivity changes in transgenic monkeys carrying the human-specific duplicated gene SRGAP2C.

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.

Large-scale genome sequencing redefines the genetic footprints of high-altitude adaptation in Tibetans.

BACKGROUND: Tibetans are genetically adapted to high-altitude environments. Though many studies have been conducted, the genetic basis of the adaptation remains elusive due to the poor reproducibility for detecting selective signatures in the Tibetan genomes. RESULTS: Here, we present whole-genome sequencing (WGS) data of 1001 indigenous Tibetans, covering the major populated areas of the Qinghai-Tibetan Plateau in China. We identify 35 million variants, and more than one-third of them are novel variants. Utilizing the large-scale WGS data, we construct a comprehensive map of allele frequency and linkage disequilibrium and provide a population-specific genome reference panel, referred to as 1KTGP. Moreover, with the use of a combined approach, we redefine the signatures of Darwinian-positive selection in the Tibetan genomes, and we characterize a high-confidence list of 4320 variants and 192 genes that have undergone selection in Tibetans. In particular, we discover four new genes, TMEM132C, ATP13A3, SANBR, and KHDRBS2, with strong signals of selection, and they may account for the adaptation of cardio-pulmonary functions in Tibetans. Functional annotation and enrichment analysis indicate that the 192 genes with selective signatures are likely involved in multiple organs and physiological systems, suggesting polygenic and pleiotropic effects. CONCLUSIONS: Overall, the large-scale Tibetan WGS data and the identified adaptive variants/genes can serve as a valuable resource for future genetic and medical studies of high-altitude populations.

Polygenic adaptation leads to a higher reproductive fitness of native Tibetans at high altitude.

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.

Investigation of hypoglycemic, hypolipidemic and anti­nephritic activities of Paecilomyces tenuipesN45 in diet/streptozotocin­induced diabetic rats.

Due to its pharmacological activities, Paecilomyces tenuipes has previously been used as a folk medicine in Asia. The primary aim of the present study was to investigate the hypoglycemic, hypolipidemic and anti­nephritic effects of P. tenuipes N45 aqueous extracts (PTNE) in a high fat diet/streptozotocin­induced diabetic rat model. The rats were treated with 120 mg/kg of metformin or 0.04, 0.2 or 1.0 g/kg PTNE for 4 weeks. The hypoglycemic activity of PTNE was confirmed by the observation of reduced fasting blood glucose level and by partially normalized oral glucose tolerance. PTNE reduced total cholesterol and triglyceride content, and balanced the levels of low­density and high­density lipoproteins. The suppressive effects of PTNE on creatinine, blood urea nitrogen, interleukin (IL)­2, IL­6 and nuclear factor­κB levels indicated its ability to provide protection against diabetic nephropathy. PTNE treatment increased superoxide dismutase, malondialdehyde and glutathione peroxidase levels, suggesting that its anti­diabetic and anti­nephropathic activities may be associated with the prevention of oxidative damage during type 2 diabetic mellitus. The findings of the present study provided experimental evidence for the application of Paecilomyces tenuipes N45 on the treatment of type 2 diabetic mellitus.