Genome Biology

Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly.

Publication Date: 2008 May 13 PMID: 18477406
Authors: Hardman, M. J. - Ashcroft, G. S.
Journal: Genome Biol

ABSTRACT: BACKGROUND: Multiple processes have been implicated in age-related delayed healing, including altered gene expression, intrinsic cellular changes, and changes in extracellular milieu (including hormones). To date, little attempt has been made to assess the relative contribution of each of these processes to a human aging phenomenon. The objective of this study is to determine the contribution of estrogen versus aging in age-associated delayed human wound healing. RESULTS: Using an Affymetrix microarray-based approach we show that the differences in gene expression between male elderly and young human wounds are almost exclusively estrogen regulated. Expression of 78 probe sets was significantly decreased and 10 probe sets increased in wounds from elderly subjects (with a fold change greater than 7). A total of 83 percent of down-regulated probe sets and 80 percent of up-regulated probe sets were estrogen-regulated. Differentially regulated genes were validated at the level of gene and protein expression, with genes identified as estrogen-regulated in human confirmed as estrogen-dependent in young estrogen depleted mice in vivo. Moreover, direct estrogen regulation is demonstrated for three array-identified genes, Sele, Lypd3 and Arg1, in mouse cells in vitro. CONCLUSIONS: These findings have clear implications for our understanding of age-associated cellular changes in the context of wound healing, the latter acting as a paradigm for other age-related repair and maintenance processes, and suggest estrogen has a more profound influence on aging than previously thought.

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CpG island density and its correlations with genomic features in mammalian genomes.

Publication Date: 2008 May 13 PMID: 18477403
Authors: Han, L. - Su, B. - Li, W. H. - Zhao, Z.
Journal: Genome Biol

ABSTRACT: BACKGROUND: CpG islands, which are clusters of CpG dinucleotides in GC-rich regions, are considered gene markers and represent an important feature of mammalian genomes. Previous studies of CpG islands have largely been on specific loci or within one genome. To date, there seems to be no comparative analysis of CpG islands and their density at the DNA sequence level among mammalian genomes and of their correlations with other genome features. RESULTS: In this study, we performed a systematic analysis of CpG islands in ten mammalian genomes. We found that both the number of CpG islands and their density vary greatly among genomes, though many of these genomes encode similar numbers of genes. We observed significant correlations between CpG island density and genomic features such as number of chromosomes, chromosome size, and recombination rate. We also observed a trend of higher CpG island density in telomeric regions. Furthermore, we evaluated the performance of three computational algorithms for CpG island identifications. Finally, we compared our observations in mammals to other non-mammal vertebrates. CONCLUSIONS: Our study revealed that CpG islands vary greatly among mammalian genomes. Some factors such as recombination rate and chromosome size might have influenced the evolution of CpG islands in the course of mammalian evolution. Our results suggest a scenario in which an increase in chromosome number increases the rate of recombination, which in turn elevates GC content to help prevent loss of CpG islands and maintain their density. These findings should be useful for studying mammalian genomes, the role of CpG islands in gene function, and molecular evolution.

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Finishing the finished human chromosome 22 sequence.

Publication Date: 2008 May 13 PMID: 18477386
Authors: Cole, C. G. - McCann, O. T. - Collins, J. E. - Oliver, K. - Willey, D. - Gribble, S. M. - Yang, F. - McLaren, K. - Rogers, J. - Ning, Z. - Beare, D. M. - Dunham, I.
Journal: Genome Biol

ABSTRACT: BACKGROUND: Although the human genome sequence was declared complete in 2004, the sequence was interrupted by 341 gaps of which 308 lay in an estimated ~28 Mb of euchromatin. While these gaps constitute only ~1% of the sequence, knowledge of the full complement of human genes and regulatory elements is incomplete without their sequences. RESULTS: We have used a combination of conventional chromosome walking (aided by the availability of end sequences) in fosmid and bacterial artificial chromosome libraries, whole chromosome shotgun sequencing, comparative genome analysis and long PCR to finish 8 of the 11 gaps in the initial chromosome 22 sequence. In addition we have patched four regions of the initial sequence where the original clones were found to be deleted, or contained a deletion allele of a known gene, with a further 126kb of new sequence. Over 1.018 Mb of new sequence has been generated to extend into and close the gaps, and we have annotated 16 new or extended gene structures and 1 pseudogene. CONCLUSIONS: Thus we have made significant progress to completing the sequence of the euchromatic regions of human chromosome 22 using a combination of detailed approaches. Our experience suggests that substantial work remains to close the outstanding gaps in the human genome sequence.

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A rational approach to cancer therapy.

Publication Date: 2008 May 7 PMID: 18466646
Authors: Gorringe, K. L. - Campbell, I. G.
Journal: Genome Biol

ABSTRACT: A report on the 20th Annual Lorne Cancer Conference, Lorne, Australia, 14-16 February 2008.

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RNA polymerase II stalling: loading at the start prepares genes for a sprint.

Publication Date: 2008 May 2 PMID: 18466645
Authors: Wu, J. Q. - Snyder, M.
Journal: Genome Biol

ABSTRACT: Stalling of RNA polymerase II near the promoter has recently been found to be much more common than previously thought. Genome-wide surveys of the phenomenon suggest that it is likely to be a rate-limiting control on gene activation that poises developmental and stimulus-responsive genes for prompt expression when inducing signals are received.

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Not debatable.

Publication Date: 2008 Apr 30 PMID: 18466637
Authors: Petsko, G. A.
Journal: Genome Biol

Science is essential to the economic future and national security. The next US President needs to understand the importance of science, communicate that to the public, and use scientific information properly.

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The AAA+ superfamily of functionally diverse proteins.

Publication Date: 2008 Apr 30 PMID: 18466635
Authors: Snider, J. - Thibault, G. - Houry, W. A.
Journal: Genome Biol

SUMMARY: The AAA+ superfamily is a large and functionally diverse superfamily of NTPases that are characterized by a conserved nucleotide-binding and catalytic module, the AAA+ module. Members are involved in an astonishing range of different cellular processes, attaining this functional diversity through additions of structural motifs and modifications to the core AAA+ module.

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The topless plant developmental phenotype explained!

Publication Date: 2008 Apr 30 PMID: 18466634
Authors: Osmont, K. S. - Hardtke, C. S.
Journal: Genome Biol

ABSTRACT: The molecular-genetic cues that regulate plant embryo pattern formation are the subject of intense scrutiny at present. Recent work in Arabidopsis implicates the TOPLESS protein in auxin-dependent transcriptional repression, highlighting once again the crucial role of auxin signaling during embryogenesis.

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New tricks for old NODs.

Publication Date: 2008 Apr 25 PMID: 18466630
Authors: Pietras, E. M. - Cheng, G.
Journal: Genome Biol

ABSTRACT: Recent work has identified the human NOD-like receptor NLRX1 as a negative regulator of intracellular signaling leading to type I interferon production. Here we discuss these findings and the questions and implications they raise regarding the function of NOD-like receptors in the antiviral response.

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The genome sequence of the model ascomycete fungus Podospora anserina.

Publication Date: 2008 May 6 PMID: 18460219
Authors: Espagne, E. - Lespinet, O. - Malagnac, F. - Da Silva, C. - Jaillon, O. - Porcel, B. M. - Couloux, A. - Aury, J. M. - Segurens, B. - Poulain, J. - Anthouard, V. - Grossetete, S. - Khalili, H. - Coppin, E. - Dequard-Chablat, M. - Picard, M. - Contamine, V. - Arnaise, S. - Bourdais, A. - Berteaux-Lecellier, V. - Gautheret, D. - de Vries, R. P. - Battaglia, E. - Coutinho, P. M. - Danchin, E. G. - Henrissat, B. - Khoury, R. E. - Sainsard-Chanet, A. - Boivin, A. - Pinan-Lucarre, B. - Sellem, C. H. - Debuchy, R. - Wincker, P. - Weissenbach, J. - Silar, P.
Journal: Genome Biol

ABSTRACT: BACKGROUND: The dung-inhabiting ascomycete fungus Podospora anserina is a model used to study various aspects of eukaryotic and fungal biology, such as ageing, prions and sexual development. RESULTS: We present a 10X draft sequence of P. anserina genome, linked to the sequences of a large expressed sequence tag collection. Similar to higher eukaryotes, the P. anserina transcription/splicing machinery generates numerous non-conventional transcripts. Comparison of the P. anserina genome and orthologous gene set with the one of its close relatives, Neurospora crassa, shows that synteny is poorly conserved, the main result of evolution being gene shuffling in the same chromosome. The P. anserina genome contains fewer repeated sequences and has evolved new genes by duplication since its separation from N. crassa, despite the presence of the repeat induced point mutation mechanism that mutates duplicated sequences. We also provide evidence that frequent gene loss took place in the lineages leading to P. anserina and N. crassa. P. anserina contains a large and highly specialized set of genes involved in utilization of natural carbon sources commonly found in its natural biotope. It includes genes potentially involved in lignin degradation and efficient cellulose breakdown. CONCLUSION: The features of the P. anserina genome indicate a highly dynamic evolution since the divergence of P. anserina and N. crassa, leading to the ability of the former to use specific complex carbon sources that match its needs in its natural biotope.

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Human-macaque comparisons illuminate variation in neutral substitution rates.

Publication Date: 2008 Apr 30 PMID: 18447906
Authors: Tyekucheva, S. - Makova, K. D. - Karro, J. E. - Hardison, R. C. - Miller, W. - Chiaromonte, F.
Journal: Genome Biol

ABSTRACT: BACKGROUND: The evolutionary distance between human and macaque is particularly attractive for investigating local variation in neutral substitution rates, because substitutions can be inferred more reliably than in comparisons with rodents and are less influenced by the effects of current and ancient diversity than in comparisons with closer primates. Here we investigate the human-macaque neutral substitution rate as a function of a number of genomic parameters. RESULTS: Using regression analyses we find that male mutation bias, male (but not female) recombination rate, distance to telomeres and substitution rates computed from orthologous regions in mouse-rat and dog-cow comparisons are prominent predictors of the neutral rate. Additionally, we demonstrate that the previously observed biphasic relationship between neutral rate and GC-content can be accounted for by properly combining rates at CpG and non-CpG sites. Finally, we find the neutral rate to be negatively correlated with the densities of several classes of computationally predicted functional elements, and less so with the densities of certain classes of experimentally verified functional elements. CONCLUSIONS: Our results suggest that while female recombination may be mainly responsible for driving evolution in GC-content, male recombination may be mutagenic, and that other mutagenic mechanisms acting near telomeres, and mechanisms whose effects are shared across mammalian genomes, play significant roles. We also have evidence that the nonlinear increase in rates at high GC levels may be largely due to hyper-mutability of CpG dinucleotides. Finally, our results suggest that the performance of conservation-based prediction methods can be improved by accounting for neutral rates.

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Lifting the veil on the transcriptome.

Publication Date: 2008 Apr 24 PMID: 18439328
Authors: Callahan, K. P. - Butler, J. S.
Journal: Genome Biol

ABSTRACT: Inhibition of the cellular RNA surveillance system in Arabidopsis thaliana results in the accumulation of thousands of transcripts arising from annotated and unannotated regions of the genome. This normally hidden transcriptome is replete with noncoding RNAs with the potential to regulate wide-ranging physiological activities.

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Genetic determinants of phenotypic diversity in humans.

Publication Date: 2008 Apr 24 PMID: 18439327
Authors: Rahim, N. G. - Harismendy, O. - Topol, E. J. - Frazer, K. A.
Journal: Genome Biol

ABSTRACT: New technologies for rapidly assaying DNA sequences have revealed that the degree and nature of human genetic variation is far more complex then previously realized. These same technologies have also resulted in the identification of common genetic variants associated with more than 30 human diseases and traits.

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Widespread duplications in the genomes of laboratory stocks of Dictyostelium discoideum.

Publication Date: 2008 Apr 22 PMID: 18430225
Authors: Bloomfield, G. - Tanaka, Y. - Skelton, J. - Ivens, A. - Kay, R. R.
Journal: Genome Biol

ABSTRACT: BACKGROUND: Duplications of stretches of the genome are an important source of individual genetic variation, but their unrecognized presence in laboratory organisms would be a confounding variable for genetic analysis. RESULTS: We report here that duplications of 15 kb or more are common in the genome of the social amoeba Dictyostelium discoideum. Most stocks of the axenic 'workhorse' strains Ax2 and Ax3/4 obtained from different laboratories can be expected to carry different duplications. The auxotrophic strains DH1 and JH10 also bear previously unreported duplications. Strain Ax3/4 is known to carry a large duplication on chromosome 2 and this structure shows evidence of continuing instability; we find a further variable duplication on chromosome 5. These duplications are lacking in Ax2, which has instead a small duplication on chromosome 1. Stocks of the type isolate NC4 are similarly variable, though we have identified some approximating the assumed ancestral genotype. More recent wild-type isolates are almost without large duplications, but we can identify small deletions or regions of high divergence, possibly reflecting responses to local selective pressures. Duplications are scattered through most of the genome, and can be stable enough to reconstruct genealogies spanning decades of the history of the NC4 lineage. The expression level of many duplicated genes is increased with dosage, but for others it appears that some form of dosage compensation occurs. CONCLUSIONS: The genetic variation described here must underlie some of the phenotypic variation observed between strains from different laboratories. We suggest courses of action to alleviate the problem.

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The complete genome, comparative and functional analysis of Stenotrophomonas maltophilia reveals an organism heavily shielded by drug resistance determinants.

Publication Date: 2008 Apr 17 PMID: 18419807
Authors: Crossman, L. C. - Gould, V. C. - Dow, J. M. - Vernikos, G. S. - Okazaki, A. - Sebaihia, M. - Saunders, D. - Arrowsmith, C. - Carver, T. - Peters, N. - Adlem, E. - Kerhornou, A. - Lord, A. - Murphy, L. - Seeger, K. - Squares, R. - Rutter, S. - Quail, M. A. - Rajandream, M. A. - Harris, D. - Churcher, C. - Bentley, S. D. - Parkhill, J. - Thomson, N. R. - Avison, M. B.
Journal: Genome Biol

ABSTRACT: BACKGROUND: Stenotrophomonas maltophilia is a nosocomial opportunistic pathogen of the Xanthomonadaceae. The organism has been isolated from both clinical and soil environments in addition to the sputum of cystic fibrosis patients and the immunocompromised. Whilst relatively distant phylogenetically, the closest sequenced relatives of S. maltophilia are the plant pathogenic xanthomonads. RESULTS: The genome of the bacteremia-associated isolate S. maltophilia K279a is 4,851,126 bp and of high G+C content. The sequence reveals an organism with a remarkable capacity for drug and heavy metal resistance. In addition to a number of genes conferring resistance to antimicrobial drugs of different classes via alternative mechanisms, nine resistance-nodulation-division (RND)-type putative antimicrobial efflux systems are present. Functional genomic analysis confirms a role in drug resistance for several of the novel RND efflux pumps. S. maltophilia possesses potentially mobile regions of DNA and encodes a number of pili and fimbriae likely to be involved in adhesion and biofilm formation that may also contribute to increased antimicrobial drug resistance. CONCLUSION: The panoply of antimicrobial drug resistance genes and mobile genetic elements found suggests that the organism can act as a reservoir of antimicrobial drug resistance determinants in a clinical environment, which is an issue of considerable concern.

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Erect wing regulates synaptic growth in Drosophila by integration of multiple signaling pathways.

Publication Date: 2008 Apr 17 PMID: 18419806
Authors: Haussmann, I. U. - White, K. - Soller, M.
Journal: Genome Biol

ABSTRACT: BACKGROUND: Formation of synaptic connections is a dynamic and highly regulated process. Little is known about the gene networks that regulate synaptic growth and how they balance stimulatory and restrictive signals. RESULTS: Here we show that the neuronally expressed transcription factor gene ewg is a major target of the RNA binding protein ELAV and that EWG restricts synaptic growth at neuromuscular junctions. Using a functional genomics approach we demonstrate that EWG acts primarily through increasing mRNA levels of genes involved in transcriptional and post-transcriptional regulation of gene expression, while genes at the end of the regulatory expression hierarchy (effector genes) represent only a minor portion, indicating an extensive regulatory network. Among EWG-regulated genes are components of Wingless and Notch signaling pathways. In a clonal analysis we demonstrate that EWG genetically interacts with Wingless and Notch, and also with TGF-beta and AP-1 pathways in the regulation of synaptic growth. CONCLUSIONS: Our results show that EWG restricts synaptic growth by integrating multiple cellular signaling pathways into an extensive regulatory gene expression network.

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