Why do our brains become ill?
- Analyzing the genomes of tens of thousands of individuals to identify genes in which common and rare variants shape risk of illness.
- Biological experiments and computational data analysis to understand how these genes and alleles affect the function of neurons, glia, and other brain cell types.
For example, we are mapping genetic influences to specific cell populations (interneurons, excitatory neurons, microglia, astrocytes) and working to understand how genetic variation perturbs the biology of those cell populations. This work involves genomic study of brain tissue from humans and mice and of cell culture models in which neurons are interacting with microglia and other kinds of cells. Our goal is to identify the key molecular and cellular events in the etiology of illness.
What cellular specializations make our brains work?
We developed the Drop-seq technology for profiling RNA expression genome-wide in thousands of individual cells at once. We are now using Drop-seq to ascertain things like: the cell types that populate the brain; the specific cell populations whose biology is altered in schizophrenia, autism and other illnesses; and the ways in which genetic variation acts at the level of specific cell types. We are also developing ways to extend this technology beyond transcriptomics to other aspects of a cell’s life.
What can we learn about human biology from sequencing?
Genome sequence data can be used in new ways to teach us novel things about human biology. We have recently used sequencing data to discover that DNA replication processes vary from person to person; to uncover a common pre-cancerous condition of the human blood; and to discover that pluripotent stem cells routinely acquire dominant negative mutations in the TP53 gene.
How do human genomes vary?
A substantial and biologically important fraction of human genome variation arises from complex and large-scale forms of variation that human genetics hadn’t had the tools and approaches to understand. We are working to figure out how these edgier parts of the human genome evolve in human populations and shape human phenotypes.