Genetic Control of Human Brain Evolution
Over the last six million years, patterns of human brain development and life history changed to triple the number of neurons produced prenatally, extend synaptic plasticity through a prolonged phase of development, and restructure connectivity between brain regions. At the same time tens of millions of mutations accumulated as fixed changes in the human genome through the processes of selection and drift. Evolutionary changes involve tradeoffs and the unequal scaling of size, connectivity, and developmental tempo among brain regions and cell types may confer vulnerabilities shared by all humans by placing cells in new contexts. However, connecting human-specific mutations to recently evolved traits and vulnerabilities remains challenging because we lack experimental systems for comparative and functional studies of great ape cortical development.
To identify genomic differences underlying unique features or vulnerabilities of the human brain, we are combining advances in single cell genomics and genome engineering with great ape cerebral organoid models of brain development. We aim to systematically connect human-specific mutations to evolved cellular specializations, vulnerabilities, and compensatory adaptations.
Great ape organoid models help bridge the gap between human-specific genetic changes and recently-evolved traits
Molecular Specializations of Neuronal Cell Types
Over 100 years ago, Ramon y Cajal appreciated the vast diversity of neurons in the human brain, poetically comparing these cells to the butterflies of the soul. Today, we are poised to identify the molecular factors that specify these diverse cell types using single cell genomics and stem cell biology approaches. Our lab participates in the BRAIN Initiative and PsychEncode consortia to map these developmental lineages. We currently utilize these maps to improve the fidelity of in vitro organoid models to primary tissue and to interpret cell-type-specific vulnerability in disease. Ultimately, we aim to develop molecular tools to monitor, target, and replace specialized cell types in the human brain.
Transitioning from the era of reading cell types and tissue organization to writing cell types and structures through single cell genomics and stem cell biology
A Resource of Genetic and Cellular Diversity from Diverse Species
As biologists, we learn from the spectacular adaptations of diverse organisms accumulated throughout the history of life. Tragically, we have entered the sixth mass extinction in the history of life. For example, over 60% of primate species are at risk of extinction in the near term. As part of our comparative studies on mammalian evolution, we aim to develop pluripotent stem cells from a range of phylogenetically informative and endangered species. Outside of human and mouse, pluripotent stem cell lines are currently only available from a limited range of species and individuals. These lines will serve as a renewable and experimentally-tractable resource of genetic variation. In the future, these lines may be used to study the influence of genetic and infectious disease on endangered species, as well as to support species-specific toxicology screens. Influential studies in the Northern white rhinoceros support the feasibility of this work and hint at the long-term possibility of using such lines to restore genetic diversity to a population. Ultimately, we hope to use and distribute these diverse lines for studies of evo-devo in a dish and for conservation efforts.
Available pluripotent stem cell lines currently sample only a limited range of evolved genetic diversity among apes