P450mediated resistance evolution

Resistance-conferring mutations in insecticide target sites (Rdl, AchE, sodium channel) have a remarkable pattern of orthology in widely divergent species. The hypothesis that a few paralogous, perhaps orthologous P450 genes would repeatedly be found to be responsible for metabolic resistance in various insect species has not been confirmed, beyond the single example of Cyp6g1 in D. melanogaster and D. simulans (that are only 2.5 million years apart). Furthermore, when resistance due to constitutive overexpression of a P450 is caused by a mutation is trans, the effect can be pleiotropic with more than one P450 gene from more than one family being overexpressed (e.g., CYP12A1 and CYP6A1). In Diptera as well as in Lepidoptera, members of the CYP4 family also appear to be involved in resistance, and there is evidence for involvement of CYP9 genes in the latter (Rose et al.,

1997). Therefore, an alternative hypothesis is that the multitude of P450 genes, whose expression is inducible and therefore not strongly expressed in most developmental stages/tissues, constitute a ''reservoir'' in which mutations affecting expression levels can be selected by insecticide exposure. In the field, this can lead to selective ''sweeps'' of these most adapted mutations as seen for the global predominance of the Rutgers and Cyp6g1 /Accord haplotypes in house flies and fruit flies. These mutations would typically be loss-of-function mutations, which inactivate the fine level regulation of expression and therefore increase overall expression of a random P450 gene. If its product happens to metabolize the insecticide, even marginally, this may constitute a selective advantage for the organism. Loss-of-function mutations in the large target of negative regulatory sequences are predicted to be more frequent than gain-of-function mutations (in the smaller open reading frame) that would improve the catalytic efficiency of a P450 enzyme towards the insecticide (Taylor and Feyereisen, 1996). However, polymorphisms in the P450 sequence may be less detrimental to fitness than (often pleiotropic) changes in expression (see, e.g., Halpern and Morton, 1987), so that more examples of point mutations in P450 coding sequences are likely to emerge. The study of insecticide resistance has clearly entered the age of genomics (Oakeshott et al., 2003) and much progress is expected in the coming years.

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