We are working to understand (i) how the human genome varies from person to person, and (ii) how inherited genome variation affects the biology of neurons and microglia on its way to affecting brain phenotypes such as risk of bipolar disorder, autism and schizophrenia. Most projects in the lab draw upon both experimental and computational or statistical approaches, and use them in integrative ways.

What can DNA sequence data teach us about human biology?

Whole-genome and whole-exome sequencing have become central ways to pursue genetics in human cohorts. We have found that that DNA sequence data can be used to reveal far more about biological systems, and about the human genome itself, than is currently appreciated today. We have recently used genome and exome sequence data to study variation in DNA replication processes, the acquisition of somatic mutations and precancerous states, and to find missing parts of the human genome sequence.

What do our genomes really look like?

There is much more to our genomes beyond long lists of single-nucleotide variants and indels. In fact, a substantial fraction of genome variation arises from complex, large-scale forms of variation that human genetics hasn't had the tools and approaches to understand. We are working to figure out what the rest of the genome is doing, and how it contributes to human phenotypes.

Can we understand the brain – both its normal function and disorders – at the level of cell types and cell states?

We have been developing technology for profiling RNA expression genome-wide in tens of 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. We call this technology Drop-Seq. We are beginning to use Drop-Seq to understand the cellular composition of the brain, the pathophysiology involved in disease states, and the ways in which genetic variation acts at the level of specific cell types.

What is the genetic and biological basis of schizophrenia?

The various threads of the work above are coming together in an effort to understand the genetic and biological basis of mental illness. We pursue this through:

– High-throughput genetic studies (of tens of thousands of individuals) of both common and rare variants, to identify genes and alleles that influence risk of schizophrenia.

– An integrated experimental/computational research program to go from these early genetic leads to biological insights. We seek to map these genetic influences to specific cell types and understand how they perturb the biology of those cell types. This work involves genomic study of brain tissue (human and mouse) and of cell culture models.