Developing new computational strategies to understand complex genetic systems.
My laboratory uses data to strengthen the interface between experimental systems and common disease in humans, such as Alzheimer's and Type 2 Diabetes. We develop computational methods to analyze genetic architecture, design translatable studies of model systems, perform data alignment to precisely quantify disease relevance, and share data through open science platforms. This work involves mapping networks of interacting genes, integrating phenotypic and molecular data, critically evaluating models with experimental tests, and exploring how biological complexity is encoded in genetic data.
Our primary disease focus is leveraging genetic and genomic data to identify and test potential treatments for Alzheimer’s disease. We are using human genetics to create the next generation of late-onset Alzheimer’s disease mouse and non-human primate models. These models comprise a multi-species strategy to understand Alzheimer’s disease origins and progression in molecular and pathophysiological detail. They are designed to be preclinical platforms for the rapid validation of diagnostic biomarkers and rigorous evaluation of precision therapeutics that target the pathways that drive dementia. We also comprehensively analyze data from human and experimental studies to critically assess therapeutic hypotheses. Through this work, we are derisking molecular targets to accelerate the discovery of precise, targeted therapeutic approaches.
We are embedded in a network of collaborative projects and centers including MODEL-AD, TREAT-AD, and Marmo-AD. By integrating knowledge and standardizing analytical strategies across these research consortia, we are maximizing the translational value of computational and experimental research. We are creating data resources and analytical tools that enable researchers to rapidly and reliably test new findings across prior studies, with the goal of accelerating Alzheimer’s research by avoiding past failures and instantly reinforcing promising new discoveries.
Chromosomal crossover via homologous recombination is both a necessary step in mammalian meiosis and the method by which genetic variation is redistributed throughout a population. Genome-wide assays of chromatin states and gene expression are revealing molecular details of this process, which is initiated with site selection by the protein Prdm9. In collaboration with the Paigen and Handel labs, we are combining data on epigenetic states with transcript abundances to understand the molecular mechanisms that drive recombination and meiosis in the mouse testis. The aim of this work is a comprehensive model of when, where, and how molecules like Prdm9 act to guide germ cell development.
There are few effective treatments for late-onset Alzheimer’s disease once the disease is diagnosed. The identification of early biomarkers and development of reliable model systems for therapeutic development are crucial for advancing potential treatments for this disease. In collaboration with the Howell Lab and the Genetic Resource Science group, we are studying hundreds of genome sequences to identify potential genetic factors and using advanced genome engineering technologies to create faithful mouse models for late-onset Alzheimer’s. Furthermore, we are studying aging mice to identify early molecular signatures of Alzheimer’s disease development, which might serve as biomarkers that can be detected decades before the neurodegenerative symptoms appear.
The genetic heterogeneity and complexity of cancer have posed significant challenges to the design of effective therapeutic strategies. The characterization of mRNA-expression subtypes in breast cancer facilitates genomic and genetic studies to identify biological processes and pathways that drive distinct molecular subtypes and elucidates the potential feasibility of subtype-specific drug targets. However, such therapies tend to have limited efficacy, often due to unpredicted compensation in the network of mutations. To address this problem we are applying a multi-trait genetic interaction analysis to genetic and genomic data from The Cancer Genome Atlas (TCGA) breast cancer project. We are discovering how somatic copy-number variations and other mutations in oncogenes and tumor suppressors interact to affect gene-expression modules that contribute to distinct breast cancer subtypes.
Recent initiatives such as the ENCODE project have mapped regions of the genome that are believed to regulate gene expression through histone modifications, DNA methylation, and proteins that bind DNA. These regions often harbor variants that have been linked to human disease in genome-wide association studies, suggesting that genetic variation modifies gene expression by changing the regulatory chromatin state. We are carrying out a systematic study of how genetic variation in laboratory mice affects chromatin states in response to environmental stimuli. This study is providing concrete evidence for genetic-epigenetic interactions that potentially underlie human disease.
The study of molecular epistasis has been used for decades in mapping pathways of linear information flow from gene to gene. However, the genetic complexity inherent in many biological systems can confound this strategy when the system is viewed on a genomic scale. Instead of mapping linear pathways, large-scale networks of genetic interactions tend to feature tangled modules of genes that function together to carry out cellular processes. Furthermore, given the prevalence and diversity of genetic interactions, it is often unclear how to optimally define the rules of genetic interaction that form the links in these networks. We are developing methods based on information theory to measure the information content of networks. This quantitative measure of complexity can serve as scoring function to find the most informative network from a given genetic data set. From this work we hope to develop both practical tools for genetic analysis and fundamental insights into how networks encode information.
Inheriting a specific genetic variant, APOEε4, is linked with 15-20 percent rise in risk of developing Alzheimer’s, with at least 20 other genes implicated. JAX researchers are studying how APOEε4 risk depends on other genes, in mice with a wide variety of genetic backgrounds.
Currently there are no effective cures for age-related macular degeneration and other heritable retinal diseases.
Alzheimer’s disease is still poorly understood despite its huge costs and burden. Greg Carter is working at the intersection between patient and mouse research to develop accurate disease models and develop effective therapies.
For the first time, researchers have the tools to build new mouse models that truly represent patients with Alzheimer’s disease.