Localization of Candidate Regions Maintaining a Common Polymorphic Inversion (2La) in Anopheles gambiae

Abstract

Chromosomal inversion polymorphisms are thought to play a role in adaptive divergence, but the genes conferring adaptive benefits remain elusive. Here we study 2La, a common polymorphic inversion in the African malaria vector Anopheles gambiae. The frequency of 2La varies clinally and seasonally in a pattern suggesting response to selection for aridity tolerance. By hybridizing genomic DNA from individual mosquitoes to oligonucleotide microarrays, we obtained a complete map of differentiation across the A. gambiae genome. Comparing mosquitoes homozygous for the 2La gene arrangement or its alternative (2L+^a), divergence was highest at loci within the rearranged region. In the 22 Mb included within alternative arrangements, two ∼1.5 Mb regions near but not adjacent to the breakpoints were identified as being significantly diverged, a conclusion validated by targeted sequencing. The persistent association of both regions with the 2La arrangement is highly unlikely given known recombination rates across the inversion in 2La heterozygotes, thus implicating selection on genes underlying these regions as factors responsible for the maintenance of 2La. Polymorphism and divergence data are consistent with a model in which the inversion is maintained by migration-selection balance between multiple alleles inside these regions, but further experiments will be needed to fully distinguish between the epistasis (coadaptation) and local adaptation models for the maintenance of 2La. A chromosomal inversion occurs when part of the chromosome breaks, rotates 180 degrees, and rejoins the broken chromosome. The result is a chromosome carrying a segment whose gene order is reversed. Whereas the physical rearrangement itself may have no direct consequences on gene function, recombination between alleles in the rearranged and wild type segments is suppressed. If multiple alleles inside the inverted or original orientations are well adapted to contrasting environmental conditions, suppressed recombination provides a mechanism to keep beneficial allelic combinations from being shuffled between different genetic backgrounds. Working with wild populations of flies, Dobzhansky provided the first evidence that selection was key to maintaining inversion polymorphism. Subsequently, examples of inversion polymorphisms under selection in other organisms have been found, notably in the mosquito that transmits most cases of human malaria, Anopheles gambiae. However, the genes or gene regions conferring fitness advantages have yet to be discovered. In this study, the authors used modern genomics tools to map such regions in an inversion at an unprecedented level of detail, and show that these regions are likely to be responsible for the maintenance of the inversion polymorphism in natural populations. This study lays the groundwork for future efforts to identify the genes themselves and their role in adaptation.