Dataset Information

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 has 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.

SUBMITTER: Hoedjes KM

PROVIDER: S-EPMC9922802 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Hoedjes Katja M KM Kostic Hristina H Flatt Thomas T Keller Laurent L

Molecular biology and evolution 20230201 2

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 has 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 lifesp ...[more]

PMID: 36703226

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Project description:BackgroundThe targeted capture and sequencing of genomic regions has rapidly demonstrated its utility in genetic studies. Inherent in this technology is considerable heterogeneity of target coverage and this is expected to systematically impact our sensitivity to detect genuine polymorphisms. To fully interpret the polymorphisms identified in a genetic study it is often essential to both detect polymorphisms and to understand where and with what probability real polymorphisms may have been missed.ResultsUsing down-sampling of 30 deeply sequenced exomes and a set of gold-standard single nucleotide variant (SNV) genotype calls for each sample, we developed an empirical model relating the read depth at a polymorphic site to the probability of calling the correct genotype at that site. We find that measured sensitivity in SNV detection is substantially worse than that predicted from the naive expectation of sampling from a binomial. This calibrated model allows us to produce single nucleotide resolution SNV sensitivity estimates which can be merged to give summary sensitivity measures for any arbitrary partition of the target sequences (nucleotide, exon, gene, pathway, exome). These metrics are directly comparable between platforms and can be combined between samples to give "power estimates" for an entire study. We estimate a local read depth of 13X is required to detect the alleles and genotype of a heterozygous SNV 95% of the time, but only 3X for a homozygous SNV. At a mean on-target read depth of 20X, commonly used for rare disease exome sequencing studies, we predict 5-15% of heterozygous and 1-4% of homozygous SNVs in the targeted regions will be missed.ConclusionsNon-reference alleles in the heterozygote state have a high chance of being missed when commonly applied read coverage thresholds are used despite the widely held assumption that there is good polymorphism detection at these coverage levels. Such alleles are likely to be of functional importance in population based studies of rare diseases, somatic mutations in cancer and explaining the "missing heritability" of quantitative traits.

Dataset Information

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

Publications

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

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