Lab Research

The microbial cells that colonize the human body outnumber human cells by an order of magnitude. Recent advances in high throughput sequencing technologies have unveiled great variability in the ecological communities of microbes that inhabit the human body, and shifts in the species composition have been associated with multiple chronic conditions, such as diabetes, inflammatory bowel disease, and obesity. Although the human microbiome is influenced by environmental factors, microbial communities also interact with human cells through the immune system and metabolic pathways.

We study host genomic factors that control and interact with the microbiome. We utilize high-throughput genomics technologies and employ computational, statistical, network-theory, data mining, and population genetic analytical approaches, with the goal of understanding how we interact with our microbial communities, how host-microbe interactions affect human disease, and how the symbiosis between us and our microbiome evolved.

Our research is driven by the following questions:

1. What are the molecular and genetic mechanisms controlling host-bacteria interactions? Which genes and pathways are involved in both the host and microbiome side?

2. How does host genetic variation control interactions with our microbiome? What are the effects of different environments and genetic backgrounds across human populations?

3. How did the complex symbiosis between us and our microbiome evolve throughout human history? Can we identify signatures of coevolution in human and microbial genomes?

4. How do host-microbiome interactions control susceptibility to complex disease? What are the unique roles of host genetics, bacterial communities, and environmental exposures?

Complex diseases in humans are thought to be affected by multiple common and rare genetic variants with varying effects on disease susceptibility. These variants are scattered in genes that may interact, or are involved in the same cellular pathway. Colleagues and I have recently completed a study on the genetics basis of neural tube defects (NTD), a severe complex developmental disorder that affects 0.1-1% of the population and involves multiple metabolic and signaling pathways. Using nanodroplet-based enrichment technologies followed by next-generation sequencing, we have identified disease-associated rare genetic mutations, for which functional studies in model organisms are currently underway. Current and future research includes using a systems-based approach to uncover and characterize disease-causing genetic variants, and use mathematical modeling of metabolic pathways to understand their effect on network dynamics.

Gene regulation is thought to have a major role in human adaptation, and recent studies have found a link between inter-primate differences in gene expression and various phenotypes. Previously, I have studied patterns of gene expression and sequence divergence to identify signatures of selection on gene regulation in primates. Recently, I have used primate transcriptomics and metabolomics data, and found that genes that physically interact, or involved in the same metabolic reactions, tend to change their expression in concert between species and across individuals.

My current and future work involves studying such co-regulation and co-evolution among interacting genes, to help elucidate how complex cellular pathways evolve to lead to novel phenotypic adaptations. I use whole genome and exome sequences of thousands of human individuals, and employ population-genetic and statistical approaches to identify signatures of co-evolution based on metabolic, signaling, and regulatory network topology.

Collaborators

Funding

We are grateful to the following organizations for their generous support of our research: