New Research from JCC Fellow Dr. Daniel Richard
JCC Fellow Dr. Daniel Richard’s latest research on the genetic and epigenetic drivers of bone development and their role in determining height was published last month. Dr. Richard is currently a JCC Fellow in Dr. Anne Brunet’s lab at Stanford University, but this article is the capstone of his PhD research in Dr. Terence Capellini’s lab at Harvard University.
Bone development as a model for biological aging
Richard is broadly interested in biological aging. During his PhD research, he first investigated osteoarthritis through the lens of human knee chondrocyte development. In this work Richard identified an enhancer variant present in billions of people that confers an elevated risk for osteoarthritis.
In this latest work, Richard was more focused on the early development of the human skeleton. Access to multiple bone types early in human development provided him with an opportunity to ask unique scientific questions. For example, since hindlimb long bones contribute the most to adult height, Richard and his colleagues thought there might be a specific transcriptional program at this anatomical site that drives hindlimb bone growth, relative to other bones.
By sampling human embryonic humerus, radius, femur, and tibia bones, Richard and his colleagues found that mostly, counter to their expectations, there was a general “growth” program shared between bones at different anatomical sites. They realized that this core growth program represented an excellent opportunity to explicitly test the omnigenic model for heritability of complex traits.
Embryonic skeletal tissues tested in Richard et al, 2024.
Testing the omnigenic model for complex trait heritability
Some traits are monogenic and discrete – think of Mendel’s experiments on the color and texture of peas, for example. Many traits, however are polygenic where many genes contribute to a trait resulting in a continuous distribution of outcomes. At an extreme, polygenic traits may essentially be omnigenic in that the perturbation of any gene in a cell or tissue type would impact that trait.
Height is one such highly polygenic trait with a continuous distribution. Richard cross-referenced the core skeletal growth program with genome-wide association studies for height to analyze height through the omnigenic model. This approach allowed Richard to identify core genetic modules – including a metabolic module and a transcriptional regulation module – that drive skeletal growth. Importantly, considering these genetic modules as a whole has much better predictive power for height than any of the individual genes on their own. Remarkably, Richard’s genetic modules better predicted height than a set of curated genes with known impacts on human skeletal development – further demonstrating the strength of this approach in predicting highly polygenic, or omnigenic, traits.
Neurodegeneration as a challenging model for biological aging
Now, as a JCC fellow in the Brunet lab, Richard will apply his skill set in teasing apart highly polygenic traits to human neurodegeneration. The additional complexity of neurodevelopment drew Richard to this field.
Dr. Daniel Richard
First, in comparison to bones, where most bone cells are more or less about the same in a given tissue, the neural system is highly structured and made up of many diverse cell types. Secondly, during his PhD Richard was studying germline mutations that have existed for hundreds of thousands of years and understanding their role at a population level. Now, he’ll examine the mosaic nature of somatic mutations in an individual to understand how these mutations collectively contribute to neurodegeneration. Lastly, Richard argues that cognitive decline and increasing risk for neurodegeneration are ubiquitous in that we all go through this process sooner or later. His aspiration is to define the highly polygenic underpinnings of neurodegeneration to set the stage for future therapeutic and lifestyle interventions.
Congrats on your recent research Dr. Richard – we look forward to seeing what you discover next during your JCC fellowship!