TY - JOUR

T1 - Semiconservative replication in the quasispecies model

AU - Tannenbaum, Emmanuel

AU - Deeds, Eric J.

AU - Shakhnovich, Eugene I.

N1 - Funding Information:
E.T. would like to thank the National Institutes of Health for funding this research. He would also like to thank his instructors in the Israel Defense Forces’ combat medic course for discussions about the effects of mutagens on slow and fast replicating cells. E.J.D. would like to thank the Howard Hughes Medical Institute for financial support.

PY - 2004/1/1

Y1 - 2004/1/1

N2 - This paper extends Eigen’s quasispecies equations to account for the semiconservative nature of DNA replication. We solve the equations in the limit of infinite sequence length for the simplest case of a static, sharply peaked fitness landscape. We show that the error catastrophe occurs when [Formula presented], the product of sequence length and per base pair mismatch probability, exceeds [Formula presented], where [Formula presented] is the first-order growth rate constant of the viable “master” sequence (with all other sequences having a first-order growth rate constant of [Formula presented]). This is in contrast to the result of [Formula presented] for conservative replication. In particular, as [Formula presented], the error catastrophe is never reached for conservative replication, while for semiconservative replication the critical [Formula presented] approaches [Formula presented]. Semiconservative replication is therefore considerably less robust than conservative replication to the effect of replication errors. We also show that the mean equilibrium fitness of a semiconservatively replicating system is given by [Formula presented] below the error catastrophe, in contrast to the standard result of [Formula presented] for conservative replication (derived by Kimura and Maruyama in 1966). From this result it is readily shown that semiconservative replication is necessary to account for the observation that, at sufficiently high mutagen concentrations, faster replicating cells will die more quickly than more slowly replicating cells. Thus, in contrast to Eigen’s original model, the semiconservative quasispecies equations are able to provide a mathematical basis for explaining the efficacy of mutagens as chemotherapeutic agents.

AB - This paper extends Eigen’s quasispecies equations to account for the semiconservative nature of DNA replication. We solve the equations in the limit of infinite sequence length for the simplest case of a static, sharply peaked fitness landscape. We show that the error catastrophe occurs when [Formula presented], the product of sequence length and per base pair mismatch probability, exceeds [Formula presented], where [Formula presented] is the first-order growth rate constant of the viable “master” sequence (with all other sequences having a first-order growth rate constant of [Formula presented]). This is in contrast to the result of [Formula presented] for conservative replication. In particular, as [Formula presented], the error catastrophe is never reached for conservative replication, while for semiconservative replication the critical [Formula presented] approaches [Formula presented]. Semiconservative replication is therefore considerably less robust than conservative replication to the effect of replication errors. We also show that the mean equilibrium fitness of a semiconservatively replicating system is given by [Formula presented] below the error catastrophe, in contrast to the standard result of [Formula presented] for conservative replication (derived by Kimura and Maruyama in 1966). From this result it is readily shown that semiconservative replication is necessary to account for the observation that, at sufficiently high mutagen concentrations, faster replicating cells will die more quickly than more slowly replicating cells. Thus, in contrast to Eigen’s original model, the semiconservative quasispecies equations are able to provide a mathematical basis for explaining the efficacy of mutagens as chemotherapeutic agents.

UR - http://www.scopus.com/inward/record.url?scp=37649032215&partnerID=8YFLogxK

U2 - 10.1103/PhysRevE.69.061916

DO - 10.1103/PhysRevE.69.061916

M3 - Article

C2 - 15244626

AN - SCOPUS:37649032215

SN - 1063-651X

VL - 69

SP - 14

JO - Physical Review E - Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics

JF - Physical Review E - Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics

IS - 6

ER -