Analyzing and Synthesizing Genomic Logic Functions

  • Nicola Paoletti
  • Boyan Yordanov
  • Youssef Hamadi
  • Christoph M. Wintersteiger
  • Hillel Kugler
Part of the Lecture Notes in Computer Science book series (LNCS, volume 8559)

Abstract

Deciphering the developmental program of an embryo is a fundamental question in biology. Landmark papers [9,10] have recently shown how computational models of gene regulatory networks provide system-level causal understanding of the developmental processes of the sea urchin, and enable powerful predictive capabilities. A crucial aspect of the work is empirically deriving plausible models that explain all the known experimental data, a task that becomes infeasible in practice due to the inherent complexity of the biological systems. We present a generic Satisfiability Modulo Theories based approach to analyze and synthesize data constrained models. We apply our approach to the sea urchin embryo, and successfully improve the state-of-the-art by synthesizing, for the first time, models that explain all the experimental observations in [10]. A strength of the proposed approach is the combination of accurate synthesis procedures for deriving biologically plausible models with the ability to prove inconsistency results, showing that for a given set of experiments and possible class of models no solution exists, and thus enabling practical refutation of biological models.

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References

  1. 1.
    Bartocci, E., Bortolussi, L., Nenzi, L.: A temporal logic approach to modular design of synthetic biological circuits. In: Gupta, A., Henzinger, T.A. (eds.) CMSB 2013. LNCS (LNBI), vol. 8130, pp. 164–177. Springer, Heidelberg (2013)CrossRefGoogle Scholar
  2. 2.
    Batt, G., Yordanov, B., Weiss, R., Belta, C.: Robustness analysis and tuning of synthetic gene networks. Bioinformatics 23(18) (2007)Google Scholar
  3. 3.
    Chaudhuri, S., Clochard, M., Solar-Lezama, A.: Bridging Boolean and quantitative synthesis using smoothed proof search. In: POPL. ACM (2014)Google Scholar
  4. 4.
    de Moura, L., Bjørner, N.: Z3: An efficient SMT solver. In: Ramakrishnan, C.R., Rehof, J. (eds.) TACAS 2008. LNCS, vol. 4963, pp. 337–340. Springer, Heidelberg (2008)CrossRefGoogle Scholar
  5. 5.
    Koksal, A., Pu, Y., Srivastava, S., Bodik, R., Fisher, J., Piterman, N.: Synthesis of biological models from mutation experimentss. In: SIGPLAN-SIGACT Symposium on Principles of Programming Languages. ACM (2013)Google Scholar
  6. 6.
    Kugler, H., Plock, C., Roberts, A.: Synthesizing Biological Theories. In: Gopalakrishnan, G., Qadeer, S. (eds.) CAV 2011. LNCS, vol. 6806, pp. 579–584. Springer, Heidelberg (2011)CrossRefGoogle Scholar
  7. 7.
    Kugler, H., Pnueli, A., Stern, M.J., Hubbard, E.J.A.: “Don’t Care” Modeling: A logical framework for developing predictive system models. In: Grumberg, O., Huth, M. (eds.) TACAS 2007. LNCS, vol. 4424, pp. 343–357. Springer, Heidelberg (2007)CrossRefGoogle Scholar
  8. 8.
    Kugler, H., Segall, I.: Compositional Synthesis of Reactive Systems from Live Sequence Chart Specifications. In: Kowalewski, S., Philippou, A. (eds.) TACAS 2009. LNCS, vol. 5505, pp. 77–91. Springer, Heidelberg (2009)CrossRefGoogle Scholar
  9. 9.
    Peter, I.S., Davidson, E.H.: A gene regulatory network controlling the embryonic specification of endoderm. Nature 474(7353) (2011)Google Scholar
  10. 10.
    Peter, I.S., Faure, E., Davidson, E.H.: Predictive computation of genomic logic processing functions in embryonic development. Proc. of the National Academy of Sciences 109(41) (2012)Google Scholar
  11. 11.
    Rabe, M.N., Wintersteiger, C.M., Kugler, H., Yordanov, B., Hamadi, Y.: Symbolic approximation of the bounded reachability probability in markov chains. In: QEST. LNCS, Springer (to appear, 2014)Google Scholar
  12. 12.
    Solar-Lezama, A., Rabbah, R.M., Bodík, R., Ebcioglu, K.: Programming by sketching for bit-streaming programs. In: PLDI. ACM (2005)Google Scholar
  13. 13.
    Srivastava, S., Gulwani, S., Foster, J.S.: From program verification to program synthesis. In: POPL. ACM (2010)Google Scholar
  14. 14.
    Yordanov, B., Wintersteiger, C.M., Hamadi, Y., Kugler, H.: Z34Bio: An SMT-based framework for analyzing biological computation. In: SMT (2013)Google Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Nicola Paoletti
    • 1
    • 2
  • Boyan Yordanov
    • 1
  • Youssef Hamadi
    • 1
  • Christoph M. Wintersteiger
    • 1
  • Hillel Kugler
    • 1
  1. 1.Microsoft ResearchCambridgeUK
  2. 2.Department of Computer ScienceUniversity of OxfordUK

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