### Organizers

This workshop will be divided into two parts, a tutorial and a conference. The first two days are intended to introduce probabilists to important biological problems that can engage probability theorists.

These lectures will be delivered by well-known biologists. The last three days will focus on new mathematical questions in probability and statistics that have been stimulated by recent biological research.

An important goal of MBI is to communicate these questions to the mathematics community. Therefore it is intended that the talks will be accessible to probabilists who have not previously worked on questions arising in biology. The lectures will begin by giving the necessary biological background. Topics will include stochastic spatial models and other aspects of ecology and epidemiology; adaptive dynamics; population genetics and evolution including coalescent theory; cancer modeling; stochastic models in neuroscience; and systems/synthetic biology.

### Accepted Speakers

Monday, September 12, 2011 | |
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Time | Session |

10:00 AM 11:30 AM | Nick Barton - Pedigrees, genealogies and genomes An individual passes on random segments of her genome to future generations: typically, most of the genome is lost, but a small fraction survives, in many copies. This distribution of surviving blocks can be calculated using a branching process argument. Remarkably, after a few tens of generations it has the same form for every individual, with variation in reproductive value between individuals only affecting the probability of survival. These results follow the descent of genomes forwards in time. The converse problem is to ask how far back we can reconstruct the pedigree, given a sample of complete genomes. |

01:30 PM 03:00 PM | John White - Noise in the Nervous System One of the principal tasks of the nervous system is to generate internal representations of the world, in order that we might best interpret the present, predict the future, and thus pass our genes to the next generation. For this reason, it seems quite surprising that the nervous system is so noisy. This noise is reasonably well characterized at the level of ion channels and individual cells, but it is not clear why such a level of noise is tolerated. In this talk, I will describe some of the major sources of noise in the nervous system, and will discuss some of the current puzzles regarding how the effects of noise scale in the large-N limit. |

03:30 PM 05:00 PM | Johan Paulsson - No title available No abstract available |

Tuesday, September 13, 2011 | |
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Time | Session |

12:00 AM 11:00 AM | Johan Paulsson - No title available No abstract available |

01:30 PM 03:00 PM | John White - Noise in the Nervous System One of the principal tasks of the nervous system is to generate internal representations of the world, in order that we might best interpret the present, predict the future, and thus pass our genes to the next generation. For this reason, it seems quite surprising that the nervous system is so noisy. This noise is reasonably well characterized at the level of ion channels and individual cells, but it is not clear why such a level of noise is tolerated. In this talk, I will describe some of the major sources of noise in the nervous system, and will discuss some of the current puzzles regarding how the effects of noise scale in the large-N limit. |

02:00 PM 03:30 PM | Nick Barton - Pedigrees, genealogies and genomes An individual passes on random segments of her genome to future generations: typically, most of the genome is lost, but a small fraction survives, in many copies. This distribution of surviving blocks can be calculated using a branching process argument. Remarkably, after a few tens of generations it has the same form for every individual, with variation in reproductive value between individuals only affecting the probability of survival. These results follow the descent of genomes forwards in time. The converse problem is to ask how far back we can reconstruct the pedigree, given a sample of complete genomes. |

Wednesday, September 14, 2011 | |
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Time | Session |

09:00 AM 10:00 AM | Rick Durrett - Cancer causes stable laws It is common to use a multitype branching process to model the accumulation of mutations that leads to cancer progression, metastasis, and resistance to treatment. In this talk I will describe results about the time until the first type k (cell with k mutations) and the growth of the type k population obtained in joint work with Stephen Moseley, and their use in evaluating possible screening strategies for ovarian cancer, work in progress with Duke undergraduate Kaveh Danesh. The point process representation of the limit, which is a one-sided stable law, together with results from 10-60 years ago leads to remarkable explicit formulas for Simpson's index and the size of the largest clone. These results are important in understanding tumor diversity which can present serious obstacles to treatment. The last topic is joint work with Jasmine Foo, Kevin Leder, John Mayberry, and Franziska Michor. |

10:30 AM 11:30 AM | Alison Etheridge - A model for evolution in a spatial continuum Classical models for gene flow fail in (at least) three ways. First, they cannot explain patterns in data observed over large scales; second, they predict much more genetic diversity than is observed; and third, they asssume that genetic loci evolve independently. I shall describe, as time permits, results of joint projects with Nick Barton, Nathanael Berestycki, Jerome Kelleher and Amandine Veber in which we have proposed a framework for modelling populations that are distributed across a spatial continuum and analysed aspects of a particular model that arises in this framework that we have called the spatial Lambda-Fleming-Viot process. |

01:00 PM 02:00 PM | Paul Joyce - A simple mutational model that produces diminishing returns epistasis and decelerating fitness trajectories in adaptive walks In relating genotypes to fitness, models of adaptation need to be both computation- ally tractable and to qualitatively match observed data. One reason tractability is not a trivial problem comes from a combinatoric problem whereby no matter in what order a set of mutations occurs, it must yield the same fitness. We refer to this problem as the bookkeeping problem. Because of their commutative property, the simple additive and multiplicative models naturally solve the bookkeeping problem. However, the fitness trajectories and epistatic patterns they predict are inconsistent with the patterns commonly observed in experimental evolution. This motivates us to propose a new and equally simple model that we call stickbreaking. Under the stickbreaking model, the intrinsic fittness effects of mutations scale by the distance of the current background to a hypothesized boundary. We use simulations and theoretical analyses to explore the basic properties of the stickbreaking model such as the distribution of fitness effects, fitness trajectories, and epistasis. Stickbreaking is compared to the additive and multiplicative models using a number of novel likelihood based approaches to account for error in the predictions. We apply or statistical methodology to a number recently published data sets and conclude the stickbreaking model is consistent with several commonly observed patterns of adaptive evolution. |

02:10 PM 03:10 PM | Ruth Williams - Stationary Distributions for Stochastic Delay Differential Equations with Positivity Constraints Deterministic dynamic models with delayed feedback and state constraints arise in a variety of applications in science and engineering, including biology. There is interest in understanding what effect noise has on the behavior of such models. Here we consider a multidimensional stochastic delay differential equation with normal reflection as a noisy analogue of a deterministic system with delayed feedback and positivity constraints. We obtain sufficient conditions for existence and uniqueness of stationary distributions for such equations. The results are applied to an example of a simple biochemical reaction system. |

03:40 PM 04:40 PM | Anton Wakolbinger - Muller's ratchet with compensatory mutations We discuss a Fleming-Viot model whose mutation process is a birth- and death process on the non-negative integers. In this model, new deleterious mutations accumulate at a constant rate per generation, and each mutation decreases the individual fitness by a constant amount. Other than in the classical case of Muller's ratchet, each of the present mutations has a small probablity per generation to disappear. In the infinite population limit we obtain the solution in a closed form by analyzing a probabilistic particle system that represents this solution. We will also discuss recent ideas to approach (yet unsolved) questions on the rate of Muller's ratchet. The talk is based on joint work with Peter Pfaffelhuber and Paul Staab. |

Thursday, September 15, 2011 | |
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Time | Session |

08:30 AM 09:30 AM | Steven Evans - Metagenomics and metrics on spaces of probability measures Metagenomics attempts to sample and study all the genetic material present in a community of micro-organisms in environments that range from the human gut to the open ocean. This enterprise is made possible by high-throughput pyrosequencing technologies that produce a "soup" of DNA fragments which are not a priori associated with particular organisms or with particular locations on the genome. Statistical methods can be used to assign these fragments to locations on a reference phylogenetic tree using pre-existing information about the genomes of previously identified species. Each metagenomic sample thus results in a cloud of points on the reference tree. In seeking to answer questions such as what distinguishes the vaginal microbiomes of women with bacterial vaginosis from those of woment who don't, one is led to consider statistical methods for distinguishing between such clouds. I will discuss joint work with Erick Matsen from the Fred Hutchinson Cancer Research Center in which we use ideas based on distances between probability measures that go back to Gaspard Monge's 1781 "M'emoir sur la th'eorie des d'eblais et des remblais" as well as some familiar objects (e.g. reproducing kernel Hilbert spaces) from the world of Gaussian processes. |

09:40 AM 10:40 AM | Sylvie Melard - Random modeling of adaptive dynamics for sexual populations We study models describing the evolution of a sexual (diploid) population with mutation and selection in the specific scales of the biological framework of adaptive dynamics. We take into account the genetics of the reproduction. Each individual is characterized by two allelic traits and the associated phenotypic trait. The population is described as a point measure valued process with support on the genotype space. Its dynamics is a birth and death dynamics with selection and Mendelian rule in the reproduction and competition between individuals. Allelic mutations may occur during the reproduction events. The population size is assumed to be large and the mutation rate small. We prove that under a good combination of the scales, and if the mutation steps are small, the population process converges in a long time scale by a jump process jumping from a monomorphic homozygote equilibrium to another one. This study involves a three-types diploid nonlinear dynamical system, which is studied using small perturbations of a neutral case. The behavior of the process is thus studied near the evolutionary singularities. This work is a joint work with Pierre Collet (Ecole Polytechnique) and Hans Metz (Leiden University). |

02:30 PM 03:30 PM | Jasmine Foo - Cancer recurrence and escape dynamics A new generation of anti-cancer drugs targeted to specific oncogenic pathways has emerged in recent years as a promising alternative to chemotherapy and radiation. However, the clinical success of such drugs has been limited by the evolution of acquired resistance, which leads to a relapse after initial response to therapy. In the first part of this talk I will discuss the use of a simple two-type branching process model to represent sensitive and resistant cells in a population. Using this validated model we propose novel scheduling strategies in the treatment of non-small cell lung cancer with targeted therapy, which will delay resistance. Then, we investigate the large population limit of these processes in the time scale of extinction of the sensitive cell population. Using these limits we can study the turnaround point when the total tumor size goes from subcritical to supercritical (corresponding to the clinical time of disease progression), as well as the population levels of sensitive and resistant cells at various clinically relevant times. |

04:00 PM 05:00 PM | Jason Schweinsberg - Dynamics of the evolving Bolthausen-Sznitman coalescent Consider a population of fixed size that evolves over time. At each time, the genealogical structure of the population can be described by a coalescent tree whose branches are traced back to the most recent common ancestor of the population. This gives rise to a tree-valued stochastic process. We will study this process in the case of populations whose genealogy is given by the Bolthausen-Sznitman coalescent. We will focus on the evolution of the time back to the most recent common ancestor and the total length of branches in the tree. |

11:30 PM 12:30 PM | Lorenzo Zambotti - How to maximize neural complexity G. Edelman, O. Sporns and G. Tononi have introduced in theoretical biology the neural complexity of a family of random variables, defining it as an average of mutual information over subsystems, with the aim of quantifying the complexity of the brain. We provide a mathematical framework for this concept, studying in particular the problem of maximization of such functional for fixed system size and the asymptotic properties of maximizers as the system size goes to infinity. We shall also discuss some possible developments and applications of our work. (Joint work with Jerome Buzzi) |

Friday, September 16, 2011 | |
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Time | Session |

08:30 AM 09:30 AM | Priscilla Greenwood - Stochastic Dynamics of some Neuron Models How does a stochastic process move between the domains of attraction of locally stable points or cycles of an associated deterministic system, and cross unstable cycles? This question arises when we try to quantify the behavior of a neuron in terms of a stochastic neuron model. In the Morris Lecar model, for instance, the much-studied interspike-interval distribution depends on a process exiting from a quasi-stationary state near a fixed point and crossing an unstable limit cycle. When a process encounters an unstable cycle it tends to follow along a bit. But we need to do better than that. References: * P Baxendale and P E Greenwood, Sustained oscillations for density dependent Markov processes. J. Math Biology, Sept 2011. * S Ditlevsen and P E Greenwood, (2011) The Morris-Lecar neuron model embeds a leaky integrate-and-fire model, arXiv 1108.0073. * P F Rowat and P E Greenwood, Identification and continuity of the distributions of burst length and inter-spike intervals in the stochastic Morris Lecar neuron. Neural Computation, to appear. |

09:40 AM 10:40 AM | Steve Krone - Antibiotic resistance plasmids and spatial structure Bacterial plasmids are circular extra-chromosomal genetic elements that code for simultaneous resistance to multiple antibiotics and are thought to be one of the most important factors in the alarmingly rapid loss of our arsenal of antimicrobial drugs. Plasmids propagate horizontally by infectious transfer, as well as vertically during cell division. Horizontal transfer requires contact between donor and recipient cells, and so spatial structure can play a key role in mediating the spread of antibiotic resistance genes. We will discuss ODE and stochastic spatial models of plasmid population dynamics, as well as empirical results. As an example of the effects of spatial structure, we will use the spatial model to evaluate the effectiveness of a commonly used estimate of plasmid transfer efficiency when applied to surface-associated populations. |

11:00 AM 12:00 PM | Thomas Kurtz - Identifying separated time scales in stochastic models of reaction networks For chemical reaction networks in biological cells, reaction rates and chemical species numbers may vary over several orders of magnitude. Combined, these large variations can lead to subnetworks operating on very different time scales. Separation of time scales has been exploited in many contexts as a basis for reducing the complexity of dynamic models, but the interaction of the rate constants and the species numbers makes identifying the appropriate time scales tricky at best. Some systematic approaches to this identification will be discussed and illustrated by application to one or more complex reaction network models. |

Name | Affiliation | |
---|---|---|

Bhardwaj, Manisha | manisha@math.uh.edu | Department of Mathematics, University of Houston |

Bundschuh, Ralf | bundschuh@mps.ohio-state.edu | Departments of Physics and Biochemistry, The Ohio State University |

Chai, JJ | chai@nimbios.org | NIMBioS, University of Tennessee |

Dinh, Vu | vdinh@math.purdue.edu | Math, Purdue University |

Gomez, Alejandro | gomezalejandroh@gmail.com | Mathematics, University of Rochester |

HE, QI | qhe@wayne.edu | Mathematics, Wayne State University |

Jhwueng, Dwueng-Chwuan Jhwueng | djhwueng@nimbios.org | NIMBioS, University of Tennessee |

Joo, Jaewook | jjoo1@utk.edu | Physics, University of Tennessee |

Joshi, Badal | joshi@math.duke.edu | Mathematics Department, Duke University |

Kariv, Jonathan | jkariv@math.upenn.edu | Mathematics, University of Pennsylvania |

Kim, Hyejin | khyejin@umich.edu | Mathematics, University of Michigan |

Lionnet, Arnaud | registeronly974@yahoo.fr | Oxford-Man Institute and Mathematical Institute, University of Oxford |

Longla, Martial | longla_m_martial@yahoo.com | Mathematical Sciences, University of Cincinnati |

Makrides, Elizabeth | ejmakrides@gmail.com | Division of Applied Mathematics, Brown University |

Martin, Mike | mmartin@jccc.edu | Mathematics, Johnson County Community College |

Matadi, Maba | Matadim@ukzn.ac.za | Mathematics, University of KwaZulu Natal |

McKinley, Scott | scott.mckinley@ufl.edu | Mathematics, University of Florida |

Nicol, Matthew | nicol@math.uh.edu | Mathematics, University of Houston |

Parsons, Todd | tparsons@sas.upenn.edu | Mathematics, University of Toronto |

Schmidt, Deena | dschmidt@mbi.osu.edu | Department of Biology & Department of Mathematics, Case Western Reserve University |

Shih, Yu-Keng | shihy@cse.ohio-state.edu | Computer Science and Engineering, The Ohio State University |

Yarahmadian, Shantia | syarahmadian@math.msstate.edu | Mathematics and Statistics, Mississippi State University |

Zhu, Quanyan | zhu31@illinois.edu | Electrical and Computer Engineering, University of Illinois at Urbana-Champaign |

References:

* P Baxendale and P E Greenwood, Sustained oscillations for density dependent Markov processes. J. Math Biology, Sept 2011.

* S Ditlevsen and P E Greenwood, (2011) The Morris-Lecar neuron model embeds a leaky integrate-and-fire model, arXiv 1108.0073.

* P F Rowat and P E Greenwood, Identification and continuity of the distributions of burst length and inter-spike intervals in the stochastic Morris Lecar neuron. Neural Computation, to appear.

This work is a joint work with Pierre Collet (Ecole Polytechnique) and Hans Metz (Leiden University).

**A model for evolution in a spatial continuum**

Alison Etheridge Classical models for gene flow fail in (at least) three ways. First, they cannot explain patterns in data observed over large scales; second, they predict much more genetic diversity than is observed; and third, they asssume that genetic loci evolve

**Pedigrees, genealogies and genomes**

Nick Barton An individual passes on random segments of her genome to future generations: typically, most of the genome is lost, but a small fraction survives, in many copies. This distribution of surviving blocks can be calculated using a branching process argum

**Pedigrees, genealogies and genomes**

Nick Barton An individual passes on random segments of her genome to future generations: typically, most of the genome is lost, but a small fraction survives, in many copies. This distribution of surviving blocks can be calculated using a branching process argum

**Noise in the Nervous System**

John White One of the principal tasks of the nervous system is to generate internal representations of the world, in order that we might best interpret the present, predict the future, and thus pass our genes to the next generation. For this reason, it seems qu

**Noise in the Nervous System**

John White One of the principal tasks of the nervous system is to generate internal representations of the world, in order that we might best interpret the present, predict the future, and thus pass our genes to the next generation. For this reason, it seems qu

**Cancer causes stable laws**

Rick Durrett It is common to use a multitype branching process to model the accumulation of mutations that leads to cancer progression, metastasis, and resistance to treatment. In this talk I will describe results about the time until the first type k (cell with

**A simple mutational model that produces diminishing returns epistasis and decelerating fitness trajectories in adaptive walks**

Paul Joyce In relating genotypes to fitness, models of adaptation need to be both computation- ally tractable and to qualitatively match observed data. One reason tractability is not a trivial problem comes from a combinatoric problem whereby no matter in what

**Muller's ratchet with compensatory mutations**

Anton Wakolbinger We discuss a Fleming-Viot model whose mutation process is a birth- and death process on the non-negative integers. In this model, new deleterious mutations accumulate at a constant rate per generation, and each mutation decreases the individual fitne

**Metagenomics and metrics on spaces of probability measures**

Steven Evans Metagenomics attempts to sample and study all the genetic material present in a community of micro-organisms in environments that range from the human gut to the open ocean. This enterprise is made possible by high-throughput pyrosequencing technolog

**Dynamics of the evolving Bolthausen-Sznitman coalescent**

Jason Schweinsberg Consider a population of fixed size that evolves over time. At each time, the genealogical structure of the population can be described by a coalescent tree whose branches are traced back to the most recent common ancestor of the population. This giv

**Stochastic Dynamics of some Neuron Models**

Priscilla Greenwood How does a stochastic process move between the domains of attraction of locally stable points or cycles of an associated deterministic system, and cross unstable cycles? This question arises when we try to quantify the behavior of a neuron in terms o

**Antibiotic resistance plasmids and spatial structure**

Steve Krone Bacterial plasmids are circular extra-chromosomal genetic elements that code for simultaneous resistance to multiple antibiotics and are thought to be one of the most important factors in the alarmingly rapid loss of our arsenal of antimicrobial drug

**Identifying separated time scales in stochastic models of reaction networks**

Thomas Kurtz For chemical reaction networks in biological cells, reaction rates and chemical species numbers may vary over several orders of magnitude. Combined, these large variations can lead to subnetworks operating on very different time scales. Separation of