Abstract
Different genetic backgrounds can modify the effect of mutated genes. Human α-synuclein (SNCA) gene encodes α-synuclein, and its oligomeric complexes accumulate with age and mediate the disruption of cellular homeostasis, resulting in the neuronal death that is characteristic of Parkinson’s Disease. Polymorphic variants modulate this complex pathologic mechanism. Previously, we constructed five transgenic introgression lines of a Caenorhabditis elegans model of α-synuclein using genetic backgrounds that are genetically diverse from the canonical wild-type Bristol N2. A gene expression analysis revealed that the α-synuclein transgene differentially affects genome-wide transcription due to background modifiers. To further investigate how complex traits are affected in these transgenic lines, we measured the α-synuclein transgene expression, the overall accumulation of the fusion protein of α-synuclein and yellow fluorescent protein (YFP), the lysosome-related organelles, and the body size. By using quantitative PCR (qPCR), we demonstrated stable and similar expression levels of the α-synuclein transgene in different genetic backgrounds. Strikingly, we observed that the levels of the a-synuclein:YFP fusion protein vary in different genetic backgrounds by using the COPAS™ biosorter. The quantification of the Nile Red staining assay demonstrates that α-synuclein also affects lysosome-related organelles and body size. Our results show that the same α-synuclein introgression in different C. elegans backgrounds can produces differing effects on complex traits due to background modifiers.
Highlights
The phenotypic effect of mutations can be modified by the genetic background
The expression levels of α-synuclein in the different genetic backgrounds were assessed by quantitative PCR in 2-day-old worms
We investigated the overall expression of the α-synuclein:yellow fluorescent protein (YFP) fusion protein
Summary
The phenotypic effect of mutations can be modified by the genetic background. Variants in the FBN1 gene are responsible for most cases of marfan syndrome, but the phenotypic effect of alleles of FBN1 is modified by other genes such as gMod-M1-9 and COL4A1 [1]. There is a general consensus that the overall effect of disease-causing mutations is often mediated by the genetic background. Genome wide screens and sequencing based approaches offer an unbiased route to the identification of genetic factors that modify complex disease traits in humans. Despite progress in such direct human studies, there is still an important role to be played by studies in model species like the nematode
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