Searching for Modifiers of Abelson Tyrosine Kinase Pathway Genes Using Natural Variation in the Drosophila Genetic Reference Panel
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Date
2021-05
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The Ohio State University
Abstract
The Abl pathway is involved in many functions within a cell, including axon pathfinding and maintaining the neuronal cytoskeleton. These functions imply a requirement of functional Abl protein within a cell, however, flies that are homozygous mutant for Abl survive to adulthood, although at reduced frequencies. Previous studies have uncovered multiple dosage-dependent modifiers of the Abl- phenotype, which can either enhance lethality, shifting it toward an earlier developmental stage, or suppress the phenotype, reducing lethality. These studies have yet to examine the effect polymorphic variation within natural population lines has on the dosage-dependent modification of Abl- phenotype. This study utilizes the inherent genetic variation of the Drosophila Genetic Reference Panel (DGRP) to carry out this analysis. With roughly 200 isogenic lines, the DGRP provides ample natural variation to carry out this investigation. We utilized six sensitized genotypes, five using a balancer chromosome containing the dominant marker, Tubby (Tb), and one using a chromosome containing the dominant marker Drop (Dr). Each genotype allowed us to observe the effect of natural polymorphic variation on the Abl- phenotype in different ways. We found that the interaction of the DGRP's inherent natural variation and the sensitized backgrounds did affect relative fitness. We also examined the correlation of mean fitness ratios between each genotype and found a range of correlations between multiple genotypes. Calculations of variance both between and within DGRP lines found that total phenotypic variation that was due to genetic differences was surprisingly low. The relative viability of each line in each sensitized background was used in a genome-wide association (GWA) analysis. The GWA analysis produced a list of nearly 200 single nucleotide polymorphisms (SNPs) within the lines that may affect viability of the Abl- phenotype. These SNPs occurred in over 100 genes. Additionally, five of those genes were shared between several genotypes.
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Keywords
DGRP, Drosophila Genetic Reference Panel, Abl Tyrosine Kinase, Natural Polymorphic Variation