Mathematical and live meningococcal models for simple sequence repeat dynamics - Coherent predictions and observations

Abstract

Evolvability by means of simple sequence repeat (SSR) instability is a feature under the constant influence of opposing selective pressures to expand and compress the repeat tract and is mechanistically influenced by factors that affect genetic instability. In addition to direct selection for protein expression and structural integrity, other factors that influence tract length evolution were studied. The genetic instability of SSRs that switch the expression of antibiotic resistance ON and OFF was modelled mathematically and monitored in a panel of live meningococcal strains. The mathematical model showed that the SSR length of a theoretical locus in an evolving population may be shaped by direct selection of expression status (ON or OFF), tract length dependent (α) and tract length independent factors (β). According to the model an increase in α drives the evolution towards shorter tracts. An increase in β drives the evolution towards a normal distribution of tract lengths given that an upper and a lower limit are set. Insertion and deletion biases were shown to skew allelic distributions in both directions. The meningococcal SSR model was tested in vivo by monitoring the frequency of spectinomycin resistance OFF→ON switching in a designed locus. The instability of a comprehensive panel of the homopolymeric SSRs, constituted of a range of 5-13 guanine nucleotides, was monitored in wildtype and mismatch repair deficient backgrounds. Both the repeat length itself and mismatch repair deficiency were shown to influence the genetic instability of the homopolymeric tracts. A possible insertion bias was observed in tracts ≤G10. Finally, an inverse correlation between the number of tract-encoded amino acids and growth in the presence of ON-selection illustrated a limitation to SSR expansion in an essential gene associated with the designed model locus and the protein function mediating antibiotic resistance. © 2014 Alfsnes et al.