Evolution of the insecticide targetRdlin AfricanAnophelesis driven by interspecific and interkaryotypic introgression

Abstract

The evolution of insecticide resistance mechanisms in natural populations of Anopheles malaria vectors is a major public health concern across Africa. Using genome sequence data, we study the evolution of resistance mutations in the resistance to dieldrin locus (Rdl), a GABA receptor targeted by several insecticides, but most notably by the long-discontinued cyclodiene, dieldrin. The two Rdl resistance mutations (296G and 296S) spread across West and Central African Anopheles via two independent hard selective sweeps that included likely compensatory nearby mutations, and were followed by a rare combination of introgression across species (from A. gambiae and A. arabiensis to A. coluzzii) and across non-concordant karyotypes of the 2La chromosomal inversion.Rdl resistance evolved in the 1950s as the first known adaptation to a large-scale insecticidebased intervention, but the evolutionary lessons from this system highlight contemporary and future dangers for management strategies designed to combat development of resistance in malaria vectors. 2 22 24 26 28 30 32locus-or Rdl-that is strongly conserved in a wide range of insects Thompson et al. 1993;Du et al. 2005). Two resistance mutations have been found in anophelines, both in codon 296: alanine-to-glycine (A296G) and alanine-to-serine (A296S).Resistant mutations in the homologous Rdl codon have also evolved in other insects, e.g. in Drosophila spp. (codon 302) Thompson et al. 1993;Du et al. 2005). Populations of Anopheles gambiae sensu stricto (henceforth, A. gambiae) and its sister species A. coluzzii possess both 296G and 296S alleles (Du et al. 2005; Lawniczak et al. 2010), whereas the 296S allele is the only one reported in A. arabiensis and the more distantly-related malaria vectors A. funestus and A. sinensis (Du et al. 2005; Wondji et al. 2011; Yang et al. 2017). Normally, dieldrin inhibits the activity of Rdl receptors, causing persistent neuronal excitation and rapid death; but codon 296 mutations confer resistance by reducing its sensitivity to the insecticide (ffrench-Constant et al. 2000). However, in the absence of exposure, Rdl mutations appear to carry fitness costs, such as lower mosquito mating success (Platt et al. 2015) or impaired response to oviposition and predation-risk signals (Rowland 1991a; Rowland 1991b) (although see (ffrench-Constant and Bass 2017)). Consequently, with seemingly limited current benefit via exposure to insecticides targeting Rdl, persistence of the mutations in Bissau gam (*) Kenya gam (*) Uganda gam Burkina Faso gam col Ghana gam col Gabon gam 43% 30% 78% 72% 65% 31% 3% col gam 62% 39% 60% 92% wt 296S 296G Haplotypes 126 128 130 132 134 95%), which were one order of magnitude higher than wt haplotypes (460 bp), and covered all non-synonymous mutations linked to codon 296 alleles (T345M, T345S, N530K, and H539Q). Next, to estimate the softness/hardness of the sweep, we calculated the profile of Garud's H statistics (Garud et al. 2015) and haplotypic diversity along the 2L chromosome arm (Figure 4B-8 138 140 142 ...

Identification of a rapidly-spreading triple mutant for high-level metabolic insecticide resistance inAnopheles gambiaeprovides a real-time molecular diagnostic for anti-malarial intervention deployment

“…There are now several cases of insecticide resistance evolution where an initial mutation in a genomic region is followed by the spread of additional mutations on the resistant haplotype background [14, 38–42]. It is not yet clear whether the sequence of mutations that we have identified rely on each-other for effect, and thus could only have spread sequentially, or whether each additional mutation coincidentally appeared on the background of an already common mutant haplotype.…”