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Natural variation in the regulation of neurodevelopmental genes modifies flight performance in Drosophila

View ORCID ProfileAdam N. Spierer, View ORCID ProfileJim A. Mossman, View ORCID ProfileSamuel Pattillo Smith, View ORCID ProfileLorin Crawford, View ORCID ProfileSohini Ramachandran, View ORCID ProfileDavid M. Rand
doi: https://doi.org/10.1101/2020.05.27.118604
Adam N. Spierer
1Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, United States of America
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  • For correspondence: Adam_Spierer@alumni.brown.edu David_Rand@brown.edu
Jim A. Mossman
1Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, United States of America
2Center for Computational Molecular Biology, Brown University, Providence, RI, United States of America
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Samuel Pattillo Smith
1Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, United States of America
2Center for Computational Molecular Biology, Brown University, Providence, RI, United States of America
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Lorin Crawford
2Center for Computational Molecular Biology, Brown University, Providence, RI, United States of America
3Department of Biostatistics, Brown University, Providence, RI, United States of America
4Center for Statistical Sciences, Brown University, Providence, RI, United States of America
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Sohini Ramachandran
1Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, United States of America
2Center for Computational Molecular Biology, Brown University, Providence, RI, United States of America
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David M. Rand
1Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, United States of America
2Center for Computational Molecular Biology, Brown University, Providence, RI, United States of America
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  • For correspondence: Adam_Spierer@alumni.brown.edu David_Rand@brown.edu
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Abstract

The winged insects of the order Diptera are colloquially named for their most recognizable phenotype: flight. These insects rely on flight for a number of important life history traits, like dispersal, foraging, and courtship. Despite the importance of flight, relatively little is known about the genetic architecture of variation for flight performance. Accordingly, we sought to uncover the genetic modifiers of flight using a measure of flies’ reaction and response to an abrupt drop in a vertical flight column. We conducted an association study using 197 of the Drosophila Genetic Reference Panel (DGRP) lines, and identified a combination of additive and marginal variants, epistatic interactions, whole genes, and enrichment across interaction networks. We functionally validated 13 of these candidate genes’ (Adgf-A/Adgf-A2/CG32181, bru1, CadN, CG11073, CG15236, CG9766, CREG, Dscam4, form3, fry, Lasp/CG9692, Pde6, Snoo) contribution to flight, two of which (fry and Snoo) also validate a whole gene analysis we introduce for the DGRP: PEGASUS_flies. Overall, our results suggest modifiers of muscle and wing morphology, and peripheral and central nervous system assembly and function are all important for flight performance. Additionally, we identified ppk23, an Acid Sensing Ion Channel (ASIC) homolog, as an important hub for epistatic interactions. These results represent a snapshot of the genetic modifiers affecting drop-response flight performance in Drosophila, with implications for other insects. It also draws connections between genetic modifiers of performance and BMP signaling and ASICs as targets for treating neurodegeneration and neurodysfunction.

Author summary Insect flight is a widely recognizable phenotype of winged insects, hence the name: flies. While fruit flies, or Drosophila melanogaster, are a genetically tractable model, flight performance is a highly integrative phenotype, making it challenging to comprehensively identify the genetic modifiers that contribute to its genetic architecture. Accordingly, we screened 197 Drosophila Genetic Reference Panel lines for their ability to react and respond to an abrupt drop. Using several computational tools, we successfully identified several additive, marginal, and epistatic variants, as well as whole genes and altered sub-networks of gene-gene and protein-protein interaction networks, demonstrating the benefits of using multiple methodologies to elucidate the genetic architecture of complex traits more generally. Many of these significant genes and variants mapped to regions of the genome that affect development of sensory and motor neurons, wing and muscle development, and regulation of transcription factors. We also introduce PEGASUS_flies, a Drosophila-adapted version of the PEGASUS platform first used in human studies, to infer gene-level significance of association based on the distribution of individual variant P-values. Our results contribute to the debate over the relative importance of individual, additive factors and epistatic, or higher order, interactions, in the mapping of genotype to phenotype.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 27, 2020.
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Natural variation in the regulation of neurodevelopmental genes modifies flight performance in Drosophila
Adam N. Spierer, Jim A. Mossman, Samuel Pattillo Smith, Lorin Crawford, Sohini Ramachandran, David M. Rand
bioRxiv 2020.05.27.118604; doi: https://doi.org/10.1101/2020.05.27.118604
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Natural variation in the regulation of neurodevelopmental genes modifies flight performance in Drosophila
Adam N. Spierer, Jim A. Mossman, Samuel Pattillo Smith, Lorin Crawford, Sohini Ramachandran, David M. Rand
bioRxiv 2020.05.27.118604; doi: https://doi.org/10.1101/2020.05.27.118604

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