All Publications

  • Between-region genetic divergence reflects the mode and tempo of tumor evolution. Nature genetics Sun, R., Hu, Z., Sottoriva, A., Graham, T. A., Harpak, A., Ma, Z., Fischer, J. M., Shibata, D., Curtis, C. 2017


    Given the implications of tumor dynamics for precision medicine, there is a need to systematically characterize the mode of evolution across diverse solid tumor types. In particular, methods to infer the role of natural selection within established human tumors are lacking. By simulating spatial tumor growth under different evolutionary modes and examining patterns of between-region subclonal genetic divergence from multiregion sequencing (MRS) data, we demonstrate that it is feasible to distinguish tumors driven by strong positive subclonal selection from those evolving neutrally or under weak selection, as the latter fail to dramatically alter subclonal composition. We developed a classifier based on measures of between-region subclonal genetic divergence and projected patient data into model space, finding different modes of evolution both within and between solid tumor types. Our findings have broad implications for how human tumors progress, how they accumulate intratumoral heterogeneity, and ultimately how they may be more effectively treated.

    View details for DOI 10.1038/ng.3891

    View details for PubMedID 28581503

  • Mutation Rate Variation is a Primary Determinant of the Distribution of Allele Frequencies in Humans PLOS GENETICS Harpak, A., Bhaskar, A., Pritchard, J. K. 2016; 12 (12)


    The site frequency spectrum (SFS) has long been used to study demographic history and natural selection. Here, we extend this summary by examining the SFS conditional on the alleles found at the same site in other species. We refer to this extension as the "phylogenetically-conditioned SFS" or cSFS. Using recent large-sample data from the Exome Aggregation Consortium (ExAC), combined with primate genome sequences, we find that human variants that occurred independently in closely related primate lineages are at higher frequencies in humans than variants with parallel substitutions in more distant primates. We show that this effect is largely due to sites with elevated mutation rates causing significant departures from the widely-used infinite sites mutation model. Our analysis also suggests substantial variation in mutation rates even among mutations involving the same nucleotide changes. In summary, we show that variable mutation rates are key determinants of the SFS in humans.

    View details for DOI 10.1371/journal.pgen.1006489

    View details for Web of Science ID 000392138700034

    View details for PubMedID 27977673

    View details for PubMedCentralID PMC5157949

  • Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling. eLife Raj, A., Wang, S. H., Shim, H., Harpak, A., Li, Y. I., Engelmann, B., Stephens, M., Gilad, Y., Pritchard, J. K. 2016; 5

    View details for DOI 10.7554/eLife.13328

    View details for PubMedID 27232982

  • Neutral null models for diversity in serial transfer evolution experiments. Evolution; international journal of organic evolution Harpak, A., Sella, G. 2014; 68 (9): 2727-2736


    Evolution experiments with microorganisms coupled with genome-wide sequencing now allow for the systematic study of population genetic processes under a wide range of conditions. In learning about these processes in natural, sexual populations, neutral models that describe the behavior of diversity and divergence summaries have played a pivotal role. It is therefore natural to ask whether neutral models, suitably modified, could be useful in the context of evolution experiments. Here, we introduce coalescent models for polymorphism and divergence under the most common experimental evolution assay, a serial transfer experiment. This relatively simple setting allows us to address several issues that could affect diversity patterns in evolution experiments, whether selection is operating or not: the transient behavior of neutral polymorphism in an experiment beginning from a single clone, the effects of randomness in the timing of cell division and noisiness in population size in the dilution stage. In our analyses and discussion, we emphasize the implications for experiments aimed at measuring diversity patterns and making inferences about population genetic processes based on these measurements.

    View details for DOI 10.1111/evo.12454

    View details for PubMedID 24889376