A Single Nucleotide Variant in the PPARγ-homolog Eip75B Affects Fecundity in Drosophila

Abstract

Single nucleotide polymorphisms are the most common type of genetic variation, but how these variants contribute to the adaptation of complex phenotypes is largely unknown. Experimental evolution and genome-wide association studies have demonstrated that variation in the PPARγ-homolog Eip75B is associated with longevity and life-history differences in the fruit fly Drosophila melanogaster. Using RNAi knockdown, we first demonstrate that reduced expression of Eip75B in adult flies affects lifespan, egg-laying rate and egg volume. We then tested the effects of a naturally occurring SNP within a cis-regulatory domain of Eip75B by applying two complementary approaches: a Mendelian randomization approach using lines of the Drosophila Genetic Reference Panel, and allelic replacement using precise CRISPR/Cas9-induced genome editing. Our experiments reveal that this natural polymorphism has a significant pleiotropic effect on fecundity and egg-to-adult viability, but not on longevity or other life-history traits. Our results provide a rare functional validation at the nucleotide level and identify a natural allelic variant affecting fitness and life-history adaptation.

A functional schizophrenia-associated genetic variant near the TSNARE1 and ADGRB1 genes

“… 22 Now, we are able to generate, study, and compare human neuronal cells with only a single nucleotide difference across the entire genome, as we and others have previously reported. 21 , 30 , 67 , 68 , 69 , 70 , 71 This approach provides the opportunity to elucidate the individual contributions of risk variants in a human- and disease-relevant system. Here, we apply this strategy to study a GWAS-identified, non-coding variant implicated in SCZ risk, rs4129585.…”

A Functional Schizophrenia-associated genetic variant near theTSNARE1andADGRB1genes

“…Cellular modeling is quickly becoming a powerful tool for the study of genetic risk variants, particularly those within non-coding regions of the genome, as technological advances are being made in genome editing, iPSC generation from somatic cells, and directed differentiation methods 22 . Now, we are able to generate, study, and compare human neuronal cells with only a single nucleotide difference across the entire genome, as we and others have previously reported 21,29,[66][67][68][69][70] . This approach provides the opportunity to elucidate the individual contributions of risk variants in a human-and disease-relevant system.…”

Dhr96[1] mutation and maternal tudor[1] mutation increase life span and reduce the beneficial effects of mifepristone in mated female Drosophila

“…Mifepristone was recently reported to inhibit an estrogen-related receptor ( ERR ) transgenic reporter in adult Drosophila, and to reduce lipid staining and magro RNA levels in the midgut in flies of undefined sex [ 46 ], and in the future it may be of interest to test loss of function of Drosophila ERR for ability to mimic the benefits of mifepristone. Finally, naturally-occurring genetic variation in the Drosophila gene Eip75B has been found to be associated with adult life span and fecundity [ 47 , 48 ], and experimental knock-down studies in adult flies show that Eip75B is required for midgut hypertrophy in response to mating [ 11 , 12 , 15 ], for normal adult life span and egg production [ 48 , 49 ], and for normal sugar tolerance and expression of de novo lipogenesis genes [ 50 ]; in the future it may be of interest to determine if adult-specific knock-down of Eip75B might affect the response to mifepristone.…”