Ryan N Gutenkunst

Ryan N Gutenkunst

Associate Department Head, Molecular and Cellular Biology
Associate Professor, Applied BioSciences - GIDP
Associate Professor, Applied Mathematics - GIDP
Associate Professor, Cancer Biology -
Associate Professor, Ecology and Evolutionary Biology
Associate Professor, Genetics - GIDP
Associate Professor, Molecular and Cellular Biology
Associate Professor, Public Health
Associate Professor, Statistics-GIDP
Associate Professor, BIO5 Institute
Member of the Graduate Faculty
Director, Graduate Studies
Primary Department
Contact
(520) 626-0569

Work Summary

We learn history from the genomes of humans, tumors, and other species. Our studies reveal how evolution works at the molecular level, offering fundamental insight into how humans and pathogens adapt to challenges.

Research Interest

The Gutenkunst group studies the function and evolution of the complex molecular networks that comprise life. To do so, they integrate computational population genomics, bioinformatics, and molecular evolution. They focus on developing new computational methods to extract biological insight from genomic data and applying those methods to understand population history and natural selection.

Publications

Casey, F. P., Baird, D., Feng, Q., Gutenkunst, R. N., Waterfall, J. J., Myers, C. R., Brown, K. S., Cerione, R. A., & Sethna, J. P. (2007). Optimal experimental design in an epidermal growth factor receptor signalling and down-regulation model. IET Systems Biology, 1(3), 190-202.

PMID: 17591178;Abstract:

We apply the methods of optimal experimental design to a differential equation model for epidermal growth factor receptor signalling, trafficking and down-regulation. The model incorporates the role of a recently discovered protein complex made up of the E3 ubiquitin ligase, Cbl, the guanine exchange factor (GEF), Cool-1 (β-Pix) and the Rho family G protein Cdc42. The complex has been suggested to be important in disrupting receptor down-regulation. We demonstrate that the model interactions can accurately reproduce the experimental observations, that they can be used to make predictions with accompanying uncertainties, and that we can apply ideas of optimal experimental design to suggest new experiments that reduce the uncertainty on unmeasurable components of the system. © 2007 The Institution of Engineering and Technology.

Stuck, T. J., Mannakee, B. K., & Gutenkunst, R. N. (2017). The impact of genome-wide association studies on biomedical research is modest and declining. Human Molecular Genetics.
Smith, A. M., Adler, F. R., McAuley, J. L., Gutenkunst, R. N., Ribeiro, R. M., McCullers, J. A., & Perelson, A. S. (2011). Effect of 1918 PB1-F2 expression on influenza a virus infection kinetics. PLoS Computational Biology, 7(2).

PMID: 21379324;PMCID: PMC3040654;Abstract:

Relatively little is known about the viral factors contributing to the lethality of the 1918 pandemic, although its unparalleled virulence was likely due in part to the newly discovered PB1-F2 protein. This protein, while unnecessary for replication, increases apoptosis in monocytes, alters viral polymerase activity in vitro, enhances inflammation and increases secondary pneumonia in vivo. However, the effects the PB1-F2 protein have in vivo remain unclear. To address the mechanisms involved, we intranasally infected groups of mice with either influenza A virus PR8 or a genetically engineered virus that expresses the 1918 PB1-F2 protein on a PR8 background, PR8-PB1-F2(1918). Mice inoculated with PR8 had viral concentrations peaking at 72 hours, while those infected with PR8-PB1-F2(1918) reached peak concentrations earlier, 48 hours. Mice given PR8-PB1-F2(1918) also showed a faster decline in viral loads. We fit a mathematical model to these data to estimate parameter values. The model supports a higher viral production rate per cell and a higher infected cell death rate with the PR8-PB1-F2(1918) virus. We discuss the implications these mechanisms have during an infection with a virus expressing a virulent PB1-F2 on the possibility of a pandemic and on the importance of antiviral treatments.

Gutenkunst, R. N., Waterfall, J. J., Casey, F. P., Brown, K. S., Myers, C. R., & Sethna, J. P. (2007). Universally sloppy parameter sensitivities in systems biology models. PLoS Computational Biology, 3(10), 1871-1878.

PMID: 17922568;PMCID: PMC2000971;Abstract:

Quantitative computational models play an increasingly important role in modern biology. Such models typically involve many free parameters, and assigning their values is often a substantial obstacle to model development. Directly measuring in vivo biochemical parameters is difficult, and collectively fitting them to other experimental data often yields large parameter uncertainties. Nevertheless, in earlier work we showed in a growth-factor- signaling model that collective fitting could yield well-constrained predictions, even when it left individual parameters very poorly constrained. We also showed that the model had a "sloppy" spectrum of parameter sensitivities, with eigenvalues roughly evenly distributed over many decades. Here we use a collection of models from the literature to test whether such sloppy spectra are common in systems biology. Strikingly, we find that every model we examine has a sloppy spectrum of sensitivities. We also test several consequences of this sloppiness for building predictive models. In particular, sloppiness suggests that collective fits to even large amounts of ideal time-series data will often leave many parameters poorly constrained. Tests over our model collection are consistent with this suggestion. This difficulty with collective fits may seem to argue for direct parameter measurements, but sloppiness also implies that such measurements must be formidably precise and complete to usefully constrain many model predictions. We confirm this implication in our growth-factor-signaling model. Our results suggest that sloppy sensitivity spectra are universal in systems biology models. The prevalence of sloppiness highlights the power of collective fits and suggests that modelers should focus on predictions rather than on parameters. © 2007 Gutenkunst et al.

Locke, D. P., Hillier, L. W., Warren, W. C., Worley, K. C., Nazareth, L. V., Muzny, D. M., Yang, S., Wang, Z., Chinwalla, A. T., Minx, P., Mitreva, M., Cook, L., Delehaunty, K. D., Fronick, C., Schmidt, H., Fulton, L. A., Fulton, R. S., Nelson, J. O., Magrini, V., , Pohl, C., et al. (2011). Comparative and demographic analysis of orang-utan genomes. Nature, 469(7331), 529-33.

'Orang-utan' is derived from a Malay term meaning 'man of the forest' and aptly describes the southeast Asian great apes native to Sumatra and Borneo. The orang-utan species, Pongo abelii (Sumatran) and Pongo pygmaeus (Bornean), are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution. Here we present a Sumatran orang-utan draft genome assembly and short read sequence data from five Sumatran and five Bornean orang-utan genomes. Our analyses reveal that, compared to other primates, the orang-utan genome has many unique features. Structural evolution of the orang-utan genome has proceeded much more slowly than other great apes, evidenced by fewer rearrangements, less segmental duplication, a lower rate of gene family turnover and surprisingly quiescent Alu repeats, which have played a major role in restructuring other primate genomes. We also describe a primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orang-utan genome structure. Orang-utans have extremely low energy usage for a eutherian mammal, far lower than their hominid relatives. Adding their genome to the repertoire of sequenced primates illuminates new signals of positive selection in several pathways including glycolipid metabolism. From the population perspective, both Pongo species are deeply diverse; however, Sumatran individuals possess greater diversity than their Bornean counterparts, and more species-specific variation. Our estimate of Bornean/Sumatran speciation time, 400,000 years ago, is more recent than most previous studies and underscores the complexity of the orang-utan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (N(e)) expanded exponentially relative to the ancestral N(e) after the split, while Bornean N(e) declined over the same period. Overall, the resources and analyses presented here offer new opportunities in evolutionary genomics, insights into hominid biology, and an extensive database of variation for conservation efforts.