Nature: Clonal distributions during human neocortical development deciphered through brain mosaicism
Come join Dr. Xiaoxu Yang from Dr. Joseph Gleeson's lab to understand how brain somatic mutations are used to trace neocortical lineages in humans.
The structure of the human neocortex underlies species-specific traits and is a reflection of intricate developmental programs. Yet there lineage tracing and clonal analysis in the human brain are hard to conduct compared with other species. Somatic mosaic mutations across the genome are potentially the neutral recorders for lineage history and early embryonic development of the human cortex. A thorough study of the distribution of mosaic clones in human cortical areas is the key to understanding early embryonic development in normal and abnormal humans.
Here we sought to understand the genetic basis in the human cortex which will explain why brain disorders such as most mosaic forms of cortical dysplasias in humans can involve an entire hemisphere but rarely involve the opposite hemisphere. To look at typically developed brains as backgrounds, we analyzed neocortical cellular lineages in postmortem human brains through a comprehensive assessment of brain somatic mosaicism. By combining comprehensive sampling of 40 distinct anatomic locations with 300x ultra-deep whole genome sequencing from 4 neurotypical cadavers, we identified hundreds of bona fide mosaic variants, then deconvolved distinct geographic, cell type, and clade organizations across the brain and other organs.
We found that clones derived after the accumulation of 90-200 progenitors in the cerebral cortex tended to respect the midline axis, well before they respect anterior-posterior or ventral-dorsal axes, and that cell fate correlated better with location rather than early lineage. We found local clonal expansion as well as broad-range sophisticated distributions of somatic variants across the cortex. Similar to rodents, cortical cells originated from both dorsal and ventral cellular populations, and microglia lineage appeared distinct from other resident brain cells.
Our data provide a comprehensive analysis of brain somatic mosaicism across the cortex, demonstrate cellular origins and migration patterns within typically developed human brains, and reveal fundamental mechanisms by which mosaic variants can lead to focal brain disease.
For more information, please visit the original publication at https://www.nature.com/articles/s4158....