Abstract
Defining genetic variants that predispose for diseases is an important initiative that can improve biological understanding and focus therapeutic development. Genetic mapping in humans and animal models has defined genomic regions controlling a variety of phenotypes known as quantitative trait loci (QTL). Causative disease determinants, including single nucleotide polymorphisms (SNPs), lie within these regions and can often be identified through effects on gene expression. We previously identified a QTL on rat chromosome 4 regulating macrophage phenotypes and immune-mediated diseases including experimental autoimmune encephalomyelitis (EAE). Gene analysis and a literature search identified lysine-specific demethylase 3A (Kdm3a) as a potential regulator of these phenotypes. Genomic sequencing determined only two synonymous SNPs in Kdm3a. The silent synonymous SNP in exon 15 of Kdm3a caused problems with quantitative PCR detection in the susceptible strain through reduced amplification efficiency due to altered secondary cDNA structure. Shape Probability Shift analysis predicted that the SNP often affects RNA folding; thus, it may impact protein translation. Despite these differences in rats, genetic knockout of Kdm3a in mice resulted in no dramatic effect on immune system development and activation or EAE susceptibility and severity. These results provide support for tools that analyze causative SNPs that impact nucleic acid structures.
Highlights
Genetic variations are used as markers to discover genes that regulate Mendelian and complex phenotypes or diseases
The confidence interval contains 15 known genes which we examined for known function, Single nucleotide polymorphisms (SNPs), and expression levels (Table S1)
Recent literature has implicated the JmjC domain-containing family in relation to immune system regulation [21,22,23,24,25]. This narrowed our focus to the lysine (K)specific demethylase 3A (Kdm3a; ENSRNOG00000007814), which is located on rat chromosome 4 at 164282438 – 164325750 bases, at the peak of the quantitative trait loci (QTL)
Summary
Genetic variations are used as markers to discover genes that regulate Mendelian and complex phenotypes or diseases. Genetic variations, including coding SNPs, may be causative of phenotypes and disease susceptibility [2]. The most frequent modes of action of causal SNPs include amino acid substitutions and alternative splicing that affect protein conformation, charge and enzymatic activity, or SNPs in regulatory regions that affect transcription [3]. Estimates from the 1000 Genome Project indicate that there are 10,000 – 11,000 non-synonymous SNPs that affect amino acid coding and 10,000 – 12,000 synonymous SNPs in the coding regions of each individual [4]. Even synonymous SNPs that do not affect the coding of amino acids are under evolutionary selection pressure as they can govern a variety of mechanisms including codon selection bias, rate of protein synthesis and mRNA stability [5]
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