BACKGROUND:Retrotransposons have been suggested to provide a substrate for non-allelic homologous recombination (NAHR) and thereby promote gene family expansion. Their precise role, however, is controversial. Here we ask whether retrotransposons contributed to the recent expansions of the Androgen-binding protein (Abp) gene families that occurred independently in the mouse and rat genomes.RESULTS:Using dot plot analysis, we found that the most recent duplication in the Abp region of the mouse genome is flanked by L1Md_T elements. Analysis of the sequence of these elements revealed breakpoints that are the relicts of the recombination that caused the duplication, confirming that the duplication arose as a result of NAHR using L1 elements as substrates. L1 and ERVII retrotransposons are considerably denser in the Abp regions than in one Mb flanking regions, while other repeat types are depleted in the Abp regions compared to flanking regions. L1 retrotransposons preferentially accumulated in the Abp gene regions after lineage separation and roughly followed the pattern of Abp gene expansion. By contrast, the proportion of shared vs. lineage-specific ERVII repeats in the Abp region resembles the rest of the genome.CONCLUSIONS:We confirmed the role of L1 repeats in Abp gene duplication with the identification of recombinant L1Md_T elements at the edges of the most recent mouse Abp gene duplication. High densities of L1 and ERVII repeats were found in the Abp gene region with abrupt transitions at the region boundaries, suggesting that their higher densities are tightly associated with Abp gene duplication. We observed that the major accumulation of L1 elements occurred after the split of the mouse and rat lineages and that there is a striking overlap between the timing of L1 accumulation and expansion of the Abp gene family in the mouse genome. Establishing a link between the accumulation of L1 elements and the expansion of the Abp gene family and identification of an NAHR-related breakpoint in the most recent duplication are the main contributions of our study.

The neuropeptide Y (NPY) system consists of 3-4 peptides and 4-7 receptors in vertebrates. It has powerful effects on appetite regulation and is involved in many other biological processes including blood pressure regulation, bone formation and anxiety. This thesis describes studies of the evolution of the NPY system by comparison of several vertebrate species and structural studies of the human Y2 receptor, which reduces appetite, to identify amino acid residues involved in peptide-receptor interactions. The NPY system was studied in zebrafish (Danio rerio), western clawed frog (Xenopus tropicalis), and sea lamprey (Petromyzon marinus). The receptors were cloned and functionally expressed and their pharmacological profiles were determined using the native peptides in either binding studies or a signal transduction assay. Some peptide-receptor preferences were observed, indicating functional specialization. A receptor family closely related to the NPY receptors, called the QRFP receptors, was investigated. A QRFP receptor was cloned from amphioxus, Branchistoma floridae, showing that the receptor arose before the origin of the vertebrates. Evolutionary studies demonstrated that the ancestral vertebrate had as many as four QRFP receptors, only one of which remains in mammals today. This correlates with the NPY receptor family, located in the same chromosomal regions, which had seven members in the ancestral vertebrate but only 4-5 in living mammals. Some vertebrates have considerably more complex NPY and QRFP receptor systems than humans and other mammals. Two studies investigated interactions of NPY-family peptides with the human Y2 receptor. Candidate residues, selected based on structural modeling and docking, were mutated to disrupt possible interactions with peptide ligands. The modified receptors were expressed in cultured cells and investigated by measuring binding and functional responses. Several receptor residues were found to influence peptide-receptor interactions, some of which are involved in maintaining receptor structure. In a pilot study, the kinetics of peptide-receptor interaction were found to be very slow, of the order several hours. In conclusion, this thesis clarifies evolutionary relationships for the complex NPY and QRFP peptide-receptor systems and improves the structural models of the human NPY-family receptors, especially Y2. These results will hopefully facilitate drug design for targeting of NPY-family receptors.

[Français] Une fraction importante des génomes eucaryotes est constituée de Gènes Répétés en Tandem (GRT). Un mécanisme fondamental dans l’évolution des GRT est la recombinaison inégale durant la méiose, entrainant la duplication locale (en tandem) de segments chromosomiques contenant un ou plusieurs gènes adjacents. Différents algorithmes ont été proposés pour inférer une histoire de duplication en tandem pour un cluster de GRT. Cependant, leur utilisation est limitée dans la pratique, car ils ne tiennent pas compte d’autres événements évolutifs pourtant fréquents, comme les inversions, les duplications inversées et les délétions. Cette thèse propose différentes approches algorithmiques permettant d’intégrer ces événements dans le modèle de duplication en tandem classique. Nos contributions sont les suivantes: • Intégrer les inversions dans un modèle de duplication en tandem simple (duplication d’un gène à la fois) et proposer un algorithme exact permettant de calculer le nombre minimal d’inversions s’étant produites dans l’évolution d’un cluster de GRT. • Généraliser ce modèle pour l’étude d’un ensemble de clusters orthologues dans plusieurs espèces. • Proposer un algorithme permettant d’inférer l’histoire évolutive d’un cluster de GRT en tenant compte des duplications en tandem, duplications inversées, inversions et délétions de segments chromosomiques contenant un ou plusieurs gènes adjacents. / [English] Tandemly arrayed genes (TAGs) represent an important fraction of most genomes. A fundamental mechanism at the origin of TAG clusters is unequal crossing-over during meiosis, leading to the duplication of chromosomal segments containing one or many adjacent genes. Such duplications are called tandem duplications, as the duplicated segment is placed next to the original one on the chromosome. Different algorithms have been proposed to infer the tandem duplication history of a TAG cluster. However, their applicability is limited in practice since they do not take into account other frequent evolutionary events such as inversion, inverted duplication and deletion. In this thesis, we propose different algorithmic approaches allowing to integrate these evolutionary events in the original tandem duplication model of evolution. Our contributions are summarized as follows: • We integrate inversion events in a tandem duplication model restricted to single gene duplications, and we propose an exact algorithm allowing to compute the minimum number of inversions explaining the evolution of a TAG cluster. • We generalize this model to the study of orthologous TAG clusters in different species. • We propose an algorithm allowing to infer the evolutionary history of a TAG cluster through tandem duplication, inverted duplication, inversion and deletion of chromosomal segments containing one or many adjacent genes.

Code cloning is the practice of duplicating existing source code for use elsewhere within a software system. Within the research community, conventional wisdom has asserted that code cloning is generally a bad practice, and that code clones should be removed or refactored where possible. While there is significant anecdotal evidence that code cloning can lead to a variety of maintenance headaches --- such as code bloat, duplication of bugs, and inconsistent bug fixing --- there has been little empirical study on the frequency, severity, and costs of code cloning with respect to software maintenance. This dissertation seeks to improve our understanding of code cloning as a common development practice through the study of several widely adopted, medium-sized open source software systems. We have explored the motivations behind the use of code cloning as a development practice by addressing several fundamental questions: For what reasons do developers choose to clone code? Are there distinct identifiable patterns of cloning? What are the possible short- and long-term term risks of cloning? What management strategies are appropriate for the maintenance and evolution of clones? When is the ``cure'' (refactoring) likely to cause more harm than the ``disease'' (cloning)? There are three major research contributions of this dissertation. First, we propose a set of requirements for an effective clone analysis tool based on our experiences in clone analysis of large software systems. These requirements are demonstrated in an example implementation which we used to perform the case studies prior to and included in this thesis. Second, we present an annotated catalogue of common code cloning patterns that we observed in our studies. Third, we present an empirical study of the relative frequencies and likely harmfulness of instances of these cloning patterns as observed in two medium-sized open source software systems, the Apache web server and the Gnumeric spreadsheet application. In summary, it appears that code cloning is often used as a principled engineering technique for a variety of reasons, and that as many as 71% of the clones in our study could be considered to have a positive impact on the maintainability of the software system. These results suggest that the conventional wisdom that code clones are generally harmful to the quality of a software system has been proven wrong.

Code cloning is the practice of duplicating existing source code for use elsewhere within a software system. Within the research community, conventional wisdom has asserted that code cloning is generally a bad practice, and that code clones should be removed or refactored where possible. While there is significant anecdotal evidence that code cloning can lead to a variety of maintenance headaches --- such as code bloat, duplication of bugs, and inconsistent bug fixing --- there has been little empirical study on the frequency, severity, and costs of code cloning with respect to software maintenance. This dissertation seeks to improve our understanding of code cloning as a common development practice through the study of several widely adopted, medium-sized open source software systems. We have explored the motivations behind the use of code cloning as a development practice by addressing several fundamental questions: For what reasons do developers choose to clone code? Are there distinct identifiable patterns of cloning? What are the possible short- and long-term term risks of cloning? What management strategies are appropriate for the maintenance and evolution of clones? When is the ``cure'' (refactoring) likely to cause more harm than the ``disease'' (cloning)? There are three major research contributions of this dissertation. First, we propose a set of requirements for an effective clone analysis tool based on our experiences in clone analysis of large software systems. These requirements are demonstrated in an example implementation which we used to perform the case studies prior to and included in this thesis. Second, we present an annotated catalogue of common code cloning patterns that we observed in our studies. Third, we present an empirical study of the relative frequencies and likely harmfulness of instances of these cloning patterns as observed in two medium-sized open source software systems, the Apache web server and the Gnumeric spreadsheet application. In summary, it appears that code cloning is often used as a principled engineering technique for a variety of reasons, and that as many as 71% of the clones in our study could be considered to have a positive impact on the maintainability of the software system. These results suggest that the conventional wisdom that code clones are generally harmful to the quality of a software system has been proven wrong.

<p>In <italic>Saccharomyces cerevisiae</italic>, proper maintenance of haploid cell identity requires the SIR complex to mediate the silenced chromatin found at the cryptic mating-type loci, <italic>HML</italic> and <itaic>HMR</italic>. This complex consists of Sir2, a histone deacetylase and the histone binding proteins Sir3 and Sir4. Interestingly, both Sir2 and Sir3 have paralogs from a genome duplication that occurred after the divergence of <italic>Saccharomyces</italic> and <italic>Kluyveromyces species</italic>. The histone deacetylase <italic>HST1</italic> is the paralog of <italic>SIR2</italic> and works with the promoter-specific SUM1 complex to repress sporulation and alpha-specific genes. <italic>ORC1</italic> is the paralog of <italic>SIR3</italic> and is an essential subunit of the Origin Recognition Complex and also recruits SIR proteins to the <italic>HM</italic> loci. I have investigated the functions of these proteins in the non-duplicated species <italic>Kluyveromyces lactis</italic> and compared these functions to those found in <italic>S. cerevisiae</italic>. </p> <p>I have shown that <italic>SIR2</italic> and <italic>HST1</italic> subfunctionalized post-duplication via the duplication, degeneration and complementation mechanism. In <italic>S. cerevisiae</italic>, Sir2 has retained the ability to function like Hst1 when in an <italic>hst1&#916;</italic> strain. I have also shown, with a chimeric Sir2-Hst1 protein, that there are distinct specificity domains for Sir2 interaction with the SIR complex and Hst1 interaction with the SUM1 complex that have diverged between Sir2 and Hst1. Trans-species complementation assays show that the non-duplicated Sir2 from <italic>K. lactis</italic> can interact with both SIR and SUM1 complexes in <italic>S. cerevisiae</italic>.</p> <p>Further analysis into the non-duplicated experimental system of <italic>K. lactis</italic> has revealed that deletion of KlSir2 de-represses the HM loci as well as sporulation and cell-type specific genes. A physical interaction between KlSir2 and the histone binding protein KlSir4 is conserved in <italic>K. lactis</italic>, and both proteins spread across the <italic>HML</italic> locus and associate with telomeres in a manner similar to <italic>S. cerevisiae</italic>. KlSir2 also physically interacts with the DNA-binding protein, KlSum1, to repress sporulation and cell-type specific genes in a promoter-specific manner and recruitment of KlSir2 to these loci is dependent on KlSum1. Surprisingly, deletion of <italic>KlSUM1</italic> also de-represses <italic>HML</italic> and <italic>HMR</italic>, a phenotype not observed in <italic>S. cerevisiae</italic>. I show by chromatin immunoprecipitation that KlSum1 directly regulates the <italic>HM</italic> loci by spreading across these regions in a mechanism that is distinct from its role in repressing sporulation-specific genes. This result indicates that KlSum1 is a key regulator of not only meiotic, but also mating-type transcriptional programming. </p> <p>The <italic>SIR3-ORC1</italic> gene pair has previously been used as an example of neofunctionalization based on accelerated rates of evolution. However, my studies of KlOrc1 show it is distributed across <italic>HML</italic> and associates with Sir2 and Sir4 at telomeres, indicative of it having Sir3-like capabilities to spread across chromatin. This ability of KlOrc1 to spread is distinct from its functions with ORC, and is entirely dependent on its BAH domain. These findings demonstrate that prior to the genome duplication there was a silencing complex that contained both KlSir2 and KlOrc1. In addition to their functions at <italic>HML</italic> and the telomeres, KlOrc1 associates with replication origins and KlSir2 and KlSum1 work in complex to repress sporulation genes in a promoter-specific manner. The multiple functions of both KlOrc1 and KlSir2 in K. lactis indicate that after duplication, these properties were divided among paralogs and subsequently specialized to perform the functions that have been characterized in <italic>S. cerevisiae</italic>.</p> / Dissertation

If nodes got failed in a distributed application service, it will not only pay more cost to handle with these results missing, but also make scheduler cause additional loadings. For whole results don¡¦t recalculated cause by fault occurs, it will be recalculated data of fault nodes in backup machines. Therefore, this paper uses three methods: N + N nodes, N + 1 nodes, and N + 1 nodes with probability to experiment and analyze their pros and cons, the third way gives jobs weight before assigning them, and converts weight into probability and nice value(defined by SLURM[1]) to influence scheduler¡¦s decision of jobs¡¦ order. When fault occurs, calculating in normal nodes¡¦ results will back to control node, and then the fault node¡¦s jobs are going to be reassigned or not be reassigned to backup machine for getting complete results. Finally, we will analyze these three ways good and bad.

It has been theorized that most proteins are under selection pressure to be soluble in crowded cellular spaces. To maintain solubility a proteins’ aggregation propensity should be inversely proportional to their maximum likely concentration. This theory was examined by comparing the proteome of the model organism S. cerevisiae, which has previously undergone a Whole Genome Duplication (WGD) event to the proteome of the closely related yeast K. waltii, which has not undergone WGD. This comparison revealed the following: 1) Predicted aggregation propensities are higher in S. cerevisiae than K. waltii. 2) Aggregation propensity does not predict which genes reverted to a single copy after WGD. 3) In genes which were retained as duplicates in S. cerevisiae after WGD, aggregation propensities rose from the inferred common ancestral protein. 4) Genes retained as duplicates showed less of an increase relative to their homologues in K. waltii than genes which were not retained as duplicates. 5) The relationship between the log predicted aggregation propensity and log mRNA expression level or log protein abundance was not linear as previously predicted. These results suggest that while there is broad selection pressure for reduced aggregation pressure for genes which have been duplicated, the precise relationship between aggregation propensity and gene expression is more complicated than previously predicted. These results also allow speculation that the whole genome duplication in S.cerevisiae may have been made possible by a general relaxation of aggregation-related selection pressure. / text

Broad Complex (BRC) is an ecdysone-pathway gene essential for entry into and progression through metamorphosis in D. melanogaster. Mutations of three BRC complementation groups cause numerous phenotypes, including a common suite of morphogenesis defects involving central nervous system (CNS), adult salivary glands (aSG), and male genitalia. Alternative splicing, of a protein-binding BTB-encoding exon (BTBBRC) to one of four tandemly duplicated, DNA-binding zinc-finger-encoding exons (Z1BRC, Z2BRC, Z3BRC, Z4BRC), produces four BRC isoforms. Highly conserved orthologs of BTBBRC and all four ZBRC were found in silico from Diptera, Lepidoptera, Hymenoptera and Coleoptera, indicating that BRC arose and underwent internal exon duplication before the split of holometalolous orders. Five Tramtrack subfamily members were characterized throughout Holometabola and used to root phylogenetic analyses of ZBRC exons, revealing that Z3BRC is the basal member. All four ZBRC domains, including Z4BRC which has no known essential function, are evolving in a manner consistent with selective constraint. Transgenic rescue and immunohistochemistry were used to explore how different BRC isoforms contribute to their shared tissue-morphogenesis functions at the onset of metamorphosis, when BRC is required for CNS reorganization. As predicted, the common CNS and aSG phenotypes were rescued by BRC-Z1 in rbp mutants, BRC-Z2 in br mutants, and BRC-Z3 in 2Bc mutants. However, the isoforms are required at two developmental stages, with BRC-Z2 and -Z3 required earlier than BRC-Z1. Each isoform had a unique expression pattern in the CNS, with no substantial three-way overlap among them. Z4 is strongly expressed in a novel subset of CNS neurons. The most prominent localizations of BRC-Z1, -Z2, -Z3 corresponded with glia, neuroblasts and neurons, respectively. There appears to be a switch from BRC-Z2 in proliferating cells to BRC-Z1 and BRC-Z3 in differentiating cells. The temporal-requirement and spatial-distribution data suggest that BRC-dependent CNS morphogenesis is the result of multicellular interactions among different cell types at different times. BRC-Z1-expressing glia in prepupae may mediate the final steps of CNS morphogenesis. Lastly, BRC is required for migration and programmed cell death of the ring gland, the site of ecdysone and juvenile hormone production. Therefore, BRC may function in ecdysone auto-regulation.

[Français] Une fraction importante des génomes eucaryotes est constituée de Gènes Répétés en Tandem (GRT). Un mécanisme fondamental dans l’évolution des GRT est la recombinaison inégale durant la méiose, entrainant la duplication locale (en tandem) de segments chromosomiques contenant un ou plusieurs gènes adjacents. Différents algorithmes ont été proposés pour inférer une histoire de duplication en tandem pour un cluster de GRT. Cependant, leur utilisation est limitée dans la pratique, car ils ne tiennent pas compte d’autres événements évolutifs pourtant fréquents, comme les inversions, les duplications inversées et les délétions. Cette thèse propose différentes approches algorithmiques permettant d’intégrer ces événements dans le modèle de duplication en tandem classique. Nos contributions sont les suivantes: • Intégrer les inversions dans un modèle de duplication en tandem simple (duplication d’un gène à la fois) et proposer un algorithme exact permettant de calculer le nombre minimal d’inversions s’étant produites dans l’évolution d’un cluster de GRT. • Généraliser ce modèle pour l’étude d’un ensemble de clusters orthologues dans plusieurs espèces. • Proposer un algorithme permettant d’inférer l’histoire évolutive d’un cluster de GRT en tenant compte des duplications en tandem, duplications inversées, inversions et délétions de segments chromosomiques contenant un ou plusieurs gènes adjacents. / [English] Tandemly arrayed genes (TAGs) represent an important fraction of most genomes. A fundamental mechanism at the origin of TAG clusters is unequal crossing-over during meiosis, leading to the duplication of chromosomal segments containing one or many adjacent genes. Such duplications are called tandem duplications, as the duplicated segment is placed next to the original one on the chromosome. Different algorithms have been proposed to infer the tandem duplication history of a TAG cluster. However, their applicability is limited in practice since they do not take into account other frequent evolutionary events such as inversion, inverted duplication and deletion. In this thesis, we propose different algorithmic approaches allowing to integrate these evolutionary events in the original tandem duplication model of evolution. Our contributions are summarized as follows: • We integrate inversion events in a tandem duplication model restricted to single gene duplications, and we propose an exact algorithm allowing to compute the minimum number of inversions explaining the evolution of a TAG cluster. • We generalize this model to the study of orthologous TAG clusters in different species. • We propose an algorithm allowing to infer the evolutionary history of a TAG cluster through tandem duplication, inverted duplication, inversion and deletion of chromosomal segments containing one or many adjacent genes.