Abstract
BackgroundGlobal analyses of human disease genes by computational methods have yielded important advances in the understanding of human diseases. Generally these studies have treated the group of disease genes uniformly, thus ignoring the type of disease-causing mutations (dominant or recessive). In this report we present a comprehensive study of the evolutionary history of autosomal disease genes separated by mode of inheritance.ResultsWe examine differences in protein and coding sequence conservation between dominant and recessive human disease genes. Our analysis shows that disease genes affected by dominant mutations are more conserved than those affected by recessive mutations. This could be a consequence of the fact that recessive mutations remain hidden from selection while heterozygous. Furthermore, we employ functional annotation analysis and investigations into disease severity to support this hypothesis.ConclusionThis study elucidates important differences between dominantly- and recessively-acting disease genes in terms of protein and DNA sequence conservation, paralogy and essentiality. We propose that the division of disease genes by mode of inheritance will enhance both understanding of the disease process and prediction of candidate disease genes in the future.
Highlights
Global analyses of human disease genes by computational methods have yielded important advances in the understanding of human diseases
When we plot the frequency distributions of the protein conservation scores of the different sets of genes, we observe that the set of dominant disease genes (DD) has a significantly different distribution to recessive disease genes (DR) (p-value for Kolmogorov-Smirnov (K-S) test = 1.95 × 10-6, Table 2 and Figure 1) and both sets of disease genes are significantly different to the non-disease genes
Level of protein conservation of paralogues of dominant and recessive disease genes Previously, it has been reported that genes involved in disease have less conserved paralogues than human genes in general [2], presumably because highly similar paralogues can potentially compensate for a mutated protein [16], in which case a disease might not be observed
Summary
Global analyses of human disease genes by computational methods have yielded important advances in the understanding of human diseases. These studies have treated the group of disease genes uniformly, ignoring the type of disease-causing mutations (dominant or recessive). There are more than 1600 human genes known to be associated with particular Mendelian disease phenotypes. The analysis of this group of genes from a global perspective has already revealed interesting insights about the nature of human disease [1,2,3,4,5]. Another study of sequence conservation at the nucleotide level between human and rat found only a small difference (page number not for citation purposes)
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