HD decodes the 3D genome map of the primate brain

the cognitive functions of the brain, such as sensation, perception, attention, memory, understanding, language and thinking, and gives human wisdom and creativity. Understanding the mechanisms that regulate the evolution of the human brain is to discover the differences between the human brain and other species in genetic regulation, which are key factors in the structure of the human brain and the origin of human intelligence.
Researchers from the Kunming Institute of Zoology of the Chinese Academy of Sciences, the School of Life Sciences of Peking University, and the Institute of Mathematics and Systems Science of the Chinese Academy of Sciences have worked for more than three years to construct the highest resolution three-dimensional (3D) genome map of the primate to date, revealing the evolutionary mechanisms of the 3D genome involved in human brain development. The findings were published online January 27 in Cell.There are millions of sequence differences betweenspecies, and only a few of them have important functional effects, how to establish a causal link between the key sequence differences in the genome and the regulatory changes of brain development, and to analyze the molecular regulatory mechanisms in them is a challenging subject.
primates have been used as biological and medical research models for nearly a hundred years. Kunming Animal Institute researcher Yu Bing team has long been engaged in primate comparative genomics and human evolutionary genetic mechanism research, macaques and humans have a closer kinship, in the human brain's origin, developmental mechanisms and brain disease research, macaques are the most ideal animal model.
" mammalian genomes, including macaques and humans, are usually about 2 meters long but folded into the nucleus of a cell that is only 10 microns long. "The genome is folded in an orderly manner in the three-dimensional space of the nucleus, and such an orderly fold is essential for cell proliferation and orderly differentiation during development. The development of
latest high-volume histology techniques, such as whole genome chromatin spatial image capture (Hi-C), provides a powerful tool for finely analyzing the three-dimensional tissue and molecular regulatory mechanisms of the genome during brain development. How to integrate multi-group data analysis and find human-specific regulatory elements and regulatory networks?
We solved this problem by collaborating on the cross-cutting disciplines of evolutionary genetics, bioinsynomics, and mathematics to study the 3D genome of cross-species brain development," said Mr. Yu.
In the course of the research, the team mainly undertakes the collection of multi-group data and functional verification experiments of fetal monkeys, the team of Li Cheng, a researcher at Peking University's School of Life Sciences, is mainly responsible for the main analysis of multi-group data, and the team of zhang Shihua, a researcher at the
Institute of Mathematics and Systems Science, is mainly responsible for the analysis of the part of the genome structure variation.talking about the main innovations in the study, Cebu said the team first used Hi-C technology to build a high-resolution 3D genome map of the peak neurodevelopment of chinese macaques. "This is the highest resolution 3D genome map of the primate brain, including humans, reaching a resolution of 1.5kb, allowing high-precision analysis of spatial tissue in the brain's developing genome."
does the fine chromatin space of the development of the macaque fetal brain look like? What are the regulatory components that play an important role in brain development? Combining multi-group map data from the macaque fetal brain, the researchers did a lot of original nature work, identifying chromatin compositions at different scales, including chromatin cells, chromatin topology domains (TADs), and chromatin rings.In addition to the public data published by , the researchers compared the 3D genomes across species (humans, macaques and mice) and found a large number of genomic bits of human-specific chromatin structures, including 499 human-specific chromatin topology domains (TADs) and 1,266 human-specific chromatin loops.
these human-specific patterns of regulation within chromosome rings suggest that brain development has evolved a more sophisticated network of transcriptional regulation among human ancestors, " said Mr. Yu.
In addition, by integrating and analyzing single-cell expression spectrum data for human brain development, the researchers found that these human-specific chromatin rings (Loops)-regulated genes were significantly expressed at the SP layer of the fetal brain, leading to speculation that human-specific chromatin rings (Loops) may play an important role in human-specific development patterns in the SP layer.
the SP layer of the fetal brain is an important brain layer in the early neural circuit and neuroplastic formation of brain development, and the SP layer has expanded significantly during human evolution, and its thickness can reach about 4 times the thickness of the cortical layer. However, due to the gradual disappearance of the brain layer after the birth of the fetus, people know less about its formation mechanism and function.
study is the first genetic confirmation of the important role of changes in the regulation of the expression of SP neurons in human brain development since SP neurons were discovered in 1974, explains Yu Yubing.as early as 2004, the team first discovered that the protein sequence of the gene had human-specific mutations at multiple points in human origin through molecular evolution studies of MCPH1, a key gene for human brain development.
The team then tested the cognitive abilities of genetically modified monkeys and found that the working memory of genetically modified monkeys improved significantly compared to wild-type control monkeys, suggesting that delays in brain development may be beneficial to the intellectual improvement of genetically modified monkeys, similar to the continuing phenomenon of young states in human brain development.
Sein continues to be a unique phenomenon in human evolution, most evident in the development of the brain, providing a longer window for the plasticity of the brain's neural networks and a key factor in the formation of human intelligence," Cebu told China Science Daily. "
" is now an extension of earlier research, that is, at the three-dimensional genome level to reveal the human brain development of specific regulatory elements. "If the previous study is a point, then the current study is a face that helps to more fully analyze the regulatory elements and regulatory networks of human larvae that persist in brain development. "
future, Cebu will lead the team to continue to explore the genetic mechanisms of human origin and evolution, further analyzing the role of the SP layer in human brain development." The study of the evolutionary development of the brain (Evo-Devo) is also an important perspective for analyzing the genetic mechanisms of the origin of the human brain. Cebu hopes the team will study more key nodes of brain development and evolutionaryly larger species (primitive vertebrates, etc.) to understand how animals evolved from small, simple brains to large and complex brains.