Ryan’s research interests integrate genomics, human disease, and bioinformatics to address five principal questions:
Fig4d from Werling et al., bioRxiv, 2017
1. Structural Variation: How does genome organization vary between individuals and cell types? The economization of whole-genome sequencing has given rise to a veritable small sea of sequenced human genomes, and with it, the realization that nearly 1% of every human genome is structurally variant; i.e. while the exact nucleotide sequences between two individuals’ DNA are highly homologous (>99.9% identity), the long-range order and content of their DNA is substantially more mutable, with thousands of segments between ~50bp and hundreds of kilobases being deleted, duplicated, inverted, or inserted in diverse arrangements that frequently differ between two individuals. This concept, known as structural variation, is a technological challenge to capture and a taxonomic challenge to categorize, so our present knowledge likely represents the tip of a much greater iceberg. Further, recent evidence has suggested that somatic alterations in genome structure occur variably in specific tissue types and even individual cells, such as neural somatic mosaicism in the brain. Collectively, all signs point to structural variation being an essential feature in a complete portrait of the human genome, thus a detailed delineation of these variations in large cohorts is an important objective facing the human genetics community.
Fig3b-d from Redin et al., Nat. Genet., 2017
2. Genome Architecture: What are the essential structural characteristics of the human genome? Technological advances permitting high-resolution surveys of chromatin states, like Hi-C and 4C, have begun to illuminate the genome as a three-dimensional, topologically regulated biological system. These new data now allow us to ask how the composition of our chromosomes at the DNA level regulates and coordinates the remarkable process of compacting six linear feet of DNA, comprising over three billion nucleotides, into the nucleus of each of the trillions of cells in every human.
Fig5 from Turner et al., Nature, 2015
3. Functional Genomics: How do alterations in genome architecture modulate gene expression and cellular regulation? Numerous studies have now cemented that regulation of gene expression is a convoluted and multifarious system refined by billions of years of evolution, and involves both the genome’s sequence and spatial topology as well as the transcriptome, the epigenome, and essentially almost everything else present within a cell’s nucleus. While significant strides have landed towards understanding each of these layers in isolation, a remaining hurdle is the synthesis of these sub-systems into a comprehensive model of how genome architecture—specifically the structure and three-dimensional organization of DNA and chromatin—drives gene expression at the organismal, tissue, and cellular scales.
Fig5a-c from Collins et al., Genome Biol., 2017
4. Human Disease: Which changes in genome structure contribute to disease risk and pathogenesis? Central to Ryan’s research interests are human genetic diseases or disorders with high heritability but non-Mendelian patterns of inheritance, such as many congenital anomalies and neurodevelopmental disorders like autism. While understanding the dynamics of the genome’s structural architecture is an essential first step, the second and perhaps more important question to ask is how this architecture differs between affected and unaffected individuals. Elucidating trends in structural variation and genome topology in human disease has the potential to expand our knowledge of the causes of many currently intractable human diseases and, with it, identify novel treatments and therapeutic targets.
5. Bioinformatics & Biotechnologies: Can we improve computational/statistical models and molecular technologies to better assess genome structure? Finally, a natural and necessary complement to investigating the human genome across its multiple biological dimensions is the advancement of molecular technologies and computational models to test otherwise-untestable hypotheses. Particularly, with the slated sequencing of hundreds of thousands of human genomes over the next several years, efficient algorithms and informatics methods will be foundational in analyzing these data. Conversely, as new insights are gleaned from these “big data” genomics analyses, innovations in molecular methods will be vital for orthogonal confirmatory studies.
Statement of Professional Objectives
Precision medicine promises to revolutionize the delivery of both preventative and palliative healthcare in the twenty-first century. The key to unlocking these promises is predicated on our understanding of the human genome as it relates to disease risk and pathogenesis, as the genome is the deterministic blueprint for a human’s biochemical individuality that represents the substrate upon which precision medicine churns. To this end, Ryan’s career goal is to expedite the realization of precision medicine by advancing our understanding of the relationship between human genome structure and function.
As an example: envision a disease model in which a rare, small deletion of a transcription factor binding site [DNA] alters the local chromatin configuration [protein/epigenome], thus resulting in reduced expression [RNA] of a proximal gene. Next, imagine this gene were involved in an essential regulatory process like chromatin remodeling: reduced expression of this gene could have profound influences on genome organization [topology] and global expression [transcriptome]. It’s not a stretch to extend this hypothetical situation by suggesting that this systemic dysregulation of genome architecture could lead to an aberrant or disease phenotype, and—given the inherently complex nature of most biological systems—it is not unreasonable to suspect that these kinds of pathogenic mechanisms occur more frequently than has been realized to date.
Yet without considering all of these various genomic sub-systems in concert, the larger picture may prove elusive. Thus, to elucidate these kinds of complicated and inherently self-regulatory models, we must first fully understand the core principles of multiscale genome structure and architecture. This is the root of Ryan’s research interests, and these kinds of integrative, multidisciplinary approaches will be necessary to deconvolve the architecture of the human genome and bring the promises of precision medicine to fruition.