Most comprehensive map of human brain development created

A map of DNA alterations in two regions of the developing human brain has been created.

An international team of scientists has created the first map of DNA modifications that occur during early brain development in the hippocampus and prefrontal cortex. These areas are critical in learning, memory and emotional regulation, and are frequently involved in autism spectrum disorder and schizophrenia.

'Neuropsychiatric disorders, even those emerging in adulthood, often stem from genetic factors disrupting early brain development,' said Dr Chongyuan Luo, who led the study at the University of California, Los Angeles (UCLA), and corresponding author of the paper published in Nature. 'Our map offers a baseline to compare against genetic studies of disease-affected brains and pinpoint when and where molecular changes occur.'

The team generated 29,691 profiles from developing and adult human frontal cortex samples and 23,372 profiles from hippocampus samples. Using a broad spectrum of developmental phases, the team put together a comprehensive map of the significant changes that occur in gene regulation during critical periods in human brain development. By including profiles from midway through pregnancy – a developmental stage rarely studied due to the scarcity of brain tissue – the scientists were able to produce the most comprehensive map to date.

Dr Mercedes Paredes, associate professor from the David Geffen School of Medicine, UCLA, said 'Our study tackles the complex relationship between DNA organisation and gene expression in the developing human brain at ages typically not interrogated: the third trimester and infancy. The connections we have identified across different cell types through this work could untangle the current challenges in identifying meaningful genetic risk factors for neurodevelopmental and neuropsychiatric conditions.'

Using single-cell profiling and multimodal imaging techniques the researchers were able to study both methylation (chemical modification of DNA) and chromatin conformation (3D arrangement of chromosomes within the nucleus) at the same time. These epigenetic processes control gene expression in single cells, and the team hypothesise that mapping these epigenetic marks will aid in the understanding of development disorders and neurological conditions.

'By studying how DNA is folded inside of individual cells, we can see where genetic variants connect with certain genes, which can help us pinpoint the cell types and developmental periods most vulnerable to these conditions,' said Dr Luo.

The researchers have made the map publicly available through an online platform, which they hope may offer new insights into how early brain development could shape mental health throughout a lifetime.

Co-author Professor Joseph Ecker, from the Salk Institute said 'Our study establishes an important database that captures key epigenetic changes that occur during brain development, in turn bringing us closer to understanding where and when failures arise in this development that can lead to neurodevelopmental disorders like autism.'

The authors also propose the map as a benchmark in the development of stem cell-based models, such as brain organoids, to make sure the models accurately replicate human brain development.