With the initial sequencing of the human genome, and subsequent sequencing of thousands of human and non-human vertebrate genomes, we have begun to make important discoveries regarding the nature of phenotypic evolution, its relationship to species-specific biology, and disease risk. Yet, we still understand little of what the majority of the base-pair sequences are doing to shape normal human and primate biological traits as well as disease risk. Students in the Capellini lab acquire training in Human Evolutionary Biology, Developmental Biology, and Genetics which places them in unique positions to have a detailed understanding of the biological traits that make humans and primates unique and to have the highly specialized skill set to functionally identify the underlying genetic basis for these traits; in other words, to link genotype to phenotype.
The goal of the research program in the Capellini Lab is to identify the DNA base-pairs that mediate human- and primate-specific biological traits and their relationships to disease. The primary focus of the lab is on the musculo-skeletal system with an emphasis on identifying key regulatory elements or enhancers for musculo-skeletal genes and finding variants, both in humans or non-human primates, which alter the functions of these enhancers to shape the skeleton. To accomplish this task, the lab uses a multi-disciplinary perspective including wet- and dry-lab assays to generate novel data-sets in the mouse and intersect them with datasets from human biology, genetics, and medicine. There are a number of other non-skeletal projects in the lab, including examining the functional effects of genetic variants introgressed from Neandertals into the modern human genome, and studies on the regulation of key genes involved in COVID-19 disease risk.
Currently, the lab focuses on three main areas of research in musculoskeletal biology and disease: the genetics of joint development and osteoarthritis, the functional genetics of human height, and the genetics of pelvic girdle development and its relationship to human obstetrics and diseases of child birth. All topics are generally understudied areas in genetics and developmental biology, yet they are essential components of our unique human condition with associated diseases that impact hundreds of millions of people worldwide.
Regarding studies on joint development and osteoarthritis, the lab studies the genetic and molecular mechanisms that underlying joint development and its relationship to osseous diseases such as osteoarthritis. We have and will continue to concentrate on the functional interrogation of the GDF5 locus, a key locus in joint development/disease, and its relationship to joint-specific osteoarthritis by determining how GDF5 regulatory elements shape specific adult joint morphologies (i.e,, knee versus hip) and whether genome-wide associated variants within them mediate human joint-specific arthritis risk. This involves the construction of mouse lines harboring enhancers, then mapping their contributions to adult tissues, and eliminating them from the mouse to observe their functional impact. In tandem, human specific genetic variants residing within these enhancers are being tested for influence on regulatory activity, and those that impact expression will be engineered/replaced into the mouse genome for functional testing. During these analyses, my lab will begin to identify DNA motifs that dictate formation of specific joints in these switches using bioinformatic analyses and in vivo testing.
The lab also also focuses on the genetics of pelvic formation. We have published functional mouse studies in this area and using bioinformatic analyses identified putative enhancers underlying the formation of pelvic tissues. Using ChIP- and RNA-seq methods, my lab has already begun to focus on the genome-wide de novo discovery of enhancers and genes that control the formation of distinct parts of the pelvic girdle. These regulatory regions can be intersected with those I previously discovered and tested for activity in mice. In this context, human-, chimpanzee-and other primate-specific genetic variants are in the process of being interrogated to see if they modulate enhancer activity, and, mice are being constructed to place these mutations in an in vivo context. Such mutations may underlie the morphological differences between humans and chimps, helping to identify the basis for our unique form of locomotion, bipedality. Ultimately, we will be searching for human population-specific variants to see how they underlie variation in pelvic morphology and the differing rates of pelvic obstruction diseases.