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On Mondays, the lab meetings are held in the Silver Room, bld 13 floor 0, while on Fridays in the Golden Room, bld 13 floor 2

Campus Meetings

• SEMMinars

• Bioinfo Seminars

• Wednesday_Seminars.pdf

DECEMBER 2007

Dec 02 PLoS Comp Biol Dec.07

Alekseyev & Pevzner Are There Rearrangement Hotspots in the Human Genome? PLoS Comput Biol 3(11): e209

• The random breakage model (RBM) of chromosome evolution postulates that there are no rearrangement hotspots in the human genome.
• The fragile breakage model (FBM) postulates that the human genome is a mosaic of solid regions (with low propensity for rearrangements) and fragile regions (rearrangement hotspots).
• It remains unclear whether some complex rearrangements (e.g., transpositions) can create an appearance of rearrangement hotspots.
• The paper reports the analysis of multi-break rearrangements that break a genome into multiple fragments and further glue them together in a new order.
• It demonstrates that (1) even if transpositions were a dominant force in mammalian evolution, the arguments in favor of FBM still stand, and (2) the “gene deletion” argument against FBM is flawed.

NOVEMBER 2007

Nov 26 Molecular Systems Biology Nov.07

H. Kitano Towards a theory of biological robustness Molecular Systems Biology 3: 137 DAVIDE

Nov 26 Nature Reviews Molecular Cell Biology Dec. 07

Lee D. et al. (Orengo), Predicting protein function from sequence and structure ature Reviews Molecular Cell Biology 8, 995-1005 FEDERICO

OCTOBER 2007

Oct 22 Nature Mar. 07

Greenman C. et al. (Stratton), Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8.

• 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers.
• substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins.
• evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes.

SEPTEMBER 2007

Sep 17 Bioinformatics Sep.07

• Reid A (C.Orengo) Methods of remote homology detection can be combined to increase coverage by 10% in the midnight zone Bioinformatics 2007 23(18):2353-2360 FEDERICO

  • Benchmark of remote homology detection methods.

Sep 06:Literature Digest: PLoS Biol Sep 07

• Ahituv N (E.Rubin) Deletion of Ultraconserved Elements Yields Viable Mice

  • Four ultraconserved elements —sequences of 200 base pairs or longer that are 100% identical among human, mouse, and rat— were removed from the mouse genome.
  • The mice lacking these elements are viable, fertile, and show no apparent abnormalities.

Sep 05: Literature Digest: Genome Res Sep 07

• Lin J (Velculescu) A multidimensional analysis of genes mutated in breast and colorectal cancers Genome Res. 17:1304-1318, 2007 DAVIDE

  • Systems biology approach to characterize 1149 cancer genes

  • SEQUENCE ANALYSIS: breast and colorectal cancers shared many common clusters, including zinc finger proteins, cadherins, and genes involved in cell adhesion and signal transduction.
  • FUNCTIONAL ANNOTATION: All mutated genes resulted in similar compositions of functional categories for both breast and colorectal cancers, with the two largest comprising signal transduction and metabolism.
  • PROTEIN INTERACTIONS: mutant proteins interacted with more partners than typical human proteins.
  • PATHWAY ANALYSIS: 21 pathways were identified to be enriched for mutations from the different pathway databases in colorectal cancer, partly different from breast.

• Dumas L et al. Gene copy number variation spanning 60 million years of human and primate evolution Genome Res. 17:1266-1277, 2007

  • Application of cDNA array-based comparative genomic hybridization (aCGH) to survey gene duplications and losses genome-wide across 10 primate species

  • 4159 genes were identified that likely represent most of the major lineage-specific gene copy number gains and losses that have occurred over the past 60 million years.
  • Many of the genes identified here are likely to be important to lineage-specific traits

Sep 03: Literature Digest: PLoS Comp Biol Sep 07

• Cédric Notredame Recent Evolutions of Multiple Sequence Alignment Algorithms PLoS Comput Biol 3(8): e123 FEDERICO

  • Review on the developments of MSA.

AUGUST 2007

Aug 29: Literature Digest: Genome Res Adv Art

• Fiston-Lavier AS A model of segmental duplication formation in Drosophila melanogaster ANNA

  • A model for SD formation is proposed named "duplication-dependent strand annealing" (DDSA).
  • The DDSA model predicts that after a double strand break, the search for an ectopic homologous region—here a repeat—initiates the repair.
  • The analysis of SDs detected by a computational analysis of the D. melanogaster genome indicates a high enrichment in transposable elements at SD ends.
  • The model has the advantage of also predicting specific traces left during synthesis.

Aug 23: Literature Digest: Nature Rev Genetics Aug 2007

• Eyre-Walker & Keightley The distribution of fitness effects of new mutations Nature Reviews Genetics 8, 610-618

  • The distribution of fitness effects (DFE) describes what proportion of new mutations are advantageous, neutral or deleterious.
  • It has important implications ranging from the genetic basis of complex disease to the stability of the molecular clock.
  • This study reports the results of 2 different approaches to determine DFE: mutation accumulation and mutagenesis experiments, and the analysis of DNA sequence data.
  • The shape of the DFE varies between species and depends on factors such as population size and genome size.
  • The DFE differs between coding and non-coding DNA.
  • Advantageous mutations are rare.
  • The DFE of strongly advantageous mutations has an exponential distribution.
  • The DFE of deleterious mutations is a complex, multi-modal distribution.

Aug 19: Literature Digest: Science 317 Aug 2007

• Katzman Sol (Haussler) Human Genome Ultraconserved Elements Are Ultraselected Science Vol. 317 p 915 ANNA

  • The derived (new) allele frequency (DAF) spectrum for the segregating human polymorphisms in the ultraconserved regions is markedly shifted toward rare derived alleles, as is characteristic of regions under negative selection.
  • The Bayesian posterior distributions show that ultraconserved sites are under purifying selection that is three times greater than that acting on nonsynonymous sites.

• Ambrosini A. et al. Human Subtelomeric Duplicon Structure and Organization Genome Biology 2007, 8:R151 ANNA

  • The study reports a systematic analysis of the duplication substructure of human subtelomeric regions.
  • (TTAGGG)n-like tracts occur at duplicon boundaries, suggesting their involvement in the generation of the complex sequence organization.
  • Identification of a class of duplicon blocks that are subtelomere-specific useful for high-resolution analysis of subtelomere repeat copy number variation as well as studies involving somatic subtelomere rearrangements.

• Wellner A. et al. Complexity, connectivity, and duplicability as barriers to lateral gene transfer Genome Biology 2007, 8:R156 DAVIDE

  • The relationship between lateral gene transfer and gene duplicability is estimated.
  • High complexity and connectivity generally do not impede gene transfer.
  • Essential genes that exhibit low duplicability and high connectivity do exhibit mostly vertical descent.

JUNE 2007

Jun 28: Literature TiBS Jun 2007

• Lu Lj (Gerstein) Comparing classical pathways and modern networks: towards the development of an edge ontology doi:10.1016/j.tibs.2007.06.003 DAVIDE

  • Combination of high-throughput data and pathway information for network studies

Jun 27: Literature Digest Genome Biology Jun 2007

• Bird CP (Dermitzakis ET group) Fast-evolving non-coding sequences in the human genome. Genome Biol. 2007 Jun 19;8(6):R118 ANNA

  • 1356 conserved non-coding sequences that appear to have undergone dramatic human-specific changes in selective pressures, at least 15% of which have substitution rates significantly above that expected under neutrality.
  • 1356 'accelerated CNCs' (or ANCs) are enriched in recent segmental duplications suggesting a recent change in selective constraint following duplication.
  • SNPs within ANCs have a significant excess of high frequency derived alleles and high FST values relative to controls indicating that acceleration and positive selection are recent in human populations.
  • a significant number of SNPs within ANCs are associated with changes in gene expression.

CONCLUSION: Our analysis suggests that ANC sequences have until very recently played a role in human evolution, potentially through lineage-specific changes in gene regulation.

Jun 20: Literature Digest Plos Biol Jun 2007

• Bertin N (M.Videl) Confirmation of Organized Modularity in the Yeast Interactome PLoS Biol 5(6): e153 DAVIDE

  • Analysis of the yeast protein-protein interaction network on the basis of new data
  • Confirmation of the different features of 'party' and 'date' hubs

  • Against Batada et al. (Plos 2006) who criticized that distintion (to be checked)

Jun 10: Literature Digest Plos One Jan 2007

• Yoshihama M, Nguyen HD, Kenmochi N. "Intron dynamics in ribosomal protein genes." PLoS ONE. 2007 Jan 3;2:e141. ANNA

  • maximum likelihood method to reconstruct the evolution of 2,961 introns in a dataset of 76 ribosomal protein genes from 22 eukaryotes and validated the results by a maximum parsimony method.
  • results show that the trends of intron gain and loss differed across species in a given kingdom but appeared to be consistent within subphyla.
  • most subphyla in the dataset diverged around 1 billion years ago, when the "Big Bang" radiation occurred. We speculate that spliceosomal introns may play a role in the explosion of many eukaryotes at the Big Bang radiation.

Jun 04: Literature Digest PLoS Comp Biol Jun 2007

• Wang Z. and Zhang J. In Search of the Biological Significance of Modular Structures in Protein Networks PLoS Comput Biol 3(6): e107 DAVIDE

  • Many complex networks are naturally divided into communities or modules, where links within modules are much denser than those across modules.
  • It is interesting to ask whether this modularity in cellular function arises from modularity in molecular interaction networks such as the transcriptional regulatory network and protein–protein interaction (PPI) network.
  • The analysis of the yeast PPI network shows that it is indeed significantly more modular than randomly rewired networks.
  • However, there is little evidence that the structural modules correspond to functional units.
  • There is no evolutionary conservation among yeast, fly, and nematode PPI modules.

  • Modular structures can arise during network growth via a simple model of gene duplication, without natural selection for modularity.

  • It appears that the structural modules in the PPI network may have originated as an evolutionary byproduct without much biological significance.

MAY 2007

MAY 21: Literature Digest PNAS May 2007

Goh KI (Vidal,Barabasi) The human disease network PNAS 104, 8685-8690 DAVIDE

• Genes associated with similar disorders show:
  • higher likelihood of physical interactions between their products
  • higher expression profiling similarity for their transcripts
• This supports the existence of distinct disease-specific functional modules.
• Essential human genes are likely to encode hub proteins and are expressed widely in most tissues.

• The vast majority of disease genes are nonessential and show no tendency to encode hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network.

• Diseases caused by somatic mutations should not be peripheral, a prediction we confirm for cancer genes.

MAY 19: Literature Digest Mol Biol Evol. May 2007

• Roy SW and Penny D. "On the Incidence of Intron Loss and Gain in Paralogous Gene Families." Mol Biol Evol. May 2007 (Epub ahead of print) ANNA

  • Understanding gene duplication and gene structure evolution are fundamental goals of molecular evolutionary biology. A previous study (Babenko et al. 2004. Prevalance of intron gain over intron loss in the evolution of paralogous gene families. Nucleic Acids Res. 32: 3724-3733) utilized Dollo parsimony to infer spliceosomal intron losses and gains in paralogous gene families, and concluded that there was a general excess of gains over losses.

  • This result contrasts with patterns in orthologous genes, in which most lineages show an excess of intron losses over gains, suggesting the possibility of fundamentally different modes of intron evolution between orthologous and paralogous genes.

  • We further studied the data and found a low level of intron position conservation with outgroups, leading to problems with using Dollo parsimony to analyze the data. Statistical reanalysis of the data suggests instead that intron losses have outnumbered intron gains in paralogous gene families.

MAY 18: Literature Digest Nature Reviews Genetics Jun 07

• Uri Alon Network motifs: theory and experimental approaches Nature Reviews Genetics 8, 450-461 DAVIDE

  • Transcription regulation networks seem to be built of a few regulatory patterns called network motifs.
  • Each network motif can carry out defined information-processing functions.

  • Negative autoregulation can speed up responses and reduce fluctuations, whereas positive autoregulation slows responses and increases variations.

  • Coherent feedforward loops can show persistence detection, whereas incoherent feedforward loops show pulse generation and response acceleration.

  • Single-input modules can generate temporal programmes of expression.
  • Dense overlapping regulons can act as arrays of gates for combinatorial decision making.
  • Network motifs in systems that have been studied experimentally so far seem to be wired together in a 'modular' way that allows us to understand the dynamics of each individual motif, even when it is connected to the rest of the network.
  • Evolution seems to have converged on the same motifs in different systems and different organisms, suggesting that they are selected for again and again on the basis of their biological functions.
  • Other biological networks, such as signalling and neuronal networks, also show network motifs, some of which are similar to the motifs that are found in transcription networks.

MAY 10: Literature Digest Genome Res Adv Art

• L.Carmel, et al. (Koonin) Three distinct modes of intron dynamics in the evolution of eukaryotes ANNA

  • A comprehensive probabilistic model to obtain a definitive reconstruction of intron evolution was developed and applied to 391 sets of conserved genes from 19 eukaryotic species.

  • This model reports that a relatively high intron density was reached early, i.e., the last common ancestor of eukaryotes contained >2.15 introns/kilobase, and the last common ancestor of multicellular life forms harbored ~3.4 introns/kilobase.

  • The rates of intron gain and intron loss appear to have been dropping during the last ~1.3 billion years, with the decline in the gain rate being much steeper.
  • Eukaryotic lineages exhibit three distinct modes of evolution of the intron–exon structure.

  • The balanced mode operates in all lineages: intron gain and loss are strongly and positively correlated.

  • The second mode involves an elevated rate of intron loss and is prevalent in several lineages, such as fungi and insects.

  • The third mode, characterized by elevated rate of intron gain, is seen only in deep branches of the tree, indicating that bursts of intron invasion occurred at key points in eukaryotic evolution, such as the origin of animals.

• L.Carmel, et al. (Koonin) Evolutionarily conserved genes preferentially accumulate introns ANNA

  • The same probabilistic model as in the paper above was used to assign intron gain and loss rates to individual genes.
  • A gene’s intron gain rate shows a highly significant negative correlation with the coding-sequence evolution rate.
  • The intron loss rate also significantly, but positively, correlates with the sequence evolution rate.
  • Correlations of the opposite signs, albeit less significant ones, are observed between intron gain and loss rates and gene expression level.
  • The increased intron gain and decreased intron loss in evolutionarily conserved genes indicate that intron insertion often might be adaptive, whereas some of the intron losses might be deleterious.

MAY 2: Literature Digest Genome Biol May 07

• I.Tirosh & N.Barkai Comparative analysis indicates regulatory neofunctionalization of yeast duplicates Genome Biology 2007, 8:R50

  • Study on the divergence of gene duplicates through the comparison of expression profiles.
  • The expression profiles of Saccharomyces cerevisiae duplicate pairs were compared with those of their pre-duplication orthologs in Candida albicans.
  • Duplicate pairs were classified into two classes, corresponding to symmetric versus asymmetric rates of expression divergence.
  • The latter class may present cases of regulatory neofunctionalization, as supported also by their dispensability and variability.
  • The asymmetry of gene sequence evolution and the asymmetry of gene expression evolution are only weakly correlated.

• Pereira-Leal JB (Teichmann) Evolution of protein complexes by duplication of homomeric interactions Genome Biology 2007, 8:R51 DAVIDE

  • This study investigates the evolutionary origins of protein complexes, modules in physical protein-protein interaction networks.
  • The duplication of homomeric interactions, a large class of protein interactions, frequently results in the formation of complexes of paralogous proteins.
  • These conclusions are further confirmed by theoretical modelling of network evolution.

MAY 1: Literature Digest Plos Comp Biol May 07

• Philip Bourne Ten Simple Rules for Making Good Oral Presentations PLoS Comput Biol 3(4): e77

  • Rule 1: Talk to the Audience

  • Rule 2: Less is More

  • Rule 3: Only Talk When You Have Something to Say

  • Rule 4: Make the Take-Home Message Persistent

  • Rule 5: Be Logical

  • Rule 6: Treat the Floor as a Stage

  • Rule 7: Practice and Time Your Presentation

  • Rule 8: Use Visuals Sparingly but Effectively

  • Rule 9: Review Audio and/or Video of Your Presentations

  • Rule 10: Provide Appropriate Acknowledgments

APRIL 2007

APR 12: Literature Digest Nature 446

• Mullighan CG Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia Nature 446, 758-764 DAVIDE

  • Genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing, to identify cooperating oncogenic lesions.

  • The analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation.
  • The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases.
  • Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS).
  • These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis.

• Collins SR Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map Nature 446, 806-810

  • Even knowing the stoichiometry of protein complexes, affinity and lifetime of every protein–protein interaction would not reveal the functional relationships between and within such complexes.

  • This study presents an epistatic miniarray profile (E-MAP) consisting of quantitative pairwise measurements of the genetic interactions between 743 Saccharomyces cerevisiae genes involved in various aspects of chromosome biology.

  • This E-MAP reveals that physical interactions fall into two well-represented classes distinguished by whether or not the individual proteins act coherently to carry out a common function.
  • Examples of new acethyltransferase pathways are provided

MARCH 2007

MAR 29: Literature Digest Nature 446

• Uri Alon Simplicity in Biology Nature 446, 497 DAVIDE

  • Essay on the role of networks to understand shared principles of biological systems

MAR 26: Literature Digest Nature Rev Cancer Apr 07

• Mitelman F. et al. The impact of translocations and gene fusions on cancer causation Nature Reviews Cancer 7, 233-245

  • Chromosome aberrations are a characteristic feature of neoplasia, and acquired chromosome changes have now been reported in more than 50,000 cases across all main cancer types.
  • Recurrent balanced chromosome rearrangements, in particular translocations, are strongly associated with distinct tumour entities, and there is compelling evidence that they represent an initial event in oncogenesis.
  • Balanced chromosome abnormalities result in the formation of gene fusions and exert their tumorigenic action by two alternative mechanisms: overexpression of a gene in one of the breakpoints or the creation of a hybrid gene through the fusion of two genes, one in each breakpoint.
  • A total of 358 gene fusions, involving 337 different genes, are known at present and have been described in all the main subtypes of human neoplasia.
  • The prevalence of gene fusions varies considerably, from 0–100%, among different tumour types. Among malignant disorders, the proportions of gene fusion-positive cases are similar in haematological disorders, sarcomas and carcinomas.

MAR 23: Literature Digest Nature Rev Mol Biol Apr 07

• Han JH (S.Teichmann) et al. The folding and evolution of multidomain proteins Nature Reviews Molecular Cell Biology 8, 319-330 2007 FEDERICO

  • Multidomain proteins account for over 50% of the proteome (over 70% in eukaryotes), yet the vast majority of folding studies focus on individual domains.
  • Single-domain folding studies have identified some broad principles, however only a small fraction of the fold space has been studied. Over half of the individual domains studied have been extracted from multidomain proteins.
  • The SCOP (Structural Classification of Proteins) and SUPERFAMILY databases have been used to identify and classify domain architecture in many genomes.
  • Analysis of three-dimensional protein structures has revealed general features of the domain structure of multidomain proteins, including the extent to which domain interface geometry is conserved and the structural characteristics of domain interfaces.
  • The few multidomain-folding studies completed so far are summarized and some general features of multidomain-protein folding emerge from this limited data set: large, dense interfaces correlate with folding dependence between domains, although there are exceptions.
  • There are many mechanisms that multidomain proteins use to protect themselves from the high local domain concentrations and to avoid misfolding.

MAR 21: Literature Digest Bioinformatics Mar 07

• Futschik ME. et al. Comparison of human protein–protein interaction maps Bioinformatics 2007 23(5):605-611 DAVIDE

  • The goal is to assess the quality of the available data on human interactome.

  • Eight large-scale maps with a total of over 10 000 unique proteins and 57 000 interactions included were analyzed.
  • The comparison reveals only a small, but statistically significant overlap.
  • The analysis gives clear indications that all interaction maps imply considerable selection and detection biases.
  • These results have to be taken into account for future assembly of the human interactome.

MAR 13: Literature Digest Genome Biol Mar 07

• Díaz-Mejía JJ. et al. A network perspective on the evolution of metabolism by gene duplication Genome Biology 2007, 8:R26 DAVIDE

  • The authors used a network based approach to determine the influence of metabolic constraints on the retention of duplicated genes.
  • The results uncover an increased retention of duplicates between reactions catalyzing consecutive reactions.
  • As a consequence, metabolic networks show a high retention of duplicates within functional modules.

• Lev-Maor G. et al. RNA-editing-mediated exon evolution Genome Biology 2007, 8:R29

  • Through mutations that create functional splice sites within intronic Alus, these elements can become new exons in a process denoted exonization.
  • The authors show that the human Nuclear prelamin A Recognition Factor (NARF) contains a primate-specific Alu-exon that exclusively depends on RNA editing for its exonization.

MAR 08: Literature Digest Nature 446

• Greenman C. et al. (CGC group) Patterns of somatic mutation in human cancer genomes Nature 446, 153-158 DAVIDE

  • Report of the systematic resequencing of cancer genomes searching for mutations.
  • A substantial variation in the number and pattern of mutations in individual cancers was found, reflecting different exposures, DNA repair defects and cellular origins.
  • Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis.
  • There was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes.

MAR 02: Literature Digest Genome Res March 2007

• Hurle B. et al. (E.Green) Comparative sequence analyses reveal rapid and divergent evolutionary changes of the WFDC locus in the primate lineage Genome Research 17:276-286, 2007

  • One of the regions of human genome undergoing fast evolution in respect to chimp contains genes that encode whey acidic protein (WAP) domain protease inhibitors and resides on chromosome 20q13.
  • This paper reports the map and sequencing of the centromeric WFDC sublocus in 12 primate species that collectively represent four different mating systems.
  • The analyses reveal a 130-kb region with a notably complex evolutionary history that has included nested duplications, deletions, and significant interspecies divergence of both coding and noncoding sequences; together, this has led to striking differences of this region among primates and between primates and rodents.
  • Further, this region contains six closely linked genes (WFDC12, PI3, SEMG1, SEMG2, SLPI, and MATN4) that show strong patterns of adaptive selection, although an unambiguous correlation between gene mutation rates and mating systems could not be established.

FEBRUARY 2007

FEB 16: Literature Digest PLoS Biology Feb 2007

• Wang HY et al. Rate of Evolution in Brain-Expressed Genes in Humans and Other Primates PLoS Biol 5(2): e13

  • The human brain has evolved rapidly relative to that of other primates. However, the extent to which genes expressed in the brain also reflect this overall pattern is unclear.
  • To address this question, it's necessary to measure any variations in the DNA sequences of these genes between human and chimpanzee. And, to do this as accurately as possible, it's also important to require an appropriate reference group to act as a benchmark against which the differences can be measured.

  • This paper reports the comparison of publicly available genomic sequences of chimps and humans with genes expressed in the brain of macaque as well as the more distantly related mouse.

  • The analyses of the rates of protein evolution in these species suggest that genes expressed in the human brain have in fact slowed down in their evolution since the split between human and chimpanzee.
  • The authors suggest that advanced brains are driven primarily by the increasing complexity in the network of gene interactions.

* Parmley JL et al. (L.Hurst) Splicing and the Evolution of Proteins in Mammals PLoS Biol 5(2): e14 Irene

• The parts of the exons near the intron–exon boundary can function as splice enhancer elements. In principle they have two functions: to specify the amino acids of the resulting protein and to enable the correct removal of introns. What impact might this have on a gene's evolution?

• This report shows that near intron–exon boundaries, amino acid usage is biased towards nucleotides involved in splice control and that these parts of genes evolve especially slowly.
• The authors estimate that a gene with many exons would evolve at under half the rate of the same gene with no introns, simply owing to the need to specify where to remove introns.
• Likewise, genes that have lost their introns evolve especially fast near the former intron's location.

FEB 09: Literature Digest Science 315/5813

• Strange BE et al. (M.Dermitzakis) Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes Science Vol. 315. no. 5813, pp. 848 - 853

  • To determine the overall contribution of CNVs to complex phenotypes, association analyses of expression levels of 14,925 transcripts with SNPs and CNVs have been performed in individuals who are part of the International HapMap project.

  • SNPs and CNVs captured 83.6% and 17.7% of the total detected genetic variation in gene expression.
  • However, the signals from the two types of variation had little overlap.

FEB 01: Literature Digest Mol Biol Evol Feb 07

• Alvarez-Venegas R et al. Origin of the Bacterial SET Domain Genes: Vertical or Horizontal? MBE, 24, 482 Irene

  • Evolutionary analysis of the origin of the SET domain

JANUARY 2007

JAN 29: Literature Digest Plos Genetics Feb 07

• Nikolaev S et al. Early History of Mammals Is Elucidated with the ENCODE Multiple Species Sequencing Data PLoS Genet 3(1): e2

  • ENCODE data to infer the phylogeny of Mammals

  • Concatenatenation of coding sequence data from 218 genes encompassing 205 kilobases of DNA sequence in 18 mammals.
  • Phylogenetic analyses have shown Afrotheria (Elephant) as a basal group of Placentalia with high statistical support.
  • Further analysis using conserved noncoding sequence alignments (430 kilobases) resulted in the same position of the placental root.
  • Topological tests rejected the possibility of Afrotheria-Xenarthra grouping with the coding sequence dataset and Boreoeutheria-Afrotheria grouping with the noncoding sequence dataset.

• Graubert TA et al. EA High-Resolution Map of Segmental DNA Copy Number Variation in the Mouse Genome PLoS Genet 3(1): e3

  • Characterization of 80 CNVs across the genomes of 21 inbred strains of mice.

  • These CNVs are located near another class of genomic features, segmental duplications, more often than would be expected by chance.
  • This supports the hypothesis that CNVs and segmental duplications are causally linked.
  • Importantly, many of the CNVs contain known genes and thus may underlie both gene expression and phenotypic variation between strains.

• Hultman KA et al. Gene Duplication of the Zebrafish kit ligand and Partitioning of Melanocyte Development Functions to kit ligand a PLoS Genet 3(1): e17 Irene

  • Report on the duplication of the kit ligand gene in zebrafish and on the coevolution of the ligands, kitla.

JANUARY 2007

JAN 04: Literature Digest Plos Comp. Biol. Jan 07

• Qi Y & Ge H Modularity and Dynamics of Cellular Networks LoS Comput Biol 2(12): e174 Davide

  • Review on the recent progress of the analysis of the architecture and dynamics of cellular networks.

JAN 04: Literature Digest Genome Res. Jan 07

• Coulombe-Huntington J. and Majewski J Characterization of intron loss events in mammals Genome Research 17:23-32, 2007 Cinzia

  • Genome-wide analysis of intron loss and gain events in >17,000 mammalian genes by whole-genome sequence alignments of human, mouse, rat, and dog.

  • No evidence for intron gain and 122 cases of intron loss, most of which occurred within the rodent lineage, were found.

  • The majority (68%) of the deleted introns were extremely small (<150 bp), significantly smaller than average.

  • The intron losses occurred almost exclusively within highly expressed, housekeeping genes, supporting the hypothesis that intron loss is mediated via germline recombination of genomic DNA with intronless cDNA.

• Chen F-C et al. Human-specific insertions and deletions inferred from mammalian genome sequences Genome Research 17:16-22, 2007

  • Systematic analysis of small indels (i.e., indels ≤ 100 bp) between human and chimp.

  • Identification of >840,000 "small" indels, which affect >7000 UCSC-annotated human genes (>11,000 transcripts).

  • Only ~0.21% sequence change in the human lineage for the regions compared, whereas in pseudogenes indels contribute to a sequence divergence of 1.40%, suggesting that most of the indels that occurred in genic regions have been eliminated.

DECEMBER 2006

DEC 22: Literature Digest Nature Review Cancer December 2006

• Merlo LMF et al. Cancer as an evolutionary and ecological process Nature Reviews Cancer 6, 924-935

  • Neoplasms are composed of an ecosystem of evolving clones, competing and cooperating with each other and other cells in their microenvironment.
  • Selection at the different levels of genes, cells and organisms might conflict, and have resulted in a legacy of tumour-suppression mechanisms and vulnerability to oncogenesis.
  • Most of the dynamics of evolution have not been measured in neoplasms, including mutation rates, fitness effects of mutations, generation times, population structure, the frequency of selective sweeps and the selective effects of our therapies.
  • Many of the genetic and epigenetic alterations observed in neoplasms are evolutionarily neutral.

DEC 22: Literature Digest Science 314-5807

• BREAKTHROUGH OF THE YEAR: The Runners-Up

  1. The Poincaré Conjencture--Proved: The work of the Russian mathematician Grigori Perelman on n-dimensional geometry solved the the mathematical study of abstract shape.

  2. Digging out fossil DNA: The studies on Neandertal DNA concluded that Neandertals diverged from our own ancestors at least 450,000 years ago, and one group's data also suggest that Neandertals and modern humans may have interbred.

• BREAKTHROUGH OF THE YEAR: Scientific Fraud: Multiple inquiries discredited two papers Hwang published in Science in 2004 and 2005, which claimed some of the greatest accomplishments to date with human embryonic stem cells. The papers were retracted. Five scientists and a top editor of Nature examined Science's handling of the Hwang papers, at the journal's request. Their report, published on Science's Web site earlier this month, concluded that operating in an atmosphere of trust is no longer sufficient.

• BREAKTHROUGH OF THE YEAR: Areas to Watch in 2007:

  1. Loads of new primate genes. The comparative analysis of several Primate genomes might finally begin to explain what sets humans apart.

  2. Whole-genome association studies. Studies comparing the genomes of healthy people to those of the sick may offer real insight into how diseases germinate

• Venkatesh B (S.Brenner) Ancient Noncoding Elements Conserved in the Human Genome Science, 314, p. 1892 Cinzia

  • Identification of ancient vertebrate CNEs by comparison of genome sequences of a cartilaginous fish, the elephant shark (Callorhinchus milii), with the human genome.
  • The generation of ~1.4x sequence coverage of the elephant shark genome and its comparison with the human genome identified 4782 CNEs with the use of discontiguous MegaBLAST.
  • BLASTN search (e-value cutoff at 1 x 10–5) of the CNEs against Ciona, fruit fly, and nematode worm genomes indicated that nearly all of them (with the exception of six CNEs that show similarity to Ciona or fly sequences) are specific to vertebrates.

• Kim PM (M.Gerstein) Relating Three-Dimensional Structures to Protein Networks Provides Evolutionary Insights Science, 314, p.1938 Davide

  • Characterization of interactions by using atomic-resolution information from three-dimensional protein structures.
  • Some previously recognized relationships between network topology and genomic features (e.g., hubs tending to be essential proteins) are actually more reflective of a structural quantity, the number of distinct binding interfaces.
  • Subdividing hubs with respect to this quantity provides insight into their evolutionary rate and indicates that additional mechanisms of network growth are active in evolution

NOVEMBER 2006

NOV 28: Literature Digest PLoS Genetics November 2006

• Gaffney DJ & Keightley PD Genomic Selective Constraints in Murid Noncoding DNA PLoS Genetics 2(11): e204 cinzia UCRs

  • The quantity and location of functional noncoding DNA in mice and rats have been studied.

  • The resulting estimation is that functional noncoding DNA is at least three times as common as coding DNA in rodents, and the majority is located large distances from known protein-coding genes.
  • Functional intronic DNA tends to be clustered towards the gene 5′ end, suggesting that much intronic sequence is instrumental in regulating gene expression.
  • This study also finds that genes involved in development and the nervous system are typically associated with much higher quantities of functional noncoding DNA, suggesting that these genes require more finely tuned control of their expression.
  • One implication of this study is the finding that disease-causing mutations have occurred more frequently in noncoding regions and may have affected gene expression, rather than protein structure.

  • Stadler MB (C.Burge) Inference of Splicing Regulatory Activities by Sequence Neighborhood Analysis PLoS Genetics 2(11): e191 cinzia SD

    • To better understand the sequences in exons that regulate the process of intron splicing, the authors have developed a method (Neighborhood Inference) that predicts the splicing regulatory activity of RNA segments based on the known splicing enhancer or silencer activity of other segments that have closely neighboring sequences.

    • The method exploits the observation that the sites bound by DNA- and RNA-binding proteins tend to cluster tightly in sequence space

    • A number of the obtained predictions were validated experimentally, indicating that the number of exonic splicing regulatory sequences is larger than previously suspected.
    • Neighborhood Inference scoring is also used to show that selection on exonic splicing enhancers (ESEs) frequently allows conversion of one ESE sequence to another over evolutionary time periods.
    • This suggests that ESEs can be interchangeable in constitutively spliced exons.

NOV 03: Literature Digest Science 314

• Prabhakar S (Paabo&Rubin) Accelerated Evolution of Conserved Noncoding Sequences in Humans Science (2006) 314, p. 786

  • Identification of 992 conserved noncoding sequences (CNSs) with a significant excess of human-specific substitutions.
  • These accelerated elements were disproportionately found near genes involved in neuronal cell adhesion.
  • The accelerated CNSs were identified through a statistical test that evaluated the likelihood of observing the configuration of human-specific substitutions present in a given CNS.
  • Each CNS was assigned a human-acceleration P value based on the probability of observing a configuration of equal or smaller likelihood under the null model of constrained evolution.
  • The cellular component GO term most significantly enriched in accelerated CNSs was basal lamina and cell adhesion was the only biological process displaying a significant excess of CNSs accelerated in human.
  • To determine whether the pattern of CNS acceleration in humans was recapitulated in other lineages, accelerated CNSs in chimpanzee and mouse were identified
  • 1050 accelerated CNSs were identified in chimpanzee, only 34 of which were also accelerated in human, indicating a general lack of overlap

NOV 02: Literature Digest Nature 444

• Islam and Science

  • Special issue of Nature dedicate to the relation between Islam and science.

  • An important point is made to cross the difference between the Islam principle of Seek knowledge, even as far as China" and the Seek knowledge, even as far as China"

  • The tension between support for science and restrictions on expression is one thread that runs through the entire special issue together with the contrast between the lack of interest in science displayed by wealthy Arab states and the development of a novel scientific thought in Muslim states of east Asia and Africa.

• Rex Dalton Ethiopian plan for Lucy tour splits museums Nature 444, 8 News

  • Few have seen the Lucy remains, found in 1974 and named after the song Lucy in the Sky with Diamonds by The Beatles.
  • The skeleton, which is 40% complete, is kept in a vault in the basement of the Ethiopian National Museum in Addis Ababa.
  • On 24 October, Ethiopian government officials announced an agreement with the Houston Museum of Natural Science to exhibit Lucy's skeleton and nearly 200 other artefacts, beginning in September 2007.
  • Details of the Lucy tour, including where it will appear and how much money Ethiopia will get, are unclear.
  • If palaeoanthropologists agree on anything, it is that original fossils should not travel, to keep them safe and available for research.

• Bourlat SJ Deuterostome phylogeny reveals monophyletic chordates and the new phylum Xenoturbellida Nature 444, 85-88

  • Deuterostomes comprise vertebrates, the related invertebrate chordates (tunicates and cephalochordates) and three other invertebrate taxa: hemichordates, echinoderms and Xenoturbella. T
  • Recent phylogenetic studies have indicated that urochordates might be the closest invertebrate sister group of vertebrates, rather than cephalochordates, as traditionally believed.
  • This paper reports an alignment of more than 35,000 homologous amino acids, including new data from a hemichordate, starfish and Xenoturbella, together with the sequencing of the mitochondrial genome of Xenoturbella.
  • The analysus supports the clades Olfactores (urochordates and vertebrates) and Ambulacraria (hemichordates and echinoderms), but not not a cephalochordate and echinoderm grouping hence concluding that chordates are monophyletic.

• Kämper J Insights from the genome of the biotrophic fungal plant pathogen Ustilago maydis Nature 444, 97-101

  • Ustilago maydis is a ubiquitous pathogen of maize and belongs to the group of biotrophic parasites (the smuts) that depend on living tissue for proliferation and development.
  • The 20.5-million-base U. maydis genome assembly contains 6,902 predicted protein-encoding genes and lacks pathogenicity signatures found in the genomes of aggressive pathogenic fungi, for example a battery of cell-wall-degrading enzymes.
  • 12 clusters of genes encoding small secreted proteins with unknown function were found.
  • Expression analysis showed that most of the genes contained in these clusters are regulated together and induced in infected tissue.
  • Deletion of individual clusters altered the virulence of U. maydis in five cases.

OCTOBER 2006

Oct 18: Literature Digest PLoS Comp Biol Nov 06

• Cowperthwaite MC From Bad to Good: Fitness Reversals and the Ascent of Deleterious Mutations PLoS Comp Biol 2(10): e141

  • Most random mutations are deleterious and it is generally assumed that mutations that start bad stay bad.
  • It may be possible, however, for an initially bad mutation to become good (beneficial) by interacting with subsequent mutations. In this study, Cowperthwaite, Bull, and Meyers show that such “fitness reversals” are surprisingly common and can lead to the fixation of initially deleterious mutations. Perhaps mutations that undergo such changes serve as stepping stones for greater evolutionary progress.

Oct 19: Literature Digest Nature 443, 733

• Heidi Ledford Kudos, not cash, is the real X-factor? News Nature 443, 733.

  • The Archon X Prize for Genomics, launched on 4 October, has announced its own latest challenge, offering $10 million to the first private team to sequence 100 human genomes in 10 days.

  • The ones chasing the genomics award will probably invest much more than $10 million: the true pot of gold is not cash, but publicity and a head start at grabbing a slice of a growing market.

• News in Brief Nature 443, 736-737

  • Big-headed mouse found on Cyprus is a new species

    • Genetic tests have confirmed that an unusual type of mouse found on Cyprus is indeed a new species, that will be called Mus cypriacus.

    • It has diverged from its mainland counterpart, Mus macedonicus, in the Middle Pleistocene era, between 650,000 and 350,000 years ago.
    • The mice were first noted in 2004 for having a normal body size but bigger heads and teeth than mouse species in mainland Europe.

    • Keith Dobney, a bioarchaeologistat Durham University, notes that there may be still more new species to discover in Europe.

• Nicholls H A life online News features Nature 443, 746-747

  • Darwin Online is a service that makes the complete works of Darwin — in the form of both scanned-in pages and searchable text — freely available to anyone with an Internet connection.

  • The ambitious idea for Darwin Online came to John van Wyhe, a historian of science at the University of Cambridge, UK, back in 2002.
  • Van Wyhe aims to add every edition and translation of Darwin's published work to the website by 2009, the bicentenary of his birth and the 150th anniversary of the publication of On the Origin.

• James TY Reconstructing the early evolution of Fungi using a six-gene phylogeny Nature 443, 818-822

  • Before now, the only broadly sampled phylogenetic trees of the fungi were based on sequences of a single gene — that encoding the small-subunit (18S) ribosomal RNA.
  • The authors collected sequence data from two additional ribosomal RNA genes, and three protein-coding genetic loci, for a total of 6 genes in a carefully selected sample of 199 species. Sequence data were directly generated from 170 fungal species
  • They then built a combined supermatrix (DNA+proteins) and built the tree by bayesian methods using a heterogeneous amino-acid and nucleotide model.
  • Support was estimated at nodes by bayesian posterior probabilities (BPP), MLBS and analysis of individual gene partitions.

  • Results:

    • There may have been at least four independent losses of the flagellum in the kingdom Fungi.
    • These losses of swimming spores coincided with the evolution of new mechanisms of spore dispersal, such as aerial dispersal in mycelial groups and polar tube eversion in the microsporidia (unicellular forms that lack mitochondria).
    • The enigmatic microsporidia seem to be derived from an endoparasitic chytrid ancestor similar to Rozella allomycis, on the earliest diverging branch of the fungal phylogenetic tree.

Oct 18: Literature Digest PLoS Biol Oct 06

• Peter Agre How to Win the Nobel Prize? PLoS Biol 4(10): e333. Recension of the autobiography of the Nobel Prize laureate Peter Doherty (Peter Doherty, The Beginner's Guide to Winning the Nobel Prize 2006, New York: Columbia University Press)

  • Doherty won the Nobel Prize for medicine il 1996, together with Rolf Zinkernagel, for their studies on cell-mediated immunity.
  • He notes that, sadly, the Nobel Prize often permanently scars the recipient with unwanted demands that usually remove the privacy and protection needed for introspection and creativity.
  • Apparently, most Nobel laureates never recover from the event, and many can no longer pursue their life's work at the former level of activity, if at all.
  • The final chapter of the book, entitled “How to Win a Nobel Prize,” is a rich source of pearls for the young scientist:
    1. Learn to write clearly and concisely. The problem with much of science is that the scientists hurt their own efforts by being unintelligible.
    2. Be generous and culturally aware. Acknowledge the achievements of others. Every young scientist needs frequent reminders that it is important to have as few enemies as possible.
    3. Time is precious. Women in particular are vulnerable to “death by committees,” and their representation is sorely needed.
    4. Avoid prestigious administrative roles. This is a major source of destruction, particularly to those from clinical backgrounds.
    5. Live a long time. It may take 50 years for the Nobel recognition of a discovery!

• Raj A. Stochastic mRNA Synthesis in Mammalian Cells PLoS Biol 4(10): e309 (Synopsis by Françoise Chanut)

  • Fluctuations in protein output could reflect a whimsy intrinsic to the expression of the coding gene, or random swings in global, or extrinsic, regulators of the gene’s expression.
  • In yeast, extrinsic causes, such as variations in cellular volume, seem to predominate.

  • On the contrary, in mammalian cells, intrinsic causes, specifically the genes’ ability to transition randomly between active and inactive transcriptional states, can be crucial.

• Batada NN (Hurst) Stratus Not Altocumulus: A New View of the Yeast Protein Interaction Network PLoS Biol 4(10): e317 (Synopsis by Richard Robinson)

  • Initial analysis of the yeast protein networks has led to a hub-centric view of interactions, in which a small number of proteins, the hubs, interact with a disproportionately large number of other proteins.
  • In this model, the hubs form the basis for functional “modules” that perform discrete tasks in the cell, and hubs of different modules tend not to interact with one another.
  • One version of this model further suggests two types of hubs: “party” hubs are co-expressed and co-localized with most members of their module (together creating a party), while “date” hubs are not, instead engaging in a series of temporally and/or spatially distinct interactions (dates), including interactions with partners in other modules.

  • The present study shows a much higher degree of interaction between hubs from different clusters, and finds no evidence for the date–party distinction

  • The global network appears more homogeneous and perhaps harder to tease into discrete modules than anticipated.

Oct 12: Literature Digest Genome Biol 7

• Doolittle WF Genomics and the bacterial species problem Opinion Genome Biology 2006, 7:116

  • species definition is a set of easily applied and stable rules by which to decide when two organisms are similar enough in their genomic and/or phenotypic properties to be given the same name.

  • species concept is a genetic and/or ecological model of bacterial diversification and adaptation.

  • The more we learn about genomes the more unlikely it seems that any unifying species concept will be possible.

  • Lateral gene transfer (LGT), within-species genomic variability and homologous recombination all make it harder to imagine how any single model for the maintenance of genomic coherence could be broadly valid.

  • LGT radically uncouples the evolution of phenotype from the evolution of the bulk of the genome, as this is reflected in overall genome similarity (coherence).
  • In some bacteria, homologous recombination is so frequent that it easily outperforms mutation as a source of strain-to-strain sequence differences.

Oct 12: Literature Digest Nature 443, 7112

• Robert Barton Chimp comparisons won't explain human evolution Correspondence Nature 443, 632

  • This letter makes the point to one of the most misinterpreted concept in (molecular) evolution:
    • Chimpanzees are not human ancestors; they have been evolving for exactly the same amount of time.
    • A mutation is, in principle, just as likely to have occurred in the chimpanzee lineage as in the human lineage, during the time since their common ancestor lived.

    • There is no way to discover from any comparison of the two species if a given mutation occurred in the chimpanzee lineage or in the human lineage, during the time since their common ancestor lived.

  • Of course, this concept applies in general to the comparison of any pair of species.

SEPTEMBER 2006

Sep 29: Literature Digest PLoS Genetics Sep 2006

• Seldin MF European Population Substructure: Clustering of Northern and Southern Populations PLoS Genetics 2(9): e143

  • The analysis of SNPs allowed the authors to distinguish individuals with northern European ancestry (Swedish, English, Irish, German, and Ukrainian) from individuals with southern European ancestry (Italian, Spanish, Portuguese, and Greek).
  • This study provides a method of taking into account these differences when searching for genetic variations that are associated with particular human traits, such as disease susceptibility, response to drug treatment, or side effects from therapy.

Sep 29: Literature Digest PLoS Comp Biol Sep 2006

• Bourne P Ten Simple Rules for Reviewers PLoS Comput Biol 2(9): e110

  • The 'Ten Rules Series' continues. This time it concerns 10 suggestions for a good reviewer:
    1. Do Not Accept a Review Assignment unless You Can Accomplish the Task in the Requested Timeframe—Learn to Say No
    2. Avoid Conflict of Interest
    3. Write Reviews You Would Be Satisfied with as an Author
    4. As a Reviewer You Are Part of the Authoring Process
    5. Be Sure to Enjoy and to Learn from the Reviewing Process
    6. Develop a Method of Reviewing That Works for You
    7. Spend Your Precious Time on Papers Worthy of a Good Review
    8. Maintain the Anonymity of the Review Process if the Journal Requires It
    9. Write Clearly, Succinctly, and in a Neutral Tone, but Be Decisive
    10. Make Use of the “Comments to Editors”

• Goodstadt, L & Ponting CP Phylogenetic Reconstruction of Orthology, Paralogy, and Conserved Synteny for Dog and Human PLoS Comput Biol 2(9): e133 DAVIDE

  • A new phylogenetic orthology prediction pipeline, PhyOP, is presented.

  • It is based on synonymous rate estimates, which accurately predicts orthology and paralogy relationships for transcripts, genes, exons, or genomic segments between closely related genomes.
  • Benchmarking against predictions from Ensembl and Inparanoid showed that PhyOP is more accurate, especially in its predictions of paralogy.
  • Using PhyOP to investigate orthologues and paralogues in the human and dog genomes, we found that the human assembly contains 3-fold more gene duplications than the dog.
  • In-paralogues are generally shorter, have fewer exons than 1:1 orthologues and have experienced elevated amino acid and synonymous nucleotide substitution rates.
  • PhyOP will be particularly useful in predicting orthology for mammalian genomes that have been incompletely sequenced, and for large families of rapidly duplicating genes.

Sep 22: Literature Digest Science 313. no. 5794

• Salehi-Ashtiani K A Genomewide Search for Ribozymes Reveals an HDV-Like Sequence in the Human CPEB3 Gene Science 5794, 1788 - 1792

  • In vitro selection of self-cleaving RNAs from the human genome.

  • One of the isolated ribozymes is a conserved mammalian sequence that resides in an intron of the CPEB3 gene, which belongs to a family of genes regulating messenger RNA polyadenylation.
  • The CPEB3 ribozyme is structurally and biochemically related to the human hepatitis delta virus (HDV) ribozymes.

Sep 19: Literature Digest Hum Mol Genetics Sept 2006

• Sun H Conserved distances between vertebrate highly conserved elements Hum Mol Gen2006 15(19):2911-2922 CINZIA

  • Putative non-random occurrence of UC-regions in the vertebrate genome.

Sep 14: Literature Digest Nature 443

• Russo G Biomedical research gets a fresh twist down on the farm NEWS Nature 443, 128-129 More info here

  • The Janelia Farm opens its doors in Virginia. The main novelty of the research institute is to encourage interdisciplinary collaborations and promote unconventional work. Some features:

  • The building is carved into a hill about 60 kilometres west of Washington DC.
  • Each floor is in the large, multi-level terrace being at ground level.
  • Labs are walled in with thick glass from floor to ceiling.
  • A modular design allows the space to be easily reconfigured to suit an investigator's needs.
  • The campus also boasts a gym, 50 apartments, a daycare facility, and a pub, complete with free coffee to entice people together and a whiteboard for spontaneous brainstorms.
  • Groups are no bigger than six members, to encourage interdisciplinary collaboration that relies on field experts rather than graduate students or postdocs. This should also ensure that group leaders are active bench scientists rather than just managers.
  • Investigators will be reviewed after six years initially, and subsequently every five years. If a panel of outside experts finds the research to be too conventional or progress insufficient, the investigator will be kicked out — albeit with two years of additional funding to soften the blow.

  • People already there: Gerry Rubin, Gene Myers, Sean Eddy.

Sep 13: Literature Digest PLoS Biology Sept 2006

• Levin S Fundamental Questions in Biology PLoS Biol 4(9): e300

  • This Editorial introduces a new Challenges Series that PLoS Biol dedicates on Fundamental Challenges in Biology.

  • After the high specialization reached by biological science in the last decades, the point raised by the author is that biology needs to unify the effort of the various sub-disciplines in order to give answers to some of the main questions in biology, such as:
    • What features convey robustness to systems?
    • How different should we expect the robustness of different systems to be, depending on whether selection is operating primarily on the whole system or on its parts?
    • How does robustness trade off against adaptability?
    • How does natural selection deal with environmental noise and the consequent uncertainty at diverse scales?
    • When does synchrony emerge, and what are its implications for robustness?
    • When and how does cooperative behavior emerge, and can we derive lessons from evolutionary history to foster cooperation in a global commons?
  • The fisrt paper of the Series is contributed by

• Wingreen NS and Levin SA Cooperation among Microorganisms. PLoS Biol 4(9): e299

  • Highlights on some of the better-studied examples of cooperation among microorganisms with the attempt to identify some of the important questions in this emerging field.

  • One of the best-studied cases of cooperation among microorganisms concern intraspecies cooperation.

    • An example is quorum sensing among bacteria in which cells produce, secrete, and detect small molecules, called autoinducers.

    • At high enough autoinducer concentrations (high cell densities), the bacteria expres genes associated with collective behaviors that are best carried out in concerted fashion by many cells.
    • These behaviors include the formation of protective biofilms, the expression of virulence factors to attack a host, the production of light, the establishment of competence to exchange DNA.

  • Interspecies cooperation is much less understood partially for practical reasons, but also because the ubiquity of communication among microorganisms has only recently been appreciated.

    • However, bacteria form biofilms on many surfaces (including human teeth, artificial joints, and organs) that consist of large consortia of different organisms.
  • Cooperative behaviors include complex social interactions such as division of labor and mutualism in providing shelter, foraging, reproduction, and dispersal.
  • Understanding how cooperation arose and is maintained, particularly among large numbers of species, presents a challenge for practitioners of both molecular biology and evolutionary biology, as well as for theorists.

Sep 7: Literature Digest Science 313. no. 5792

• Kaiser J IFirst Pass at Cancer Genome Reveals Complex Landscape NEWS OF THE WEEK

  • Gigantic effort to sequence the coding portion of the breast and colorectal cancer genome
  • Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ~90 mutant genes but that only a subset of these contribute to the neoplastic process.
  • 189 genes (average of 11 per tumor) are mutated at significant frequency.
  • The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion.

Sep 5: Literature Digest PLoS Comp Biol Aug 2006

• Haynes C Intrinsic Disorder Is a Common Feature of Hub Proteins from Four Eukaryotic Interactomes PLoS Comput Biol 2(8): e100

  • According to the protein structure–function paradigm, a protein can perform its biological function(s) only after folding into a specific rigid 3-D structure. However, many proteins exist in a natively unfolded (or intrinsically disordered) state, and function without a prerequisite stably folded structure, and in many cases, the lack of structure is required for biological function.

  • In this study the interaction networks from four eukaryotic organisms (yeast, worm, fly, and human) have been compared.
  • The results show that within these networks the proteins that interact with multiple protein partners (network hubs) are significantly more disordered than proteins that interact with a single protein partner (network ends).
  • Intrinsic structural disorder seems to be a distinctive and common characteristic of hub proteins, and disorder may serve as a determinant of protein interactivity.

• Ding G Insights into the Coupling of Duplication Events and Macroevolution from an Age Profile of Animal Transmembrane Gene Families PLoS Comput Biol 2(8): e102

  • This study presents a systematic analysis of the animal transmembrane gene duplication events on a macroevolutionary scale by integrating the palaeontology repository.
  • The age of duplication events was calculated by maximum likelihood method, and the age distribution was estimated by density histogram and normal kernel density estimation.
  • The results show that the density of the duplicates displays a positive correlation with the estimates of maximum number of cell types of common ancestors, and the oxidation events played a key role in the major transitions of this density trace.

• Spencer SL Modeling Somatic Evolution in Tumorigenesis PLoS Comput Biol 2(8): e108 DAVIDE

  • Modelling of cancer cells as autonomous agents in order to observe the order in which mutations are acquired, the diversity of tumors, and the competition and cooperation between cells in the tumor microenvironment.
  • One key finding is that early-onset and late-onset tumors take different mutational paths to cancer.

• Björklund ÅK Expansion of Protein Domain Repeats PLoS Comput Biol 2(8): e114 IRENE

  • The authors have investigated how protein repeats may have evolved.
  • It is believed that the repeats are created through internal duplications where the duplicated region is inserted next to its origin.
  • Therefore, the pairwise sequence similarity between all repeated domains in a protein was used to identify recent duplications, and a method based on autocorrelation vectors was employed to distinguish patterns of duplication.
  • Repeat regions are often created from the duplication of several domains at a time while duplication of one domain is less common.
  • The internal duplications often occur in the middle of the repeats. This is in contrast to the evolution of nonrepeating, multidomain proteins, which are thought to evolve by the addition of a single domain at the N-termini or C-termini.

  • For human C2H2, 78% of the long repeats were found within one exon.

  • The mean alignment score between domains in single-exon Zn-finger repeats is slightly higher than for repeats that are distributed on several exons. Thus, they are more likely to be recently duplicated repeats.

Sep 4: Literature Digest Molecular Systems Biology

• Jamshidi N & Palsson BØ Systems biology of SNPs Molecular Systems Biology 2 doi:10.1038/msb4100077 DAVIDE, CINZIA

  • Review on the possibility to define co-sets of functionally related genes based on their SNP distribution.

AUGUST 2006

Aug 17: Literature Digest Nature 442-725

• Pollard KS (D.Haussler) An RNA gene expressed during cortical development evolved rapidly in humans Nature 442

  • The vast majority of the approximately 15 million changes in the human genome since the common ancestor with the chimpanzee are likely to represent neutral drift.
  • This paper reports a scan of ancestrally conserved genomic regions among vertebrates to find those that show a significantly accelerated rate of substitution in the human lineage since divergence from our common ancestor with the chimpanzee.
  • Many of the human accelerated regions (HARs) found in this scan are associated with genes known to be involved in transcriptional regulation and neurodevelopment.
  • HAR1, the most dramatically changed element, is part of a novel RNA gene expressed during human cortical development.

• Gore J (Bustamante) DNA overwinds when stretched

  • This paper shows that for small distortions, contrary to intuition, DNA overwinds under tension, reaching a maximum twist at a tension of approx30 pN.
  • As tension is increased above this critical value, the DNA begins to unwind.
  • These results have implications for the action of DNA-binding proteins that must stretch and twist DNA to compensate for variability in the lengths of their binding sites

• Segal E A genomic code for nucleosome positioning Nature 442 772-778

  • The nucleosome, the fundamental repeating unit of chromatin, consists of 160–240 base pairs of DNA (depending on the species and tissue type) wrapped around a core of proteins called histones.

  • Nucleosomes have higher affinity for particular DNA sequences, but it is not known whether these sequence preferences have a significant influence on nucleosome position in vivo, and thus regulate the access of other proteins to DNA.
  • The paper reports the isolated nucleosome-bound sequences at high resolution from yeast and used these sequences in a new computational approach to construct and validate experimentally a nucleosome–DNA interaction model, and to predict the genome-wide organization of nucleosomes.
  • The results demonstrate that genomes encode an intrinsic nucleosome organization and that this intrinsic organization can explain approx50% of the in vivo nucleosome positions.
  • This nucleosome positioning code may facilitate specific chromosome functions including transcription factor binding, transcription initiation, and even remodelling of the nucleosomes themselves.

Aug 11: Literature Digest Nature Biotechnology Aug 2006

• D'haeseleer P How does DNA sequence motif discovery work? Nature Biotechnology - 24, 959 - 961 (2006) CINZIA

  • Review on the state-of-the-art of pattern searching for DNA motif discovery.

• Papadopoulos N (Kinzler/Vogelstein) The role of companion diagnostics in the development and use of mutation-targeted cancer therapies Nature Biotechnology - 24, 985-995 (2006)

  • Review on the tools currently used for cancer diagnostic based on genetic mutations.

Aug 10: Literature Digest Nature

• Chourrout D Minimal ProtoHox cluster inferred from bilaterian and cnidarian Hox complements Nature 442, 684-687

  • The ancient cluster ProtoHox contained up to four genes with at least the precursors of anterior and posterior bilaterian Hox/ParaHox genes.

  • The way in which genes diversified within the ProtoHox, Hox and ParaHox clusters remains unclear

  • This paper characterizes the full Hox/ParaHox gene complements and genomic organization in two cnidarian species (Nematostella vectensis and Hydra magnipapillata)

  • The resulting ProtoHox cluster is simpler than originally thought and might have consisted of only two anterior genes.

  • The supports for this finding are:

    • 1- both species possess bilaterian-like anterior Hox genes, but no non-anterior gene;
      2- two clustered ParaHox genes, Gsx and a gene related to Xlox and Cdx, are found in Nematostella vectensis;
      3- there is no clear phylogenetic support for a common origin of bilaterian Cdx and posterior genes, which might therefore have appeared after the ProtoHox cluster duplication.

Aug 8: Literature Digest PNAS August 2006

• Gray TA. The putatively functional Mkrn1-p1 pseudogene is neither expressed nor imprinted, nor does it regulate its source gene in trans PNAS, 103, 12039-12044 DAVIDE

  • This paper changelles the model of pseudogene functionality based on the analysis of a serendipitous mouse mutant in which a transgene insertion/deletion caused severe polycystic kidney disease and osteogenesis imperfecta with {approx}80% perinatal lethality, when inherited paternally.
  • This model postulated that the transgene reduced the expression of a nearby transcribed and imprinted pseudogene, Mkrn1-p1. This reduction in chromosome 5-imprinted Mkrn1-p1 transcripts was proposed to destabilize the cognate chromosome 6 Mkrn1 source gene mRNA, with a partial reduction in one Mkrn1 isoform leading to the imprinted phenotype.
  • This study invalidates the data upon which the pseudogene trans-regulation model is based and therefore strongly supports the view that mammalian pseudogenes are evolutionary relics.

Aug 7: Literature Digest PLoS Comp Biol July 2006

• Li YY. Systematic Analysis of Head-to-Head Gene Organization: Evolutionary Conservation and Potential Biological Relevance PLoS Comput Biol 2(7): e74

  • A “head-to-head” or “bidirectional” gene pair is a genomic locus in which two adjacent genes are divergently transcribed, and the region between two transcription start sites (TSSs) is commonly designated as a putative bidirectional promoter
  • Computational analysis revealed that more than 10% of human genes were organized in this head-to-head manner separated by less than 1,000 base pairs (bp)
  • A systematic investigation of head-to-head gene pairs in terms of the genomic structure, evolutionary conservation, expressional correlation, and functional association was performed

  • A conservation tendency of head-to-head gene pairs in vertebrates is detected

  • Analyses of expressional and functional association yielded a significant expression correlation of head-to-head genes, especially for the pairs with significant functional association.

Aug 4: Literature Digest PLoS Genetics July 2006

• Sandovici I. Human Imprinted Chromosomal Regions Are Historical Hot-Spots of Recombination PLoS Genet 2(7): e101

  • Chromosomal regions containing imprinted genes (i.e., genes transcribed only from one allele in a parent-of-origin–specific manner) exhibit higher rates of meiotic recombination than nonimprinted chromosomal regions.

  • This characteristic is common for all major human populations.
  • The major sequence determinants of recombination rates are likely to be different at imprinted and nonimprinted regions.
  • Epigenetic modifications associated with imprinted regions may play an important role in increasing the frequency of meiotic crossovers and determining their position.

• Escriva H. Neofunctionalization in Vertebrates: The Example of Retinoic Acid Receptors PLoS Genet 2(7): e102

  • Retinoic acid receptors (RARs) are chordate-specific transcription factors which, upon binding the natural morphogen retinoic acid, bind to and activate transcription from target genes.
  • The ligand specificity of RARs has changed during vertebrate evolution in parallel with changes in expression.

  • Of the three vertebrate RARs, RARβ has retained the ancestral characteristics in terms of both function and expression, while RARα and γ have evolved by acquiring new functions, both new binding specificity and new expression patterns. IRENE

• Plagnol V and Wall JD Possible Ancestral Structure in Human Populations

  • While Neanderthals form an obvious archaic source population candidate in Europe, there is not yet a clear source population candidate in West Africa.
  • Using sequence data from the Environmental Genome Project, strong evidence for ancient admixture in both a European and a West African population was found, with contributions to the modern gene pool of at least 5%.
  • These estimates of non-negligible contributions of archaic populations to the modern gene pool are inconsistent with strict forms of the Recent African Origin model, which posits that modern humans evolved in a single location in Africa and from there spread and replaced all other existing hominines.

• Guryev V Haplotype Block Structure Is Conserved across Mammals

  • By comparing the orthologous rat, mouse, and human haplotype structure of a 5-megabase region from rat Chromosome 1, a conservation in the haplotype block structure across mammals was shown, most prominently in genic regions.
  • This suggests the existence of an evolutionary selection process that drives the conservation of long-range allele combinations.

  • Indeed, genome-wide gene-centric analysis of human HapMap data revealed that equally spaced polymorphic positions in genic regions and their upstream regulatory regions are genetically more tightly linked than in non-genic regions.

JULY 2006

July 4: Literature Digest Genome Research Vol.16, Issue 7

* Freeling M. Gene-balanced duplications, like tetraploidy, provide predictable drive to increase morphological complexity Genome Res 16:805-814 Davide

• Each type of duplication provides a one-way injection of a biased set of genes into the gene pool.
• Tetraploidies and balanced segments inject bias for those genes whose products are the subunits of the most complex biological machines or cascades, like transcription factors (TFs) and proteasome core proteins.
• Genic balance is maintained by not removing those genes that are dose-sensitive, which tends to leave duplicate "functional modules" as the indirect products (spandrels) of purifying selection.

• Prabhakar S. (L. Pennacchio) Close sequence comparisons are sufficient to identify human cis-regulatory elements Genome Res 16:855-863 Cinzia

  • Results of the screening for enchancer activity of the UC-regions

• Nishihara H. Functional noncoding sequences derived from SINEs in the mammalian genome Genome Res 16:864-874 Cinzia

  • Some nonprotein-coding genomic regions that are under strong selective constraint have been derived from a newly defined family of ancient SINEs.
  • AmnSINE1, for Amniota SINE1, are present in mammals as well as in birds, and some copies predate the mammalian-bird split 310 million years ago (Mya).
  • Of the ~1000 still identifiable copies of AmnSINE1 in the human genome, 105 correspond to loci phylogenetically highly conserved among mammalian orthologs.

• Sun M. (L.Hurst) Evidence for variation in abundance of antisense transcripts between multicellular animals but no relationship between antisense transcriptionand organismic complexity Genome Res 16:922-933

  • Is there a functional connection between antisense transcription and organismic complexity, that is, is antisense regulation especially prevalent in humans?
  • By using the same robust protocol to identify antisense transcripts in humans and five other metazoan genomes (mouse, rat, chicken, fruit fly, and nematode), the estimated proportions of genes involved in antisense transcription was found to be highly sensitive to the number of transcripts included in the analysis.

JUNE 2006

Nature puts human genome online

• Human Genome Collection: freely available resource with a collection of analysis on the human genome and chromosomes.

June 21: Literature Digest PNAS vol. 103 | no. 25 2006

• Mellars P. Why did modern human populations disperse from Africa ca. 60,000 years ago? A new model PNAS 103 9381-9386

  • How and why the dispersal and replacement of ancient populations (European Neanderthals) by African Homo sapiens took place around 60ky ago?

  • Why did it take Homo sapiens, who had already emerged in Africa by at least 150,000 years ago, a further 100,000 years to disperse to other regions of the world?

  • What were the reasons for such migration?

    • Apparently there were major cultural and technological changes around 80000 years bp, which led to the migration.
  • mtDNA "mismatch" distributions (i.e., frequency distributions of genetic differences between pairs of individuals within a population) revealed a clearly defined peak in African populations dated broadly to ~80,000 years ago, while sharply defined peaks followed in Asian and European populations at ~60,000 and 40,000 B.P.
  • The evidence points to an expansion centered initially in one small area of Africa (most probably in eastern or southern Africa) followed by an expansion to other regions, apparently reaching western Africa by at least 30,000–40,000 B.P., and perhaps across the mouth of the Red Sea to the adjacent parts of southern Asia by ~60,000–65,000 B.P.

June 20: Literature Digest Nature Rev Genetics July 2006

• Xing, Y & Lee C Alternative splicing and RNA selection pressure — evolutionary consequences for eukaryotic genomes Nature Reviews Genetics 7, 499-509

  • Nearly three-quarters of human multi-exon genes are alternatively spliced.
  • Alternative splicing is associated with an increased rate of new exon creation in mammalian genomes.

  • The frequency of alternative splicing in a multi-gene family is negatively correlated with the size of the family, indicating that alternative splicing and gene duplication are inversely correlated evolutionary mechanisms. Davide

  • Evolutionarily conserved alternatively spliced exons have greatly reduced synonymous substitution rates, and have highly conserved flanking intronic regions.

• Bailey, JA & Eichler EE Primate segmental duplications: crucibles of evolution, diversity and disease Nature Reviews Genetics 7, 552-564

  • Primate segmental duplications are organized into complicated structures (duplication hubs) that are made up of many independent duplication events.
  • There are distinct mechanisms for their origin, including
    • - Alu repetitive elements - mediated transposition - mechanisms that are mediated by both homology-driven and non-homology-driven events
  • Segmental duplications are enriched at the breakpoints of chromosomal synteny between human and mammalian genomes.
  • Both fusion genes and genes showing signatures of adaptive evolution have been documented among some of the most abundant and recently duplicated intrachromosomal duplications.
  • Segmental duplications mediate rare structural rearrangements and common copy-number polymorphisms that are associated with disease and disease susceptibility.

June 16: Literature Digest Science 312 5780

• Duret et a; The Xist RNA Gene Evolved in Eutherians by Pseudogenization of a Protein-Coding Gene Science 312 1653 - 1655

  • In eutherians and in marsupials, the desiquilibrium in gene dosage between XY males and XX females is compensated for by silencing one of the X chromosomes in females
  • This silencing involves the Xist gene, which is located in the X inactivation center (Xic) and encodes a long untranslated RNA

  • Xic is located on the long arm of the human X chromosome, which corresponded to the proto–X chromosome in the mammalian cenancestor (last common ancestor)
    

Results

• Xist orthologs are in all eutherians and the genomic region surrounding the Xist gene contains three protein-coding genes (Cdx4, Chic1, and Xpct) that have orthologs in all vertebrate classes.
• In eutherians, besides Xist, the Xic region contains two RNA genes (Jpx and Ftx) and two protein-coding genes (Tsx and Cnbp2). The latter is a retrotransposed gene that is specific to eutherians.

June 12: New Hopes for Italian Science...

• Leonardo Morsut, player in the Italian National Volley team, left professional sport for science: he decided to start a PhD program in Biotecnology at Padova University and, since this effort could not be matched with a high-level sport career, he chose science... Given the average condition of scientists in Italy, this choice is even more relevant! You can find more info here

June 9: Literature Digest Science 312 5779

• News Focus DNA's Molecular Gymnastics Science 312 1467-1468

  • Focus on the possible roles of left-handed twist DNA (Z-DNA). Some examples:
  • In 1979 a poxvirus virulence factor, called E3L, was shown to mimick a mammalian protein that binds Z-DNA. After infecting animals with mutated poxviruses, it became clear that attaching to Z-DNA was crucial to E3L's then-unknown function: If the protein lacked the Z-DNA binding region, then mice infected by an otherwise lethal poxvirus survived.

  • Hurley's group discovered a particular DNA structure, called quadruplex, that arises naturally from the regulatory sequence that controls the expression of the oncogene cMYC. Cells typically produce proteins that stabilize cMYC's regulatory sequence into a quadruplex, preventing transcription.

  • These unusual DNA structures appear to be central to certain "fragile sites," where DNA readily breaks as it's copied.

• While the role of Z-DNA is still under debate, have a look at the arty DNA structures The Left Handed DNA Hall of Fame

June 7: Sequence Locator on a World Scale!

• It is now possible to describe precisely where the genomic samples used for sequencing specimen were collected, and also in a gorgeous way... They are indeed mapped onto the NASA Visible Earth. Have a look!

June 7: Literature Digest Nature 441 7094

• Editorials Peer review on trial Nature 441, 668

  • Nature starts a discussion about changing/renewing the article reviewing system, to date mainly based on peer reviewing.
  • For the next 3 months, there will be a trial period in which articles submitted to Nature could be reviewd both under the 'classical' scheme and under an 'open-comment' scheme.
  • The latter would be an attempt to explore alternative ways of judging scientific works.

  • You can find articles for open comments at Peer Review Trial

  • There is also a Web Debate going on on this topic.

June 2: PLoS Genetics May 2006

• Degnan JH & Rosenberg NH Discordance of Species Trees with Their Most Likely Gene Trees PLoS Genet 2(5): e68

  • Different genomic regions evolving along the branches of a tree of species relationships can have different evolutionary histories. There are a bunch of methods to circumvent this problem.
  • However, the use of multiple genomic regions for species tree inference is subject to a surprising new difficulty, the problem of “anomalous gene trees.” Not only can individual genes or genomic regions have genealogical histories that differ in shape, or topology, from a species tree, the gene tree topology most likely to evolve can differ from the species tree topology.
  • As a result, the “democratic vote” procedure of using the most frequently observed gene tree topology as an estimate of the species tree topology can converge on the wrong species tree as more genes are added.
  • Species trees with at least one short branch, especially if it is deep in the tree, are particularly susceptible to producing anomalous gene trees, so species trees with many taxa can have problems as they typically contain some deep short branches.

June 2: PLoS Comput Biol May 2006

• Svensson O Genome-Wide Survey for Biologically Functional Pseudogenes PLoS Comput Biol 2(5): e46

  • Genome-wide survey for and analysis of human pseudogenes (gene copies with lost protein-coding ability) with the aim of discovering biologically functional ones. The main motivation was a 2002 Nature paper revealing in vivo functionality for a mouse Makorin pseudogene, Makorin1-p1.
  • Some 4%–6% of all human processed pseudogenes show evidence of expression and the vast majority of transcribed human pseudogenes are lineage specific. Only some 5% were found to have potential orthologs in mouse. Transcribed pseudogenes are potentially functional.
    • Two processed sequences were observed for which the conservation since the human–mouse split is as high as most protein-coding genes: one is derived from the protein Ataxin 7-like 3 (ATX7NL3), and one from the Spinocerebellar ataxia type 1 protein (ATX1).

• Vogel C & Chothia C Protein Family Expansions and Biological Complexity PLoS Comput Biol 2(5): e48

  • Due to their duplication, divergence, and recombination proteins can be grouped into families whose members are descended from a common ancestor.
  • By examining the sizes of 1,219 protein families in 38 eukaryotes of different complexity, they show that only a small fraction of protein families have expansions that are correlated with increasing complexity.
  • Other families do have expansions but in a lineage-specific manner.

June 1: Literature Digest Nature Reviews Molecular Cell Biology June 2006

• Jensen O. Interpreting the protein language using proteomics Nature Rev Mol Cell Biol 7, 391-403

  • Review on the state-of-the-art methods in modern proteomics.

MAY 2006

May 31: Literature Digest Nature 441

• News Feature Genetics: What is a gene? Nature 441, 398-401

  • Interesting review on the concept of gene during the past years of molecular biology.

  • Classic Genetics: a unit of inheritance that ferried a characteristic from parent to child.

  • Biochemistry: each gene was associated with enzyme or protein.

  • Molecular biology: sequences of DNA which when converted into strands of so-called messenger RNA could be used as the basis for building their associated protein piece by piece.

  • Over the years geneticists have documented overlapping genes (genes within genes) and alternative splicing (messages that can code for different proteins).

• Rassoulzadegan M RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse Nature 441 469-474

  • Focus on epigenetic inheritance in which information is passed from parent to offspring independent of the DNA sequence. (e.g. paramutation which allows heritable epigenetic modification by cross-talk between allelic loci in plants)

  • In mice, mutations in the Kit gene cause white patches on the tail and feet: if a mouse has one normal Kit gene and one mutated one it will have the spots. However, some of the offspring of such mice, who inherit two normal Kit genes, still have the white tail.
  • The white spotted tail mice show reduced expression of Kit and had an accumulation of a mixture of smaller RNAs with sequences that matched various parts of the Kit mRNA.
  • Sperm precursor cells from male mutants had aberrant Kit mRNAs, and their sperm showed an unexpected accumulation of RNA. It is possible that these RNAs are transmitted to the next generation on fertilization, even if the allele from which they arose is not passed on.
  • These bits of RNA somehow silence the normal Kit gene (via microRNAs?) in the next generation and subsequent ones, producing the spotted-tail effect.

May 31: Literature Digest PNAS 103

• Perry GH (C.Lee) Hotspots for copy number variation in chimpanzees and humans PNAS 103 8006-8011

  • By using two array-based comparative genomic hybridization platforms a total of 355 copy number variants (CNVs) in the genomes of 20 wild-born chimpanzees have been identifiied.
  • Especially those CNVs of higher frequency were observed in the corresponding regions to known human CNVs from previous studies.
  • These loci are enriched 20-fold for ancestral segmental duplications, which may facilitate CNV formation through nonallelic homologous recombination mechanisms.

• Cordaux R Birth of a chimeric primate gene by capture of the transposase gene from a mobile element PNAS 103 8001-8006

  • SETMAR, a new primate chimeric gene, results from fusion of a SET histone methyltransferase gene to the transposase gene of a mobile element.
  • The transposase gene was recruited as part of SETMAR 40–58 million years ago, after the insertion of an Hsmar1 transposon downstream of a preexisting SET gene, followed by the de novo exonization of previously noncoding sequence and the creation of a new intron.
  • The N-terminal half of the transposase is evolving under strong purifying selection

May 21: Literature Digest Science 312

• Pósfai G Emergent Properties of Reduced-Genome Escherichia coli Science 312, 1044-1046

  • Because E. coli evolved in animal intestines and in the environment, parts of its genome are unnecessary for some applications, possibly even counterproductive.
  • In this study the genome of E.coli has been reduced in order to construct a genetically stable "tabula rasa" strains with robust metabolic performance, to which genes for practical applications may be added.
  • Different straints have been constructed by means of a rational design strategy and avoiding loss of robustness that would result from more extensive deletions or an attempt to construct a minimal genome.
  • Removal of mainly large islands, insertion-sequence-containing islands and individual genes containing insertion-sequence elements led to some unexpected properties.
  • Without compromising growth dynamics, the authors created a strain that showed increased electroporation efficiency and enhanced propagation and stability of plasmids, which are used as delivery vehicles in vaccine and gene therapy research.

May 19: Literature Digest Nature Review Genetics June 2006

• Khare A First among equals: competition between genetically identical cells Nature Reviews Genetics, advance online publication

  • Interesting hypothesis that evolution competition between genetically identical cells could improve the fitness of a multicellular organism by directing fitter cells to the germ line or by eliminating unfit cells.

• Research Highlight Evolution: A tinkerer's tales Nature Reviews Genetics June 2006

  • Highlight on 3 evol papers which deal with fundamental open questions in mol. evolution:

  • How does a trait get from A to B? Bridgham et al. address this question with respect to the distinct specificity of the mineral corticoid hormone receptor for its ligand, aldosterone. This and similar relationships present a conundrum: the receptor and ligand match each other perfectly, so how could the evolution of one partner be explained unless the other is already present? The authors used phylogenetic information to reconstruct ('resurrect') the sequence of the ancestral receptor. Surprisingly, the receptor already had some affinity for aldesterone — not because aldesterone was present but because of the existence of a structurally related molecule. This is a case of an old molecule being exploited to acquire a new function — a switch that, the authors discovered, was only two amino-acid mutations away.

  • How many paths can evolution take? Prud'homme et al (S.Carroll) concentrated on the black spot that exists on the male wing of some Drosophila species. The wing spot has evolved independently in two lineages, where it is used to woo females, and in both cases the evolution of the pattern involves the yellow pigmentation gene. What is most interesting is that the cis-regulatory elements that have been used in the two cases are distinct, indicating that evolution can use different mechanisms to reach a convergent, adaptive endpoint.

  • Are these paths all equally probable? Weinreich et al.(D.Hartl) chose the evolution of bacterial beta-lactamase, which can evolve a 100,000-fold increase in antibiotic resistance by acquiring just five point mutations. Of the 120 hypothetical trajectories to drug-resistant alleles, 102 are inaccessible to evolution. This prediction was based on the probability of fixation of mutant combinations; in fact, the situation is more extreme than this, because of the 18 plausible combinations as few as 2 are probable, indicating that the path to adaptive protein evolution is largely predictable.

May 18: Literature Digest Nature 441

• DENSE ISSUE!!!

• News Neanderthal DNA yields to genome foray Nature 441, 260-261

  • During the last CSHL 'Biology of the Genomes' meeting Svante Pääbo has announced the completion of the Neanderthal Genome Project begun about two years ago.
  • He and his team have probed 60 Neanderthal specimens that lived across Europe and western Asia from 300,000 to around 30,000 years ago, with the first specimen found in 1856 near Dusseldorf, Germany.
  • Two of the specimens showed promise, and they had managed to sequence around a million base pairs of nuclear DNA — around 0.03% of the genome — from one of them. This is a 45,000-year-old male specimen found in Vindija Cave outside Zagreb, Croatia.
  • Pääbo and his colleagues used the new sequencing technique, developed by 454 Life Sciences, as the DNA from Neanderthal specimens were fragmented in tiny pieces.

• Essay Time for a change Nature 441, 289

  • The prokaryote/eukaryote model posits that there are two kinds of cells: prokaryotic, those without nuclei (specifically, without nuclear membranes) and eukaryotic, those with a classical membrane-bounded nucleus. The model further posits that the former gave rise to the latter.

  • Molecular-sequence comparisons, first of ribosomal RNA genes in the late 1970s and of many other genes since, replaced analyses based on morphological subjectivities (such as the presence or absence of a nuclear membrane) and have rendered the prokaryote/eukaryote model obsolete.
  • Although some details of ribosomal RNA-based trees remain controversial, the basic three-domains structure and the relationships between the domains are generally accepted and are supported by observed biochemical variation. Phylogenetic trees based on all genes encoding the information-processing machinery needed to express genetic sequences are congruent with the three-domains tree.

  • The root, or origin, of this universal tree, cannot be determined from ribosomal RNA sequences, but other phylogenetic results and biochemical correlates show that the genetic lines of eukarya and archaea have a common ancestral branch that is independent of that giving rise to the bacteria.

• Gregory SG The DNA sequence and biological annotation of human chromosome 1 Nature 441, 315-321

  • Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap.
  • Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident.

• Arnold K Language evolution: Semantic combinations in primate calls Nature 441, 303

  • Free-ranging putty-nosed monkeys combine two vocalizations into different call sequences that are linked to specific external events, such as the presence of a predator and the imminent movement of the group.
  • These findings indicate that non-human primates can combine calls into higher-order sequences that have a particular meaning.

May 17: Literature Digest PLoS Biology & PNAS May 2006

• Kristensen VN Genetic variation in putative regulatory loci controlling gene expression in breast cancer PNAS 2006, 103, 7735-7740

  • The main goal of this study was to explore the genetic determinants of expression in breast tumors.

  • Actual genotyping of 203 genes in 50 unrelated breast cancer patients whose tumors have previously been analyzed by genome-wide expression by using microarrays was performed.
  • SNPs in EGF, IL1A, MAPK8, XPC, SOD2, and ALOX12 that are associated with the expression patterns of a significant number of transcripts were identified, indicating the presence of regulatory SNPs in these genes.

• Abascal F Parallel Evolution of the Genetic Code in Arthropod Mitochondrial Genomes PLoS 2006, 5, e88

  • Generally, nonstandard mitochondrial codes within an animal phylum have all been considered the same, which has been interpreted to mean that these nonstandard codes arose very early in each lineage and remained unchanged thereafter.
  • This study compared the mitochondrial coding sequences from 626 different animal species, aligning the sequences to find codons conserved within a gene from one species to the next.
  • They it was asked what amino acid any particular codon specified in the protein. The most frequent AA was taken to be the canonical translation of that codon.
  • By checking whether that same codon is translated as that amino acid in any particular species, it was possible to identify potential variant genetic codes.

  • While almost every codon translated into the expected amino acid (as deduced from the annotated genetic code) in all species, there was a surprising trend in the arthropods: in all invertebrates AGG typically translates as the amino acid serine. Among the 92 mitochondrial genomes from the arthropods, however, AGG coded for serine in 34 species and lysine in 24 other species.

  • One explanation for this variety is that pairing of AGG and lysine is disadvantageous for the organism employing it, so that loss or reversion over time would be favored. If true, this explanation suggests there may be multiple other nonstandard codes residing within other lineages that began with a nonstandard and selectively unfavorable coding change.

May 16: Literature Digest PNAS February 2006

• Shiu SH (WH Li) Role of positive selection in the retention of duplicate genes in mammalian genomes PNAS 2006, 103, 2232-2236 Davide

  • important role of positive selection in duplicate retention than duplication–degeneration–complementation
  • certain functional categories show a higher tendency of lineage-specific expansion than expected, suggesting lineage-specific selection or functional bias in retained duplicates

May 11: Literature Digest Nature 441 7090

• News Feature Epigenetics: Unfinished symphony Nature 441, 143-145

  • The term 'epigenetics' was first coined in the 1940s by British embryologist and geneticist Conrad Waddington, to describe "the interactions of genes with their environment, which bring the phenotype into being". The term now refers to the extra layers of instructions that influence gene activity without altering the DNA sequence. Epigenetic control of gene expression occurs in two main ways: either the DNA itself is chemically altered, or the proteins that package DNA into chromatin (the histones), are modified.

  • By studying 80 pairs of identical twins, ranging in age between 3 and 74, Esteller's team in 2005 found that epigenetic differences were hardly detectable in the youngest twins, but increased markedly with age. These changes had a striking effect on gene activity: the number of genes that differ in activity between 50-year-old twins was more than three times that in pairs aged 3.

  • The International Human Epigenome Project, or IHEP, proposed in 1999, faces daunting challenges: The sequence of the human genome is the same in all our cells, whereas the epigenome differs from tissue to tissue, and changes in response to the cell's environment. Can researchers really hope to pin down this vast, complex and ever-changing code in a meaningful way?

  • Initially eight to ten tissues, including the blood, should be studied simultaneously. Ultimately, the epigenome of all tissues, including embryonic stem cells, will be mapped out.

May 4: Literature Digest Nature 441 7089

• Ngo, VN (LM Staudt) A loss-of-function RNA interference screen for molecular targets in cancer Nature 441, 106-110

  • description of an approach for identifying genes that become essential for the survival of cancer cells

  • Two genes are synthetically lethal if the cell containing them dies when both genes are mutated, but it can survive if either gene alone is mutated.

  • Synthetic-lethal interactions could be used to develop anticancer drugs. In the case of tumour-suppressor genes, the protein products of which inhibit tumour growth, are often inactivated in cancers by mutations: A drug that inhibits the protein product of a gene that is synthetically lethal to a tumour-suppressor gene would, by definition, kill those cells in which the tumour-suppressor gene was inactivated, but not their normal counterparts.

  • So far, there are only a few reports of synthetic-lethal interactions involving human cancer genes, and we do not know enough about the genetic networks in cancer cells to predict such interactions.
  • The method reported in this paper is based on RNA interference, in which a 'short interfering RNA' (siRNA) molecule is used to target a specific messenger RNA for destruction within the cell . It is possible to perform large-scale genetic screens in human cells using libraries of genes that encode numerous siRNAs or 'short hairpin RNAs'.

  • Many shRNAs did not affect cellular fitness, or affected fitness negatively in both lymphomas. However, shRNAs targeting the genes IKBKB, CARD11, MALT1 and BCL10 were depleted after doxycycline addition only in the ABC cells. These shRNAs inhibited ABC proliferation selectively in further experiments, suggesting that IKBKB, CARD11, MALT1 and BCL10 are synthetically lethal to one or more mutations responsible for ABC.

May 3: Music

• Neil Young is releasing his new album Living With War, due for May 8 2006. Enjoy your listening!

May 3: Literature Digest Genome Biol

• Hulsen, T (M.Hunyen) Benchmarking ortholog identification methods using functional genomics data Genome Biol 2006, 7:R31 Interesting for Davide

  • Comparison of several of the most popular ortholog identification methods and usage of functional genomics data, such as expression data and protein interaction data to measure the similarity in function of proteins from different species.

  • Results: the functional similarity scores per orthologous pair of sequences become higher when the number of proteins included in the ortholog groups decreases. The InParanoid program is the best ortholog identification method in terms of identifying functionally equivalent proteins.

May 2: Literature Digest Genome Res

• She, X (E.Eichler) A preliminary comparative analysis of primate segmental duplications shows elevated substitution rates and a great-ape expansion of intrachromosomal duplications Genome Res 16:576-583

  • human segmental duplications appear larger, more interspersed, and disproportionately represented as high-sequence identity alignments.

  • The molecular clock for the divergence of SD shows a significant increase in the effective substitution rate when compared with unique genomic sequence

  • FISH from 1053 random nonhuman primate BACs indicate that great-ape species have been enriched for interspersed segmental duplications compared with representative Old World and New World monkeys

• Hamilton, AT (L.Stubbs) Evolutionary expansion and divergence in the ZNF91 subfamily of primate-specific zinc finger genes Genome Res 16:584-594 Interesting for Irene

  • Genes of the ubfamily of KRAB-ZNF Zinc-Fingers, including ZNF91, has expanded specifically in primates to comprise more than 110 loci in the human genome
  • Phylogenetic analysis indicates that many of these genes arose before the split between the New and Old World monkeys.
  • The ZNF91 subfamily has continued to expand and diversify throughout the evolution of apes and humans.

• Chen, N (L.Stein) Conservation and functional significance of gene topology in the genome of Caenorhabditis elegans Genome Res16:606-617

  • Strong positive correlation was found in the expression patterns of neighboring gene pairs that are close together and transcribed in the same direction as well as for neighboring pairs that are located on opposing strands and transcribed in divergent directions

  • Genes that are on opposing strands and transcribed in convergent directions are less transcriptionally coupled than the genome-wide background, suggesting a mutual inhibition mechanism

May 1: Literature Digest Plos Comput Biol

• MacIsaac, KD Practical Strategies for Discovering Regulatory DNA Sequence Motifs PLoS Comput Biol 4, e36

  • Interesting and complete tutorial on the state-of-the-art for TF binding site identification by using computational methods.

• Pedersen, JH (D.Haussler) Identification and Classification of Conserved RNA Secondary Structures in the Human Genome PLoS Comput Biol 4, e33

  • method for identification of functional RNA structures based on phylogenetic analysis of multiple alignments.

  • the stem-pairing regions of fRNA structures evolve mostly with a characteristic substitution pattern such that only substitutions that maintain the pairing capability between paired bases will be allowed, which leads to compensatory double substitutions (e.g., GC ↔ AU).

APRIL 2006

April 27: Literature Digest

• Muzny, D (R.Gibbs) The DNA sequence, annotation and analysis of human chromosome 3 Nature 440, 1194-98

  • Chr.3 has the lowest rate of segmental duplication in the human genome.
  • 1585 gene loci (1425 known genes, 8 novel, 27 novel transcripts, 3 put genes and 122 pseudos). The gene density is 8.8 genes/Mb (very low), nut the genes are larger
  • there are 2 gene clusters that account for 26% of the chr.
  • chr.3 arose from a fission of the ancestor of African apes that gave rise to chr.3 and chr.21

April 24: Literature Digest

• Research Highlight: Robey, R Genomic instability: Beyond Boveri Nature Rev Cancer 6, 340-341 (May 2006)

  • Thea Tlsty and colleagues show that the generation of aneuploid daughter cells can result from the generation of too many centrosomes through a pathway that involves the tumour suppressor p16INK4a Plos Biology Mar 2006

  • Tlsty and colleagues investigated the concept that aneuploidy results from an increase in the number of centrosomes through the use of a variant population of primary human mammary epithelial cells (vHMECs) that accumulate additional centrosomes with continued population doublings and become aneuploid
  • The additional centrosomes are not due to polyploidy, and inhibiting DNA synthesis with hydroxyurea (HU) led to the acquisition of too many centrosomes in these cells, which indicates that centrosome duplication and DNA replication are uncoupled
  • The loss of p16INK4a expression is a distinguishing characteristic of vHMECs, so could this have a causal role in the acquisition of additional centrosomes?
  • RNA interference with the mRNA that encodes p16INK4a in normal HMECs (which express p16INK4a and do not accumulate additio

Feb 2006

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