Home and away- the evolutionary dynamics of homing endonucleases

Using mathematical analysis and computational modeling, we present here a novel account for the evolution and population dynamics of HEase genes (HEGs). We describe HEGs as paradoxical selfish elements whose long-term persistence in a single population relies on low transmission rates and a positive correlation between transmission efficiency and toxicity.Plausible conditions allow HEGs to sustain at high frequency through long evolutionary periods, with the endonuclease frequency being either at equilibrium or periodically oscillating. The predictions of our model may prove important not only for evolutionary theory but also for gene therapy and bio-engineering applications of HEases.Self-splicing introns and inteins are genetic elements that are transcribed as part of genes; they remove themselves from the transcript before translation (introns) or from the translated protein (inteins) [1,2]. Homing endonuclease genes (HEGs) are molecular parasites that are frequently encoded as open reading frames on class I introns, or as part of inteins [3]. The recognition site of these HEases is so large that they cleave a genome only in one or very few places. This has prompted attempts to use HEases in gene therapy and in the genetic engineering of large and complex genomes [4-6]. HEases have been designed to target disease-associated genes, such as XPC [7] and RAG1 [8], to induce targeted integration in cell lines [9,10], and for targeted mutagenesis in crop [11]. In the natural host, a HEase promotes the horizontal propagation of its respective intron/intein into an intron-less or intein-less allele by cleaving the vacant allele to induce double strand break repair by homologous recombination (HR). The finding that the HEases encoded in inteins and introns belong to different endonuclease families [12,13] reveals that the unions between HEGs and self-splicing elements occurred several times, possibly because both HEases and introns/inteins evolved to target similar sites