Statistical Analysis of Molecular Signal Recording

Joshua I. Glaser, Bradley M. Zamft, Adam H. Marblestone, Jeffrey R. Moffitt, Keith E. J. Tyo, Edward S. Boyden III, George M. Church, Konrad P. Körding

Abstract: Author Summary Recording of physiological signals from inaccessible microenvironments is often hampered by the macroscopic sizes of current recording devices. A signal-recording device constructed on a molecular scale could advance biology by enabling the simultaneous recording from millions or billions of cells. We recently proposed a molecular device for recording time-varying ion concentration signals: DNA polymerases (DNAPs) copy known template DNA strands with an error rate dependent on the local ion concentration. The resulting DNA polymers could then be sequenced, and with the help of statistical techniques, used to estimate the time-varying ion concentration signal experienced by the polymerase. We develop a statistical framework to treat this inverse problem and describe a technique to decode the ion concentration signals from DNA sequencing data. We also provide a novel method for estimating properties of DNAP dynamics, such as polymerization rate and pause frequency, directly from sequencing data. We use this framework to explore potential application scenarios for molecular recording devices, achievable via molecular engineering within the biochemical parameter ranges of known polymerases. We find that accurate recording of neural firing rate responses across several experimental conditions would likely be feasible using molecular recording devices with kinetic properties similar to those of known polymerases.