Properties of Yeast Orthologs to Human Disease Genes within the Mitochondrial System

<div><p>(A) Five modules enriched in human disease gene orthologs. Node color identifies human orthologs to yeast genes with and without associated Mendelian diseases (OMIM database). Proteins that belong to physical complexes are shown by overlapping nodes or in some cases are connected by solid lines; functional associations are shown by dotted lines. Disease genes within the same functional module had a tendency to have similar clinical phenotypes: glutaricaciduria II (NAD metabolism/tricarboxylic acid cycle), glycine encephalopathy (folate and glycine metabolism), mainly susceptibility to hereditary pheochromocytoma and paraganglioma (RCC-II), and variants of inherited disease of porphyrin metabolism (heme biosynthesis). <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020170#pgen-0020170-st006" target="_blank">Table S6</a> contains descriptions for each disease gene.</p><p>(B) Conservation of disease genes to proteobacteria. Venn diagram of the overlap of yeast genes having human orthologs, proteobacterial orthologs, and human disease gene orthologs. Of the proteins with a disease ortholog, 31% (31/99) have a proteobacterial ortholog—whereas only 18% (100/565) of all human orthologs have a proteobacterial ortholog (hypergeometric test, <i>p</i> < 10⁻⁴).</p><p>(C) Fitness distribution of yeast orthologs of disease genes. Empirical cumulative distributions of NF fitness scores are shown for all human disease gene orthologs compared to the remaining human orthologs. NF fitness represents the growth and survival of single gene deletion mutants under respiratory conditions (NF carbon source): higher fitness represents a milder growth defect. As a group, disease orthologs have higher fitness (i.e., milder mutant phenotypes) (<i>t</i>-test, <i>p</i> < 0.01).</p>