Adaptive deletion in resistance gene duplications in the malaria vector Anopheles gambiae

Abstract

While gene copy‐number variations play major roles in long‐term evolution, their early dynamics remains largely unknown. However, examples of their role in short‐term adaptation are accumulating: identical repetitions of a locus (homogeneous duplications) can provide a quantitative advantage, while the association of differing alleles (heterogeneous duplications) allows carrying two functions simultaneously. Such duplications often result from rearrangements of sometimes relatively large chromosome fragments, and even when adaptive, they can be associated with deleterious side effects that should, however, be reduced by subsequent evolution. Here, we took advantage of the unique model provided by the malaria mosquito Anopheles gambiae s.l. to investigate the early evolution of several duplications, heterogeneous and homogeneous, segregating in natural populations from West Africa. These duplications encompass ~200 kb and 11 genes, including the adaptive insecticide resistance ace‐1 locus. Through the survey of several populations from three countries over 3–4 years, we showed that an internal deletion of all coamplified genes except ace‐1 is currently spreading in West Africa and introgressing from An. gambiae s.s. to An. coluzzii. Both observations provide evidences of its selection, most likely due to reducing the gene‐dosage disturbances caused by the excessive copies of the nonadaptive genes. Our study thus provides a unique example of the early adaptive trajectory of duplications and underlines the role of the environmental conditions (insecticide treatment practices and species ecology). It also emphasizes the striking diversity of adaptive responses in these mosquitoes and reveals a worrisome process of resistance/cost trade‐off evolution that could impact the control of malaria vectors in Africa.

Resistance to pirimiphos-methyl in West AfricanAnophelesis spreading via duplication and introgression of theAce1locus

“…After these two mutations, the joint duplication-280S resistance haplotype introgressed from A. gambiae into A. coluzzii (Figures 8 and 9). This A. gambiae origin is consistent with earlier studies of Ace1 variation in West African locations, which generally reported higher frequencies of 280S (Djogbénou et al 2008;Dabiré et al 2009;Essandoh et al 2013) and CNVs (Assogba et al 2018) in A. gambiae than in A. coluzzii, as one would expect if they had a longer evolutionary history in the former. Whilst previous studies had suggested that the similarity of 280S haplotypes in A. coluzzii and A. gambiae was due to inter-specific introgression (Djogbénou et al 2008;Essandoh et al 2013;, they were focused on partial sequencing of the Ace1 gene and could not assess the relationship between introgression and the wider duplicated region (ca.…”

“…Therefore, our genome-wide analyses would only capture pre-existing variants that were enriched in the resistant specimens. Ace1 mutations and duplications, which cause cross-resistance with previously employed insecticides (Djogbénou et al , 2008Essandoh et al 2013;Edi et al 2014a;Assogba et al 2015Assogba et al , 2016Assogba et al , 2018, fit this definition and are sufficient to sustain high levels of resistance. However, future analyses on recent collections from populations subjected to regular pirimiphos-methyl-based IRS may reveal additional mechanisms more specifically selected by this insecticide.…”

“…Furthermore, monitoring studies must note that this resistance haplotype is still evolving, especially in the light of the fitness trade-offs associated with Ace1 resistance alleles -namely, that heterozygous duplications offset the fitness cost of 280S alleles in the absence of insecticide exposure (Labbé et al 2007;Assogba et al 2015), and that variably copy number can result in gene dosage disturbances (Assogba et al 2016). A recent survey has shown that internal deletions within the duplicated region, downstream to Ace1, are spreading in both A. gambiae and A. coluzzii (Assogba et al 2018). The authors have proposed that these deletions reduce the fitness costs of duplications by ameliorating deleterious changes in gene expression (Assogba et al 2018).…”

“…A recent survey has shown that internal deletions within the duplicated region, downstream to Ace1, are spreading in both A. gambiae and A. coluzzii (Assogba et al 2018). The authors have proposed that these deletions reduce the fitness costs of duplications by ameliorating deleterious changes in gene expression (Assogba et al 2018). These small deletions are absent from the Ivorian A. coluzzii genomes analysed here (Lucas et al 2019), but future genome monitoring studies could investigate their spread and identify signals of selection associated with their proposed selective advantage.…”

“…The distribution of duplication-280S resistance haplotypes observed in the 1000 Genomes cohort can explained by three evolutionary events: the G280S mutation, an internally heterozygous duplication, and interspecific introgression. Furthermore, recent sampling efforts have identified internal deletions within the duplication in both A. gambiae and A. coluzzii(Assogba et al 2018). Homogeneous duplications are rare in…”