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The availability of diverse genomes makes it possible to predict gene function based on shared evolutionary history. This approach can be challenging, however, for pathways whose components do not exhibit a shared history but rather consist of distinct "evolutionary modules." We introduce a computational algorithm, clustering by inferred models of evolution (CLIME), which inputs a eukaryotic species tree, homology matrix, and pathway (gene set) of interest. CLIME partitions the gene set into disjoint evolutionary modules, simultaneously learning the number of modules and a tree-based evolutionary history that defines each module. CLIME then expands each module by scanning the genome for new components that likely arose under the inferred evolutionary model. Application of CLIME to ~1,000 annotated human pathways and to the proteomes of yeast, red algae, and malaria reveals unanticipated evolutionary modularity and coevolving components. CLIME is freely available and should become increasingly powerful with the growing wealth of eukaryotic genomes. [ABSTRACT FROM AUTHOR]

For nearly three decades, the sequence of the human mitochondrial genome (mtDNA) has provided a molecular framework for understanding maternally inherited diseases. However, the vast majority of human mitochondrial disorders are caused by nuclear genome defects, which is not surprising since the mtDNA encodes only 13 proteins. Advances in genomics, mass spectrometry, and computation have only recently made it possible to systematically identify the complement of over 1,000 proteins that comprise the mammalian mitochondrial proteome. Here, we review recent progress in characterizing the mitochondrial proteome and highlight insights into its complexity, tissue heterogeneity, evolutionary origins, and biochemical versatility. We then discuss how this proteome is being used to discover the genetic basis of respiratory chain disorders as well as to expand our definition of mitochondrial disease. Finally, we explore future prospects and challenges for using the mitochondrial proteome as a foundation for systems analysis of the organelle. [ABSTRACT FROM AUTHOR]

The aspergilli comprise a diverse group of filamentous fungi spanning over 200 million years of evolution. Here we report the genome sequence of the model organism Aspergillus nidulans, and a comparative study with Aspergillus fumigatus, a serious human pathogen, and Aspergillus oryzae, used in the production of sake, miso and soy sauce. Our analysis of genome structure provided a quantitative evaluation of forces driving long-term eukaryotic genome evolution. It also led to an experimentally validated model of mating-type locus evolution, suggesting the potential for sexual reproduction in A. fumigatus and A. oryzae. Our analysis of sequence conservation revealed over 5,000 non-coding regions actively conserved across all three species. Within these regions, we identified potential functional elements including a previously uncharacterized TPP riboswitch and motifs suggesting regulation in filamentous fungi by Puf family genes. We further obtained comparative and experimental evidence indicating widespread translational regulation by upstream open reading frames. These results enhance our understanding of these widely studied fungi as well as provide new insight into eukaryotic genome evolution and gene regulation. [ABSTRACT FROM AUTHOR]

Neurospora crassa is a central organism in the history of twentieth-century genetics, biochemistry and molecular biology. Here, we report a high-quality draft sequence of the N. crassa genome. The approximately 40-megabase genome encodes about 10,000 protein-coding genes-more than twice as many as in the fission yeast Schizosaccharomyces pombe and only about 25% fewer than in the fruitfly Drosophila melanogaster. Analysis of the gene set yields insights into unexpected aspects of Neurospora biology including the identification of genes potentially associated with red light photobiology, genes implicated in secondary metabolism, and important differences in Ca2+ signalling as compared with plants and animals. Neurospora possesses the widest array of genome defence mechanisms known for any eukaryotic organism, including a process unique to fungi called repeat-induced point mutation (RIP). Genome analysis suggests that RIP has had a profound impact on genome evolution, greatly slowing the creation of new genes through genomic duplication and resulting in a genome with an unusually low proportion of closely related genes. [ABSTRACT FROM AUTHOR]