How is functional variation at large-effect loci maintained in natural populations? Thrilled to share our work on how beneficial dominance reversal helps flies maintain an insecticide resistance polymorphism as selection varies in their environment! 1/n https://t.co/XReYFeahog

VERY excited to have this work out at Molecular Ecology Resources today - Next-Generation Snow Leopard Population Assessment Tool: Multiplex-PCR SNP Panel for Individual Identification From Faeces https://t.co/nZPITRb1Ia @PetrovADmitri @_ellie_cat @AhmadIcup68 @nawazma_SL

Another study on the interaction between seasonal and pesticide selection co-led with @egor_lappo and team is in prep. Stay tuned! 19/n

Thanks to @NIH @NIGMS K99 Award for supporting my research on the genetics of adaptation to extreme environments! 18/n

The big picture? Beneficial dominance reversal can maintain adaptive variation at large-effect loci while enabling rapid responses to environmental change. A mechanism first proposed in the 1970s, finally caught in action! 17/n

One more surprise! W/ @egor_lappo, we showed these rapid and large frequency changes of the resistant Ace drove a chromosome-scale sweep during insecticide selection and a reverse sweep after its reversal . Fluctuating selection's footprints extend far beyond the target! 16/n

But how does dominance switch between environments? We speculate that Wright's theory of dominance (Wright 1937) can give us an elegant answer: it naturally emerges from a concave mapping of gene activity to fitness of each beneficial allele in each favored environment. 15/n

@nastialyulina's modeling revealed the smoking gun: low fitness costs & low dominance are required to explain the resistant Ace allele dynamics in both treated and untreated populations—confirming recessive costs! 14/n

The resistant Ace alleles and resistance rapidly increase during insecticide treatment, then decline after insecticide selection reversal —but they persisted at low frequency without insecticides. The pattern suggested recessive costs hidden in heterozygotes! 13/n

With dedicated undergrad Caitlynn Tran, we measured resistance in over 100K(!) flies. With @sharGblum and Mark Bitter, we analyzed pooled whole-genome sequencing data from 20 evolving populations. A clear pattern of beneficial dominance reversal emerged... 12/n

From Jun to Dec 2021, we tracked genome-wide allele frequencies and resistance with and without a seasonal insecticide pulse every ~1-2 generations. @andyvhuynh's population analyses revealed our first surprise. The insecticide pulse didn't suppress the treated populations! 11/n

Perfect timing—Mark Bitter's adaptive tracking study (Bitter et al., 2024) had a set of untreated mesocosms running. Adding another set of treated mesocosms created a powerful test for beneficial dominance reversal! 10/n

To measure the selective and dominance effects of the resistant Ace alleles on fitness in a semi-natural context, we used @paulrschmidt & @PetrovADmitri's powerful system combining field mesocosms with large-scale phenotypic and genomic measurements (Rudman et al, 2022)

The lab results were exciting! The resistance benefits of Ace alleles are dominant with malathion, while some fitness costs are recessive (or codominant) in its absence. But lab phenotyping has limits. Which traits really matter in nature? 8/n

We first tested for dominance of the resistant Ace alleles in the lab! With amazing undergrad Zach Mouza, we created all Ace genotype combinations using a panel of inbred lines from @paulrschmidt lab and measured fitness-related traits with and without malathion 7/n

Using 20 years of population genomic data from the DEST consortium & pesticide use data from FAOSTAT, we found that the resistant Ace alleles persist worldwide, and their frequency responds to selection but neither fix nor disappear. Exactly what we were trying to explain! 6/n

We tested this idea with insecticide resistance. Living closely with us, fruit flies have evolved resistance to widely-used organophosphates through large-effect resistant alleles at the Ace locus—their molecular target. Ideal genetic system to study how variants persist! 5/n

Theory suggests a solution: beneficial dominance reversal. Alleles could persist if they're dominant when beneficial but recessive when costly. But wait—isn't dominance an inherent property of alleles, as Mendel taught us? 4/n

From the classic peppered moth story to today, we see large-effect variants responding to selection pressures that vary over time. But temporally varying selection should quickly fix or remove them. How do some variants survive these strong selection bouts and persist? 3/n

Quick background: I've long been fascinated by how organisms adapt to extreme environments. My previous work w/ @NKWhiteman on monarch butterfly toxin resistance led me to an old evolutionary puzzle. How do large step mutations persist rather than fix in populations? 2/n