We are interested in how human genomes vary from person to person and shape the biology of neurons and other brain cell populations on their way to affecting key events in normal brain development and brain illness. We develop new experimental and computational approaches, then use them together in almost every project.

Genetics and neurobiology in brain illness

Genetics and neurobiology in brain illnessWe combine the above approaches in work to understand the genetic and biological basis of brain illnesses. We pursue this through:

  • 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.

Single-cell biology

Single-cell biologyWe recently developed a new technology for profiling RNA expression genome-wide in thousands of individual cells at once.  We do this by separating cells into millions of nanoliter-sized droplets, lysing the cells in droplets, and massively barcoding the contents of these droplets to remember the cell-of-origin of each RNA. In a single sequencing reaction, we routinely profile gene expression genome-wide in thousands of individual cells. We call this technology Drop-seq. We are beginning to use Drop-seq to ascertain things like: the cell types that populate the brain; the pathophysiology involved in schizophrenia, autism and other illnesses; and the ways in which genetic variation acts at the level of specific cell populations within complex tissues.

Human biology from sequencing

Human biology from sequencingTens of thousands of human genomes are being sequenced every year. We believe such data can be used in new ways to teach us novel things about human biology. In recent studies, we used sequencing data to discover that DNA replication varies from person to person; to find genes hiding in and around centromeres; and to discover a common pre-cancerous condition that puts people at twelve-fold greater risk of future cancer.