Rapid selection of transposon-based resistance in malaria
vectors with 4.3kb fixation in less than 5 years.
PoolSeq data analysis identified this 4.3kb insertion between theCYP6P5 and CYP6P9b loci on Chromosome 2 found only in
Uganda and Cameroon samples of 2014 out of 8 countries assessed. This
4.3bk SV contains 2 open reading frames (a gag-like and reverse
transcriptase-like proteins), which correspond to 2 (gag andpol ) out of the 3 open reading frames that characterised LTR-
retrotransposons. The gagencodes capsid
proteins, pol encodes enzymes regulating the transposition of a
mobile element, while the missing env encodes a product
responsible for the recognition
of cell
receptors and the penetration of a virus into a cell (L. N. Nefedova,
Kuzmin, Makhnovskii, & Kim, 2014). The Drosophila melanogastergag-related gene (gagr), a homolog to the Gypsy group of LTR
retroelements, is possibly associated with the origin of new functions
and the involvement in stress response in Drosophila species (L.
Nefedova, Gigin, & Kim, 2022). This SV was at a high frequency in
Uganda and observed at a low frequency in Cameroon in 2014. Therefore,
we hypothesised that this SV spread from Uganda to Cameroon as it is
inserted in an identical position but does not rule out a de novoorigin in Cameroonian populations.
Interestingly population structure analyses using ddRADseq, Poolseq, and
microsatellites have revealed a low level of divergence between Cameroon
and Ugandan populations of An. funestus indicating that there is
likely little barrier to gene flow and increased introgression of
alleles between them (Barnes et al., 2017; Weedall et al., 2020).
Temporal analysis of the changes in the allelic frequency of the 4.3kb
SV in Cameroon collected across the years (2014-2021) revealed a rapid
selection of this marker, with its frequency reaching fixation in less
than 5 years. The such rapid selection indicates that this insertion
will likely provide mosquitoes with an essential adaptive advantage.
This is supported by the low nucleotide diversity and negative Tajima’s
D values in the CYP6P5 to CYP6P9b intergenic region
(Figure S1, Table S2). These high frequencies observed show a similar
pattern to the 6.5 kb structural variant previously identified inAn. funestus populations from southern Africa in Malawi and
Mozambique (Mugenzi et al., 2020) and was correlated with an increase in
deltamethrin/permetrhin resistance observed in field populations. This
6.5kb SV was shown to increase in frequency from 5% in 2002 to about
90% in 2016 in Mozambique samples (Mugenzi et al., 2020). Similarly, inAn. gambiae , an upstream insertion of a partial Zanzibar-like
transposable element (TE), was identified in association with two other
mutations (nonsynonymous point mutation in CYP6P4 (I236M) and a
duplication of the CYP6AA1 gene) in Uganda populations at high
frequency and shown to have spread to Kenya, the Democratic Republic of
Congo and Tanzania (Njoroge et al., 2022).
Genotyping of recently collected samples for the 4.3kb SV revealed its
presence in West Africa in Ghana and Benin at low frequencies,
suggesting that this resistance allele is migrating westward. Future
works with up-to-date genomic data are needed to understand the origin
of this structural variant which could be through adaptive gene flow
from East to Central to West, or it could be occurring de novo.