Regulation at Drosophila’s Malic Enzyme highlights the complexity of transvection and its sensitivity to genetic background

• Published in: Genetics (Austin) Vol. 223; no. 2
• Main Authors: Rzezniczak, Teresa Z, Rzezniczak, Mark T, Reed, Bruce H, Dworkin, Ian, Merritt, Thomas J S
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 09.02.2023; Genetics Society of America
• Subjects: Alleles; Animals; Biological effects; Cell cycle; Chromosomes; Complexity; Drosophila; Drosophila melanogaster - enzymology; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Enzymes; Extracellular matrix; Fruit flies; Gene expression; Gene Expression Regulation; Gene polymorphism; Gene regulation; Genes; Genetic diversity; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Heritability; Insects; Investigation; Malate Dehydrogenase - metabolism; Malic enzyme; Matrix protein; Nucleotides; Phenotypes; Phenotypic variations; Polymorphism; Proteins; Regulatory sequences; Regulatory Sequences, Nucleic Acid; RNA-binding protein; Single-nucleotide polymorphism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; genetic background; transvection; malic enzyme
• ISSN: 0016-6731; 1943-2631; 1943-2631
• DOI: 10.1093/genetics/iyac181

Abstract Transvection, a type of trans-regulation of gene expression in which regulatory elements on one chromosome influence elements on a paired homologous chromosome, is itself a complex biological phenotype subject to modification by genetic background effects. However, relatively few studies have explored how transvection is affected by distal genetic variation, perhaps because it is strongly influenced by local regulatory elements and chromosomal architecture. With the emergence of the “hub” model of transvection and a series of studies showing variation in transvection effects, it is becoming clear that genetic background plays an important role in how transvection influences gene transcription. We explored the effects of genetic background on transvection by performing two independent genome wide association studies (GWASs) using the Drosophila genetic reference panel (DGRP) and a suite of Malic enzyme (Men) excision alleles. We found substantial variation in the amount of transvection in the 149 DGRP lines used, with broad-sense heritability of 0.89 and 0.84, depending on the excision allele used. The specific genetic variation identified was dependent on the excision allele used, highlighting the complex genetic interactions influencing transvection. We focussed primarily on genes identified as significant using a relaxed P-value cutoff in both GWASs. The most strongly associated genetic variant mapped to an intergenic single nucleotide polymorphism (SNP), located upstream of Tiggrin (Tig), a gene that codes for an extracellular matrix protein. Variants in other genes, such transcription factors (CG7368 and Sima), RNA binding proteins (CG10418, Rbp6, and Rig), enzymes (AdamTS-A, CG9743, and Pgant8), proteins influencing cell cycle progression (Dally and Eip63E) and signaling proteins (Atg-1, Axo, Egfr, and Path) also associated with transvection in Men. Although not intuitively obvious how many of these genes may influence transvection, some have been previously identified as promoting or antagonizing somatic homolog pairing. These results identify several candidate genes to further explore in the understanding of transvection in Men and in other genes regulated by transvection. Overall, these findings highlight the complexity of the interactions involved in gene regulation, even in phenotypes, such as transvection, that were traditionally considered to be primarily influenced by local genetic variation. Transvection, a chromosome pairing-dependent mechanism influencing gene expression, is a complex phenotype modified by genetic background effects. It is strongly influenced by local regulatory elements and chromosomal architecture, as well as by distal genetic variation. Rzezniczak et al. explore the effects of genetic background on transvection via GWAS using a pair of Malic enzyme (Men) excision alleles. Both local and distal genetic variation associated significantly with transvection at Men. The specific genetic variation identified was dependent on the excision allele used, highlighting the complex genetic interactions influencing transvection.