Inversions and the dynamics of eukaryotic gene order

Comparisons of the gene order in closely related genomes reveal a major role for inversions in the genome shuffling process. In contrast to prokaryotes, where the inversions are predominantly large, half of the inversions between Saccharomyces cerevisiae and Candida albicans appear to be small, often encompassing only a single gene. Overall the genome rearrangement rate appears higher in eukaryotes than in prokaryotes, and the current genome data do not indicate that functional constraints on the co-expression of neighboring genes have a large role in conserving eukaryotic gene order. Nevertheless, qualitatively interesting examples of conservation of gene order in eukaryotes can be observed.     

The genome and the nucleus: a marriage made by evolution

Genomes are housed within cell nuclei as individual chromosome territories. Nuclei contain several architectural structures that interact and influence the genome. In this review, we discuss how the genome may be organised within its nuclear environment with the position of chromosomes inside nuclei being either influenced by gene density or by chromosomes size. We compare interphase genome organisation in diverse species and reveal similarities and differences between evolutionary divergent organisms. Genome organisation is also discussed with relevance to regulation of gene expression, development and differentiation and asks whether large movements of whole chromosomes are really observed during differentiation. Literature and data describing alterations to genome organisation in disease are also discussed. Further, the nuclear structures that are involved in genome function are described, with reference to what happens to the genome when these structures contain protein from mutant genes as in the laminopathies. Review related to the 15th International Chromosome Conference (ICC XV), held in September 2004, Brunel University, London, UK     

Low occurrence of gene transposition events during the evolution of the genus Drosophila

Abstract.— The role played by gene transpositions during the evolution of eukaryotic genomes is still poorly understood and indeed has been analyzed in detail only in nematodes. In Drosophila , a limited number of transpositions have been detected by comparing the chromosomal location of genes between different species. The relative importance of gene transposition versus other types of chromosomal rearrangements, for example, inversions, has not yet been evaluated. Here, we use physical mapping to perform an extensive search for long-distance gene transpositions and assess their impact during the evolution of the Drosophila genome. We compare the relative order of 297 molecular markers that cover 60% of the euchromatic fraction of the genome between two related Drosophila species and conclude that the frequency of gene transpositions is very low, namely one order of magnitude lower than that of nematodes. In addition, gene transpositions seem to be events almost exclusively associated with genes of repetitive nature such as the Histone gene complex ( HIS-C ).     

Genomic characterization of POS5, the Saccharomyces cerevisiae mitochondrial NADH kinase

Disruption of the Saccharomyces cerevisiae mitochondrial NADH kinase POS5 increases the mitochondrial mutation rate 50-fold. Whereas most multicellular eukaryotic genomes have one NADH kinase gene, the yeast genome contains three distinct genes encoding NAD/H kinase activity. To determine if all three genes are essential for viability we constructed combinations of gene knockouts. We show that only the pos5Deltautr1Delta combination is synthetically lethal, demonstrating an essential overlapping function, and showing that NAD/H kinase activity is essential for eukaryotic viability. The single human NAD/H kinase gene can rescue the lethality of the double knockout in yeast, demonstrating that the single human gene can fill the various functions provided by the three yeast genes. The human NAD/H kinase gene harbors very common sequence variants, but all of these equally complement the synthetic lethality in yeast, illustrating that each of these are functionally wild-type. To understand the molecular mechanism of the mitochondrial genome instability of pos5 mutation we performed gene expression analysis on the pos5Delta. The pos5Delta resulted in an increase in expression of most of the iron transport genes including key genes involved in iron-sulfur cluster assembly. Decreased expression occurred in many genes involved in the electron transport chain. We show that the pos5Delta expression pattern is similar to the frataxin homolog knockout (yfh1Delta), the yeast model for Friedreich's ataxia. These combined data show that the POS5 NAD/H kinase is an important protein required for a variety of essential cellular pathways and that deficient iron-sulfur cluster assembly may play a critical role in the mitochondrial mutator phenotype observed in the pos5Delta.     

The slow road to the eukaryotic genome

The eukaryotic genome is a mosaic of eubacterial and archaeal genes in addition to those unique to itself. The mosaic may have arisen as the result of two prokaryotes merging their genomes, or from genes acquired from an endosymbiont of eubacterial origin. A third possibility is that the eukaryotic genome arose from successive events of lateral gene transfer over long periods of time. This theory does not exclude the endosymbiont, but questions whether it is necessary to explain the peculiar set of eukaryotic genes. We use phylogenetic studies and reconstructions of ancestral first appearances of genes on the prokaryotic phylogeny to assess evidence for the lateral gene transfer scenario. We find that phylogenies advanced to support fusion can also arise from a succession of lateral gene transfer events. Our reconstructions of ancestral first appearances of genes reveal that the various genes that make up the eukaryotic mosaic arose at different times and in diverse lineages on the prokaryotic tree, and were not available in a single lineage. Successive events of lateral gene transfer can explain the unusual mosaic structure of the eukaryotic genome, with its content linked to the immediate adaptive value of the genes its acquired. Progress in understanding eukaryotes may come from identifying ancestral features such as the eukaryotic splicesome that could explain why this lineage invaded, or created, the eukaryotic niche.     

Actin Genes in the Mediterranean Fruit Fly, Ceratitis Capitata

We have undertaken the study of actin gene organization and expression in the genome of the Mediterranean fruit fly (medfly), Ceratitis capitata. Actin genes have been extensively characterized previously in a wide range of eukaryotic organisms, and they have valuable properties for comparative studies. These genes are typically highly conserved in coding regions, represented in multiple copies per genome and regulated in expression during development. We have isolated a gene in the medfly using the cloned Drosophila melanogaster 5C actin gene as a probe. This medfly gene detects abundant messages present during late larval and late pupal development as well as in thoracic and leg tissue preparations from newly emerged adults. This pattern of expression is consistent with what has been seen for actin genes in other organisms. Using either the D. melanogaster 5C actin gene or the medfly gene as a probe identifies five common cross reacting EcoRI fragments in genomic DNA, but only under less than fully stringent hybridization conditions.     

A 17-marker panel for global genomic instability in breast cancer

Genomic instability is a hallmark of cancer that plays a pivotal role in breast cancer development and evolution. A number of existing prognostic gene expression signatures for breast cancer are based on proliferation-related genes. Here, we identified a 17-marker panel associated with genome stability. A total of 136 primary breast carcinomas were stratified by genome stability. Matched gene expression profiles showed an innate segregation based on genome stability. We identified a 17-marker panel stratifying the training and validation cohorts into high- and low-risk patients. The 17 genes associated with genomic instability strongly impacted clinical outcome in breast cancer. Pathway analyses determined chromosome organisation, cell cycle regulation, and RNA processing as the underlying biological processes, thereby offering options for drug development and treatment tailoring. Our work supports the applicability of the 17-marker panel to improve clinical outcome prediction for breast cancer patients based on a signature accounting for genomic instability.     

Genome SEGE: A database for 'intronless' genes in eukaryotic genomes

Background  

A number of completely sequenced eukaryotic genome data are available in the public domain. Eukaryotic genes are either 'intron containing' or 'intronless'. Eukaryotic 'intronless' genes are interesting datasets for comparative genomics and evolutionary studies. The SEGE database containing a collection of eukaryotic single exon genes is available. However, SEGE is derived using GenBank. The redundant, incomplete and heterogeneous qualities of GenBank data are a bottleneck for biological investigation in comparative genomics and evolutionary studies. Such studies often require representative gene sets from each genome and this is possible only by deriving specific datasets from completely sequenced genome data. Thus Genome SEGE, a database for 'intronless' genes in completely sequenced eukaryotic genomes, has been constructed.     

Identifying conserved gene clusters in the presence of homology families.

The study of conserved gene clusters is important for understanding the forces behind genome organization and evolution, as well as the function of individual genes or gene groups. In this paper, we present a new model and algorithm for identifying conserved gene clusters from pairwise genome comparison. This generalizes a recent model called "gene teams." A gene team is a set of genes that appear homologously in two or more species, possibly in a different order yet with the distance of adjacent genes in the team for each chromosome always no more than a certain threshold. We remove the constraint in the original model that each gene must have a unique occurrence in each chromosome and thus allow the analysis on complex prokaryotic or eukaryotic genomes with extensive paralogs. Our algorithm analyzes a pair of chromosomes in O(mn) time and uses O(m+n) space, where m and n are the number of genes in the respective chromosomes. We demonstrate the utility of our methods by studying two bacterial genomes, E. coli K-12 and B. subtilis. Many of the teams identified by our algorithm correlate with documented E. coli operons, while several others match predicted operons, previously suggested by computational techniques. Our implementation and data are publicly available at euler.slu.edu/ approximately goldwasser/homologyteams/.     

Theoretical and practical advances in genome halving

MOTIVATION: Duplication of an organism's entire genome is a rare but spectacular event, enabling the rapid emergence of multiple new gene functions. Over time, the parallel linkage of duplicated genes across chromosomes may be disrupted by reciprocal translocations, while the intra-chromosomal order of genes may be shuffled by inversions and transpositions. Some duplicate genes may evolve unrecognizably or be deleted. As a consequence, the only detectable signature of an ancient duplication event in a modern genome may be the presence of various chromosomal segments containing parallel paralogous genes, with each segment appearing exactly twice in the genome. The problem of reconstructing the linkage structure of an ancestral genome before duplication is known as genome halving with unordered chromosomes. RESULTS: In this paper, we derive a new upper bound on the genome halving distance that is tighter than the best known, and a new lower bound that is almost always tighter than the best known. We also define the notion of genome halving diameter, and obtain both upper and lower bounds for it. Our tighter bounds on genome halving distance yield a new algorithm for reconstructing an ancestral duplicated genome. We create a software package GenomeHalving based on this new algorithm and test it on the yeast genome, identifying a sequence of translocations for halving the yeast genome that is shorter than previously conjectured possible.