Oana Carja

Scientist @Stanford + @CZBiohub
Starting January 2019: Assistant Professor, Carnegie Mellon University, School of Computer Science
Founder Stanford Complexity Group
oana.carja@gmail.com, @oanacarja

“not try to describe the future, but to define the boundaries within which possible futures must lie. If we regard the ages which stretch ahead of us as an unmapped and unexplored country, what I am attempting to do is to survey its frontiers and to get some idea of its extent. The detailed geography of the interior must remain unknown - until we reach it.” -- Arthur C. Clarke, Profiles of the Future

Work

  • At the nanometer scale enzymes interconvert chemical potential and force; at the micrometer scale cells communicate, move and organize; at the millimeter scale organisms develop and further organize into larger biological systems. We are far from understanding even the simplest of these collective behaviors and how collective computation makes these emergent systems resilient. I think collective behavior, be it of biomolecules, cells or individuals, can only be understood and predicted through the lens of evolution. I work to quantitatively understand the evolutionary architecture of intelligent, collective systems, using the tools of dynamical systems, network theory, population genetics, machine learning and statistical inference, and widely available, yet underused, datasets.

Currently working with













Papers and previous projects





The evolutionary advantage of cultural memory in spatially structured populations
Oana Carja, Nicole Creanza

Submitted.



Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution by a novel RAP tool
Hongshuo Song, Elena E. Giorgi, Vitaly V. Ganusov, Fangping Cai, Gayathri Athreya, Hyejin Yoon, Oana Carja, Bhavna Hora, Peter Hraber, Ethan Romero-Severson, Chunlai Jiang, Shuyi Wang, Hui Li, Jesus F. Salazar-Gonzalez, Maria G. Salazar, Nilu Goonetilleke, Brandon F. Keele, David C. Montefiori, Myron S. Cohen, George M. Shaw, Beatrice H. Hahn, Andrew J. McMichael, Barton F. Haynes, Bette Korber, Tanmoy Bhattacharya, and Feng Gao

Accepted, Nature Communications.



Worldwide patterns of human epigenetic variation
Oana Carja*, Julia L. MacIsaac, Sarah M. Mah, Brenna Henn, Michael S. Kobor, Marcus W. Feldman, and Hunter B. Fraser

https://www.nature.com/articles/s41559-017-0299-z
* corresponding author

DNA methylation is an epigenetic modification, influenced by both genetic and environmental variation, that can affect transcription and many organismal phenotypes. Although patterns of DNA methylation have been shown to differ between human populations, it remains to be determined whether epigenetic diversity mirrors the patterns observed for DNA polymorphisms or gene expression levels. We measured DNA methylation at 480,000 sites in 34 individuals from five diverse human populations in the Human Genome Diversity Panel, and analyzed these together with single nucleotide polymorphisms (SNPs) and gene expression data. We found greater population-specificity of DNA methylation than of mRNA levels, which may be driven by the greater genetic control of methylation. This study provides insights into gene expression and its epigenetic regulation across populations and offers a deeper understanding of worldwide patterns of epigenetic diversity in humans.

Play




Trends in DNA methylation with age replicate across diverse human populations
Shyamalika Gopalan, Oana Carja*, Maud Fagny, Etienne Patin, Justin W Myrick, Lisa McEwen, Sarah M Mah, Michael S Kobor, Alain Froment, Marcus W Feldman, Lluis Quintana-Murci, Brenna M Henn

Genetics, 206(3), 1659-1674; https://doi.org/10.1534/genetics.116.195594

Aging is associated with widespread changes in genome-wide patterns of DNA methylation. Thousands of CpG sites whose tissue-specific methylation levels are strongly correlated with chronological age have been previously identified. However, the majority of these studies have focused primarily on cosmopolitan populations living in the developed world; it is not known if age-related patterns of DNA methylation at these loci are similar across a broad range of human genetic and ecological diversity. We investigated genome-wide methylation patterns using saliva and whole blood derived DNA from two traditionally hunting and gathering African populations: the Baka of the western Central African rainforest and the ≠Khomani San of the South African Kalahari Desert. We identify hundreds of CpG sites whose methylation levels are significantly associated with age, thousands that are significant in a meta-analysis, and replicate trends previously reported in populations of non-African descent. We confirm that an age-associated site in the gene ELOVL2 shows a remarkably congruent relationship with aging in humans, despite extensive genetic and environmental variation across populations. We also demonstrate that genotype state at methylation quantitative trait loci (meQTLs) can affect methylation trends at some known age-associated CpG sites. Our study explores the relationship between CpG methylation and chronological age in populations of African hunter-gatherers, who rely on different diets across diverse ecologies. While many age-related CpG sites replicate across populations, we show that considering common genetic variation at meQTLs further improves our ability to detect previously identified age associations.



Evolutionary rescue through partly heritable phenotypic variability
(Alternative title: Only the paranoid survive indeed. :) )
Oana Carja*, Joshua B. Plotkin

Accepted, Genetics + Biorxiv.
* corresponding author

Environmental variation is commonplace, but unpredictable. Populations that encounter a deleterious environment can sometimes avoid extinction by rapid evolutionary adaptation. Phenotypic variability, whereby a single genotype can express multiple different phenotypes, might play an important role in rescuing such populations from extinction. This type of evolutionary bet-hedging need not confer a direct benefit to a single individual, but it may increase the chance of long-term survival of a lineage. Here we develop a population-genetic model to explore how partly heritable phenotypic variability influences the probability of evolutionary rescue and the mean duration of population persistence in changing environments. We find that the probability of population persistence depends non-monotonically on the degree of phenotypic heritability between generations: some heritability can help avert extinction, but too much heritability removes any benefit of phenotypic variability. We discuss the implications of these results in the context of therapies designed to eradicate populations of pathogens or aberrant cellular lineages.

Play




The evolutionary advantage of heritable phenotypic heterogeneity
Oana Carja*, Joshua B. Plotkin

Scientific Reports 7, 5090(2017), doi:10.1038/s41598-017-05214-2
* corresponding author

Phenotypic plasticity is an evolutionary driving force in diverse biological processes, including the adaptive immune system, the development of neoplasms, and the bacterial acquisition of drug resistance. It is essential, therefore, to understand the evolutionary advantage of an allele that confers cells the ability to express a range of phenotypes. Of particular importance is to understand how this advantage of phenotypic plasticity depends on the degree of heritability of non-genetically encoded phenotypes between generations, which can induce irreversible evolutionary changes in the population. Here, we study the fate of a new mutation that allows the expression of multiple phenotypic states, introduced into a finite population otherwise composed of individuals who can express only a single phenotype. We analyze the fixation probability of such an allele as a function of the strength of inter-generational phenotypic heritability, called memory, the variance of expressible phenotypes, the rate of environmental changes, and the population size. We find that the fate of a phenotypically plastic allele depends fundamentally on the environmental regime. In a constant environment, the fixation probability of a plastic allele always increases with the degree of phenotypic memory. In periodically fluctuating environments, by contrast, there is an optimum phenotypic memory that maximizes the probability of the plastic allele's fixation. This same optimum value of phenotypic memory also maximizes geometric mean fitness, in steady state. We interpret these results in the context of previous studies in an infinite-population framework. We also discuss the implications of our results for the design of therapies that can overcome resistance, in a variety of diseases.



Evolution in changing environments: modifiers of mutation, recombination, and migration
Oana Carja*, Uri Liberman, Marcus W. Feldman

2014, PNAS, 111: 17935-17940
* corresponding author

The production and maintenance of genetic and phenotypic diversity under temporally fluctuating selection and the signatures of environmental changes in the patterns of this variation have been important areas of focus in population genetics. On one hand, periods of constant selection pull the genetic makeup of populations toward local fitness optima. On the other, to cope with changes in the selection regime, populations may evolve mechanisms that create a diversity of genotypes. By tuning the rates at which variability is produced--such as the rates of recombination, mutation, or migration--populations may increase their long-term adaptability. Here we use theoretical models to gain insight into how the rates of these three evolutionary forces are shaped by fluctuating selection. We compare and contrast the evolution of recombination, mutation, and migration under similar patterns of environmental change and show that these three sources of phenotypic variation are surprisingly similar in their response to changing selection. We show that the shape, size, variance, and asymmetry of environmental fluctuation have different but predictable effects on evolutionary dynamics.



The role of migration in the evolution of phenotypic switching
Oana Carja*, Robert E. Furrow, Marcus W. Feldman

2014, Proc. Biol. Sci B, 281: 20141677
* corresponding author

Stochastic switching is an example of phenotypic bet hedging, where an individual can switch between different phenotypic states in a fluctuating environment. Although the evolution of stochastic switching has been studied when the environment varies temporally, there has been little theoretical work on the evolution of phenotypic switching under both spatially and temporally fluctuating selection pressures. Here, we explore the interaction of temporal and spatial change in determining the evolutionary dynamics of phenotypic switching. We find that spatial variation in selection is important; when selection pressures are similar across space, migration can decrease the rate of switching, but when selection pressures differ spatially, increasing migration between demes can facilitate the evolution of higher rates of switching. These results may help explain the diverse array of non-genetic contributions to phenotypic variability and phenotypic inheritance observed in both wild and experimental populations.



The evolution of phenotypic switching in subdivided populations
Oana Carja*, Uri Liberman, Marcus W. Feldman

2014, Genetics, 196: 1185-1197
* corresponding author

Stochastic switching is an example of phenotypic bet hedging, where offspring can express a phenotype different from that of their parents. Phenotypic switching is well documented in viruses, yeast, and bacteria and has been extensively studied when the selection pressures vary through time. However, there has been little work on the evolution of phenotypic switching under both spatially and temporally fluctuating selection pressures. Here we use a population genetic model to explore the interaction of temporal and spatial variation in determining the evolutionary dynamics of phenotypic switching. We find that the stable switching rate is mainly determined by the rate of environmental change and the migration rate. This stable rate is also a decreasing function of the recombination rate, although this is a weaker effect than those of either the period of environmental change or the migration rate. This study highlights the interplay of spatial and temporal environmental variability, offering new insights into how migration can influence the evolution of phenotypic switching rates, mutation rates, or other sources of phenotypic variation.



Evolution with stochastic fitnesses: a role for recombination
Oana Carja*, Uri Liberman, Marcus W. Feldman

2013, Theor. Popul. Biol, 86: 29-42
* corresponding author

Phenotypic adaptation to fluctuating environments has been an important focus in the population genetic literature. Previous studies have shown that evolution under temporal variation is determined not only by expected fitness in a given generation, but also by the degree of variation in fitness over generations; in an uncertain environment, alleles that increase the geometric mean fitness can invade a randomly mating population at equilibrium. This geometric mean principle governs the evolutionary interplay of genes controlling mean phenotype and genes controlling phenotypic variation, such as genetic regulators of the epigenetic machinery. Thus, it establishes an important role for stochastic epigenetic variation in adaptation to fluctuating environments: by modifying the geometric mean fitness, variance-modifying genes can change the course of evolution and determine the long-term trajectory of the evolving system. The role of phenotypic variance has previously been studied in systems in which the only driving force is natural selection, and there is no recombination between mean- and variance-modifying genes. Here, we develop a population genetic model to investigate the effect of recombination between mean- and variance-modifiers of phenotype on the geometric mean principle under different environmental regimes and fitness landscapes. We show that interactions of recombination with stochastic epigenetic variation and environmental fluctuations can give rise to complex evolutionary dynamics that differ from those in systems with no recombination.



An equilibrium for phenotypic variance in fluctuating environments owing to epigenetics
Oana Carja*, Marcus W. Feldman

2012, J. R. Soc. Interface, 9: 613-623
* corresponding author

The connection between random environments and genetic and phenotypic variability has been a major focus in the population genetic literature. By providing differential access to the underlying genetic information, epigenetic variation could play an important role in the interaction between environmental and phenotypic variation. Using simulation, we model epigenetic plasticity during development by investigating the dynamics of genetic regulators of the epigenetic machinery that change the variance of the phenotype, while having no effect on the phenotype's mean. Previous studies have found that increased phenotypic variance is selected for if the environment is fluctuating. Here, we find that when a variance-increasing allele achieves a sufficiently high frequency, it can be out-competed by a variance-reducing allele, with the consequence that the population evolves to an equilibrium phenotypic variability. This equilibrium is shown to be robust to different initial conditions, but to depend heavily on parameters of the model, such as the mutation rate, the fitness landscape and the nature of the environmental fluctuation. Indeed, if there is no mutation at the genes controlling the variance of the phenotype, reduction of this variance is favoured.



Open science and reproducibility work

riboviz: analysis and visualization of ribosome profiling datasets
Oana Carja*, Tongji Xing, Joshua B. Plotkin, Premal Shah*

2017, BMC Bioinformatics, 18:461 + Biorxiv.
* corresponding author

Using high-throughput sequencing to monitor translation in vivo, ribosome profiling can provide critical insights into the dynamics and regulation of protein synthesis in a cell. Since its introduction in 2009, this technique has played a key role in driving biological discovery, and yet it requires a rigorous computational toolkit for widespread adoption. We developed a processing pipeline and browser-based visualization, riboviz, that allows convenient exploration and analysis of riboseq datasets. In implementation, riboviz consists of a comprehensive and flexible backend analysis pipeline that allows the user to analyze their private unpublished dataset, along with a web application for comparison with previously published public datasets. Availability and implementation: JavaScript and R source code and extra documentation are freely available from https://github.com/OanaCarja/RiboViz, while the web-application is live at www.riboviz.org.





Convex optimization work

A gradient constraint variational approach to image reconstruction
Oana Carja*

2009, Differential and Integral Equations, 22: 285-301
* corresponding author

In this paper we propose a variational model for image restoration based on the minimization of a convex functional with a gradient constraint. This approach has a smoothing effect on the degraded image, as it does not allow rapid changes in the image content. We also consider the evolutionary model of the resulting nonlinear differential equation. Furthermore, we discuss the dual problem associated with the model and propose a numerical algorithm for approximating its solution.

Other writing

Un procedeu de calcul al limitelor unor siruri de forma (a(n +1) − a( n)), n ≥ 1. (A procedure to compute the limit of sequences of type (a(n +1) − a( n)) for n ≥ 1.)
Oana Carja*

2003, Recreatii Matematice


Aplicatii ale rotatiei în planul complex (Applications of the rotation in the complex plane)
Oana Carja*

2002, Recreatii Matematice

Education

Stanford University. PhD in Biology.

Thesis: The Evolution of Genetic and Epigenetic Diversity in Changing Environments.



Cuza University, Romania. B.Sc. in Mathematics.

Teaching





© 2017 Oana Carja