Complex Genetic Architecture of Cardiac Disease in a Wild Type Inbred Strain of Drosophila melanogaster
| Autor: | Benjamin Hsieh, Karen Ocorr, Julie Anderson, Amy Poe, Rolf Bodmer, Zhi Zhang, Greg Gibson |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Multifactorial Inheritance Heredity Genome Insect Gene Identification and Analysis lcsh:Medicine 0302 clinical medicine Inbreeding Genome Sequencing lcsh:Science Genetics 0303 health sciences Multidisciplinary Drosophila Melanogaster Linkage (Genetics) Genomics Animal Models Functional Genomics Phenotypes Phenotype Female Drosophila melanogaster Cardiomyopathies Research Article Physiogenomics Quantitative Trait Loci DNA Recombinant Biology Quantitative trait locus Deep sequencing Molecular Genetics 03 medical and health sciences Model Organisms Genetic Mutation Animals 030304 developmental biology Whole genome sequencing Evolutionary Biology Autosome lcsh:R Bulked segregant analysis Arrhythmias Cardiac biology.organism_classification Chromosomes Insect Genetics of Disease Epistasis lcsh:Q 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE, Vol 8, Iss 4, p e62909 (2013) PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0062909 |
| Popis: | Natural populations of the fruit fly, Drosophila melanogaster, segregate genetic variation that leads to cardiac disease phenotypes. One nearly isogenic line from a North Carolina peach orchard, WE70, is shown to harbor two genetically distinct heart phenotypes: elevated incidence of arrhythmias, and a dramatically constricted heart diameter in both diastole and systole, with resemblance to restrictive cardiomyopathy in humans. Assuming the source to be rare variants of large effect, we performed Bulked Segregant Analysis using genomic DNA hybridization to Affymetrix chips to detect single feature polymorphisms, but found that the mutant phenotypes are more likely to have a polygenic basis. Further mapping efforts revealed a complex architecture wherein the constricted cardiomyopathy phenotype was observed in individual whole chromosome substitution lines, implying that variants on both major autosomes are sufficient to produce the phenotype. A panel of 170 Recombinant Inbred Lines (RIL) was generated, and a small subset of mutant lines selected, but these each complemented both whole chromosome substitutions, implying a non-additive (epistatic) contribution to the "disease" phenotype. Low coverage whole genome sequencing was also used to attempt to map chromosomal regions contributing to both the cardiomyopathy and arrhythmia, but a polygenic architecture had to be again inferred to be most likely. These results show that an apparently simple rare phenotype can have a complex genetic basis that would be refractory to mapping by deep sequencing in pedigrees. We present this as a cautionary tale regarding assumptions related to attempts to map new disease mutations on the assumption that probands carry a single causal mutation. |
| Databáze: | OpenAIRE |
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