CiteULike: djkt's library [443 articles]

Asymmetric histone modifications between the original and derived loci of human segmental duplications

Deyou Zheng — 2008-07-03T21:33:50-00:00

Genome Biology, Vol. 9, No. 7. (2008)

BACKGROUND:Sequencing and annotation of several mammalian genomes have revealed that segmental duplications are a common architectural feature of primate genomes; in fact, about 5% of the human genome is comprised of large blocks of interspersed segmental duplications. These segmental duplications have been implicated in genomic copy-number variation, gene novelty, and various genomic disorders. However, the molecular processes involved in the evolution and regulation of duplicated sequences remain largely unexplored.RESULTS:In this study, the profile of about 20 histone modifications within human segmental duplications was characterized using high-resolution, genome-wide data derived from a ChIP-Seq study. The analysis demonstrated that derivative loci of segmental duplications often differ significantly from the original with respect to many histone methylations. Further investigation showed that genes are present 3x more frequently in the original than in the derivative, whereas pseudogenes exhibit the opposite trend. These asymmetries tend to increase with the age of segmental duplications. The uneven distribution of genes and pseudogenes did not, however, fully account for the asymmetry in the profile of histone modifications.CONCLUSIONS:The first systematic analysis of histone modifications between segmental duplications demonstrates that two seemingly "identical" genomic copies are distinct in their epigenomic properties. Results here suggest that local chromatin environments may be implicated in the discrimination of derived copies of segmental duplications from their originals, leading to a biased pseudogenization of the new duplicates. The data also indicate that further exploration of the interactions between histone modification and sequence degeneration is necessary in order to understand the divergence of duplicated sequences.

Automated mapping of large-scale chromatin structure in ENCODE.

Heng Lian — 2008-07-03T21:27:08-00:00

Bioinformatics (Oxford, England) (30 June 2008)

MOTIVATION: A recently developed DNase I assay has given us our first genome-wide view of chromatin structure. In addition to cataloging DNase I hypersensitive sites, these data allows us to more completely characterize overall features of chromatin accessibility. We employed a Bayesian hierarchical change point model (CPM), a generalization of a hidden Markov Model, to characterize tiled microarray DNase I sensitivity data available from the ENCODE project. RESULTS: Our analysis shows that the accessibility of chromatin to cleavage by DNase I is well described by a four state model of local segments with each state described by a continuous mixture of Gaussian variables. The CPM produces a better fit to the observed data than the HMM. The large posterior probability for the fourstate CPM suggests that the data falls naturally into four classes of regions, which we call major and minor DNase I hypersensitive sites (DHSs), regions of intermediate sensitivity, and insensitive regions. These classes agree well with a model of chromatin in which local disruptions (DHSs) are concentrated within larger domains of intermediate sensitivity, the accessibility islands. The CPM assigns 92% of the bases within the ENCODE regions to the insensitive regions. The 5.8% of the bases that are in regions of intermediate sensitivity are clearly enriched in functional elements, including genes and activating histone modifications, while the remaining 2.2% of the bases in hypersensitive regions are very strongly enriched in these elements. AVAILABILITY: The CPM software is available upon request from the authors. CONTACT: jstam@stamlab.org; wnoble@u.washington.edu; Charles_Lawrence@brown.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Dissecting direct reprogramming through integrative genomic analysis

Tarjei Mikkelsen — 2008-05-29T14:02:31-00:00

Nature (28 May 2008)

Identification and analysis of ancestral hominoid transcriptome inferred from cross-species transcript and processed pseudogene comparisons

Yao-Ting Huang — 2008-07-01T18:26:30-00:00

Genome Res., Vol. 18, No. 7. (1 July 2008), pp. 1163-1170.

Comparative transcriptomics studies in hominoids are difficult because of lack of EST information in the great apes. Nevertheless, processed pseudogenes (PPGs), which are reverse-transcribed ancient transcripts present in the current genome, can be regarded as a virtual transcript resource that may compensate for the paucity of ESTs in non-human hominoids. Here we show that chimpanzee PPGs can be applied to identification of novel human exons/alternatively spliced variants (ASVs) and inference of the ancestral hominoid transcriptome and chimpanzee exon loss events. We develop a method for comparatively extracting novel transcripts from PPGs (designated "CENTP") and identify 643 novel human exons/ASVs. RT-PCR-sequencing experiments confirmed >50% of the tested exons/ASVs, supporting the effectiveness of the CENTP pipeline. With reference to the ancestral transcriptome inferred by CENTP, 47 chimpanzee exon loss events are identified. Furthermore, by combining out-group and PPG information, we identify 20 chimpanzee-specific exon loss and 10 human-specific exon gain events. We also demonstrate that the ancestral transcriptome and exon loss/gain events inferred based on comparisons of current transcripts may be incomplete (or occasionally inappropriate) because ancestral transcripts may not be represented in the ESTs of existing species. Finally, functional analysis reveals that the novel exons identified based on chimpanzee transcripts are significantly enriched in genes related to translation regulatory activity and viral life cycle, suggesting different expression levels of the associated transcripts, and thus divergent splicing isoform composition between human and chimpanzee in these functional categories. 10.1101/gr.075556.107

Two strategies for gene regulation by promoter nucleosomes

Itay Tirosh — 2008-04-30T23:22:56-00:00

Genome Res. (30 April 2008), gr.076059.108.

Chromatin structure is central for the regulation of gene expression, but its genome-wide organization is only beginning to be understood. Here, we examine the connection between patterns of nucleosome occupancy and the capacity to modulate gene expression upon changing conditions, i.e. transcriptional plasticity. By analyzing a genome-wide data of nucleosome positioning in yeast, we find that the presence of nucleosomes close to the transcription start site is associated with high transcriptional plasticity, while nucleosomes at more distant upstream positions are negatively correlated with transcriptional plasticity. Based on this, we identify two typical promoter structures associated with low or high plasticity, respectively. The first class is characterized by a relatively large nucleosome free region close to the start site coupled with well-positioned nucleosomes further upstream, whereas the second class displays a more evenly distributed and dynamic nucleosome positioning, with high occupancy close to the start site. The two classes are further distinguished by multiple promoter features, including histone turnover, binding sites location, H2A.Z occupancy, expression noise and expression diversity. Analysis of nucleosome positioning in human promoters reproduce the main observations. Our results suggest two distinct strategies for gene regulation by chromatin, which are selectively employed by different genes. 10.1101/gr.076059.108

Evolutionary dynamics of segmental duplications from human Y-chromosomal euchromatin/heterochromatin transition regions

Stefan Kirsch — 2008-06-19T23:13:23-00:00

Genome Res. (12 June 2008), gr.076711.108.

Human chromosomal regions enriched in segmental duplications are subject to extensive genomic reorganization. Such regions are particularly informative for illuminating the evolutionary history of a given chromosome. We have analyzed 866 kb of Y-chromosomal non-palindromic segmental duplications delineating four euchromatin/heterochromatin transition regions (Yp11.2/Yp11.1, Yq11.1/Yq11.21, Yq11.23/Yq12, and Yq12/PAR2). Several computational methods were applied to decipher the segmental duplication architecture and identify the ancestral origin of the 41 different duplicons. Combining computational and comparative FISH analysis, we reconstruct the evolutionary history of these regions. Our analysis indicates a continuous process of transposition of duplicated sequences onto the evolving higher primate Y chromosome, providing unique insights into the development of species-specific Y-chromosomal and autosomal duplicons. Phylogenetic sequence comparisons show that duplicons of the human Yp11.2/Yp11.1 region were already present in the macaque-human ancestor as multiple paralogs located predominantly in subtelomeric regions. In contrast, duplicons from the Yq11.1/Yq11.21, Yq11.23/Yq12, and Yq12/PAR2 regions show no evidence of duplication in rhesus macaque, but map to the pericentromeric regions in chimpanzee and human. This suggests an evolutionary shift in the direction of duplicative transposition events from subtelomeric in Old World monkeys to pericentromeric in the human/ape lineage. Extensive chromosomal relocation of autosomal-duplicated sequences from euchromatin/heterochromatin transition regions to interstitial regions as demonstrated on the pygmy chimpanzee Y chromosome support a model in which substantial reorganization and amplification of duplicated sequences may contribute to speciation. 10.1101/gr.076711.108

A diversity profile of the human skin microbiota.

Elizabeth A Grice — 2008-05-28T14:47:11-00:00

Genome research (23 May 2008)

The many layers and structures of the skin serve as elaborate hosts to microbes, including a diversity of commensal and pathogenic bacteria that contribute to both human health and disease. To determine the complexity and identity of the microbes inhabiting the skin, we sequenced bacterial 16S small-subunit ribosomal RNA genes isolated from the inner elbow of five healthy human subjects. This analysis revealed 113 operational taxonomic units (OTUs; "phylotypes") at the level of 97% similarity that belong to six bacterial divisions. To survey all depths of the skin, we sampled using three methods: swab, scrape, and punch biopsy. Proteobacteria dominated the skin microbiota at all depths of sampling. Interpersonal variation is approximately equal to intrapersonal variation when considering bacterial community membership and structure. Finally, we report strong similarities in the complexity and identity of mouse and human skin microbiota. This study of healthy human skin microbiota will serve to direct future research addressing the role of skin microbiota in health and disease, and metagenomic projects addressing the complex physiological interactions between the skin and the microbes that inhabit this environment.

Population genetic analysis of shotgun assemblies of genomic sequences from multiple individuals

Ines Hellmann — 2008-07-01T18:13:39-00:00

Genome Res., Vol. 18, No. 7. (1 July 2008), pp. 1020-1029.

We introduce a simple, broadly applicable method for obtaining estimates of nucleotide diversity theta from genomic shotgun sequencing data. The method takes into account the special nature of these data: random sampling of genomic segments from one or more individuals and a relatively high error rate for individual reads. Applying this method to data from the Celera human genome sequencing and SNP discovery project, we obtain estimates of nucleotide diversity in windows spanning the human genome and show that the diversity to divergence ratio is reduced in regions of low recombination. Furthermore, we show that the elevated diversity in telomeric regions is mainly due to elevated mutation rates and not due to decreased levels of background selection. However, we find indications that telomeres as well as centromeres experience greater impact from natural selection than intrachromosomal regions. Finally, we identify a number of genomic regions with increased or reduced diversity compared with the local level of human-chimpanzee divergence and the local recombination rate. 10.1101/gr.074187.107

Mouse segmental duplication and copy number variation

Xinwei She — 2008-06-27T04:54:26-00:00

Nature Genetics, Vol. 40, No. 7. (22 May 2008), pp. 909-914.

Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation.

Kristi Kerkel — 2008-06-25T09:22:52-00:00

Nature genetics (22 June 2008)

Allele-specific DNA methylation (ASM) is a hallmark of imprinted genes, but ASM in the larger nonimprinted fraction of the genome is less well characterized. Using methylation-sensitive SNP analysis (MSNP), we surveyed the human genome at 50K and 250K resolution, identifying ASM as recurrent genotype call conversions from heterozygosity to homozygosity when genomic DNAs were predigested with the methylation-sensitive restriction enzyme HpaII. Using independent assays, we confirmed ASM at 16 SNP-tagged loci distributed across various chromosomes. At 12 of these loci (75%), the ASM tracked strongly with the sequence of adjacent SNPs. Further analysis showed allele-specific mRNA expression at two loci from this methylation-based screen-the vanin and CYP2A6-CYP2A7 gene clusters-both implicated in traits of medical importance. This recurrent phenomenon of sequence-dependent ASM has practical implications for mapping and interpreting associations of noncoding SNPs and haplotypes with human phenotypes.

Combinatorial patterns of histone acetylations and methylations in the human genome

Zhibin Wang — 2008-06-26T19:38:09-00:00

Nat Genet, Vol. 40, No. 7. (July 2008), pp. 897-903.

Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks.

Jun Zhu — 2008-06-18T06:58:33-00:00

Nature genetics (15 June 2008)

A key goal of biology is to construct networks that predict complex system behavior. We combine multiple types of molecular data, including genotypic, expression, transcription factor binding site (TFBS), and protein-protein interaction (PPI) data previously generated from a number of yeast experiments, in order to reconstruct causal gene networks. Networks based on different types of data are compared using metrics devised to assess the predictive power of a network. We show that a network reconstructed by integrating genotypic, TFBS and PPI data is the most predictive. This network is used to predict causal regulators responsible for hot spots of gene expression activity in a segregating yeast population. We also show that the network can elucidate the mechanisms by which causal regulators give rise to larger-scale changes in gene expression activity. We then prospectively validate predictions, providing direct experimental evidence that predictive networks can be constructed by integrating multiple, appropriate data types.

Estimating coverage and power for genetic association studies using near-complete variation data

Tushar Bhangale — 2008-06-26T23:45:46-00:00

Nat Genet, Vol. 40, No. 7. (July 2008), pp. 841-843.

Global Mapping of DNA Methylation in Mouse Promoters Reveals Epigenetic Reprogramming of Pluripotency Genes

Cassandra Farthing — 2008-06-27T18:47:56-00:00

PLoS Genet, Vol. 4, No. 6. (27 June 2008), e1000116.

DNA methylation patterns are reprogrammed in primordial germ cells and in preimplantation embryos by demethylation and subsequent de novo methylation. It has been suggested that epigenetic reprogramming may be necessary for the embryonic genome to return to a pluripotent state. We have carried out a genome-wide promoter analysis of DNA methylation in mouse embryonic stem (ES) cells, embryonic germ (EG) cells, sperm, trophoblast stem (TS) cells, and primary embryonic fibroblasts (pMEFs). Global clustering analysis shows that methylation patterns of ES cells, EG cells, and sperm are surprisingly similar, suggesting that while the sperm is a highly specialized cell type, its promoter epigenome is already largely reprogrammed and resembles a pluripotent state. Comparisons between pluripotent tissues and pMEFs reveal that a number of pluripotency related genes, including Nanog, Lefty1 and Tdgf1, as well as the nucleosome remodeller Smarcd1, are hypomethylated in stem cells and hypermethylated in differentiated cells. Differences in promoter methylation are associated with significant differences in transcription levels in more than 60% of genes analysed. Our comparative approach to promoter methylation thus identifies gene candidates for the regulation of pluripotency and epigenetic reprogramming. While the sperm genome is, overall, similarly methylated to that of ES and EG cells, there are some key exceptions, including Nanog and Lefty1, that are highly methylated in sperm. Nanog promoter methylation is erased by active and passive demethylation after fertilisation before expression commences in the morula. In ES cells the normally active Nanog promoter is silenced when targeted by de novo methylation. Our study suggests that reprogramming of promoter methylation is one of the key determinants of the epigenetic regulation of pluripotency genes. Epigenetic reprogramming in the germline prior to fertilisation and the reprogramming of key pluripotency genes in the early embryo is thus crucial for transmission of pluripotency.

Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation

Emily Hare — 2008-06-27T18:46:42-00:00

PLoS Genet, Vol. 4, No. 6. (27 June 2008), e1000106.

The gene expression pattern specified by an animal regulatory sequence is generally viewed as arising from the particular arrangement of transcription factor binding sites it contains. However, we demonstrate here that regulatory sequences whose binding sites have been almost completely rearranged can still produce identical outputs. We sequenced the even-skipped locus from six species of scavenger flies (Sepsidae) that are highly diverged from the model species Drosophila melanogaster, but share its basic patterns of developmental gene expression. Although there is little sequence similarity between the sepsid eve enhancers and their well-characterized D. melanogaster counterparts, the sepsid and Drosophila enhancers drive nearly identical expression patterns in transgenic D. melanogaster embryos. We conclude that the molecular machinery that connects regulatory sequences to the transcription apparatus is more flexible than previously appreciated. In exploring this diverse collection of sequences to identify the shared features that account for their similar functions, we found a small number of short (20–30 bp) sequences nearly perfectly conserved among the species. These highly conserved sequences are strongly enriched for pairs of overlapping or adjacent binding sites. Together, these observations suggest that the local arrangement of binding sites relative to each other is more important than their overall arrangement into larger units of cis-regulatory function.

Dynamic repertoire of a eukaryotic transcriptome surveyed at single-nucleotide resolution

Brian Wilhelm — 2008-05-19T01:16:04-00:00

Nature (18 May 2008)

Tuning in to the signals: noncoding sequence conservation in vertebrate genomes

Greg Elgar — 2008-06-20T01:35:22-00:00

Trends in Genetics, Vol. In Press, Corrected Proof

Aligning and comparing genomic sequences enables the identification of conserved sequence signatures and can enrich for coding and noncoding functional regions. In vertebrates, the comparison of human and rodent genomes and the comparison of evolutionarily distant genomes, such as human and pufferfish, have identified specific sets of [`]ultraconserved' sequence elements associated with the control of early development. However, is this just the tip of a [`]conservation iceberg' or do these sequences represent a specific class of regulatory element? Studies on the zebrafish phox2b gene region and the ENCODE project suggest that many regulatory elements are not highly conserved, posing intriguing questions about the relationship between noncoding sequence conservation and function and the evolution of regulatory sequences.

An Evolutionarily Conserved Sexual Signature in the Primate Brain

Björn Reinius — 2008-06-21T00:17:11-00:00

PLoS Genet, Vol. 4, No. 6. (20 June 2008), e1000100.

The question of a potential biological sexual signature in the human brain is a heavily disputed subject. In order to provide further insight into this issue, we used an evolutionary approach to identify genes with sex differences in brain expression level among primates. We reasoned that expression patterns important to uphold key male and female characteristics may be conserved during evolution. We selected cortex for our studies because this specific brain region is responsible for many higher behavioral functions. We compared gene expression profiles in the occipital cortex of male and female humans (Homo sapiens, a great ape) and cynomolgus macaques (Macaca fascicularis, an old world monkey), two catarrhine species that show abundant morphological sexual dimorphism, as well as in common marmosets (Callithrix Jacchus, a new world monkey) which are relatively sexually monomorphic. We identified hundreds of genes with sex-biased expression patterns in humans and macaques, while fewer than ten were differentially expressed between the sexes in marmosets. In primates, a general rule is that many of the morphological and behavioral sexual dimorphisms seen in polygamous species, such as macaques, are typically less pronounced in monogamous species such as the marmosets. Our observations suggest that this correlation may also be reflected in the extent of sex-biased gene expression in the brain. We identified 85 genes with common sex-biased expression, in both human and macaque and 2 genes, X inactivation-specific transcript (XIST) and Heat shock factor binding protein 1 (HSBP1), that were consistently sex-biased in the female direction in human, macaque, and marmoset. These observations imply a conserved signature of sexual gene expression dimorphism in cortex of primates. Further, we found that the coding region of female-biased genes is more evolutionarily constrained compared to the coding region of both male-biased and non sex-biased brain expressed genes. We found genes with conserved sexual gene expression dimorphism in the occipital cortex of humans, cynomolgus macaques, and common marmosets. Genes within sexual expression profiles may underlie important functional differences between the sexes, with possible importance during primate evolution.

A Drastic Reduction in the Life Span of Cystatin C L68Q Carriers Due to Life-Style Changes during the Last Two Centuries

Astridur Palsdottir — 2008-06-21T00:14:32-00:00

PLoS Genet, Vol. 4, No. 6. (20 June 2008), e1000099.

Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here, we report, based both on linkage disequilibrium and genealogical evidence, that all known copies of this mutation derive from a common ancestor born roughly 18 generations ago. Intriguingly, the genealogies reveal that obligate L68Q carriers born 1825 to 1900 experienced a drastic reduction in life span, from 65 years to the present-day average. At the same time, a parent-of-origin effect emerged, whereby maternal inheritance of the mutation was associated with a 9 year reduction in life span relative to paternal inheritance. As these trends can be observed in several different extended families, many generations after the mutational event, it seems likely that some environmental factor is responsible, perhaps linked to radical changes in the life-style of Icelanders during this period. A mutation with such radically different phenotypic effects in reaction to normal variation in human life-style not only opens the possibility of preventive strategies for HCCAA, but it may also provide novel insights into the complex relationship between genotype and environment in human disease.

Evaluating Statistical Methods Using Plasmode Data Sets in the Age of Massive Public Databases: An Illustration Using False Discovery Rates

Gary Gadbury — 2008-06-21T00:13:13-00:00

PLoS Genet, Vol. 4, No. 6. (20 June 2008), e1000098.

Plasmode is a term coined several years ago to describe data sets that are derived from real data but for which some truth is known. Omic techniques, most especially microarray and genomewide association studies, have catalyzed a new zeitgeist of data sharing that is making data and data sets publicly available on an unprecedented scale. Coupling such data resources with a science of plasmode use would allow statistical methodologists to vet proposed techniques empirically (as opposed to only theoretically) and with data that are by definition realistic and representative. We illustrate the technique of empirical statistics by consideration of a common task when analyzing high dimensional data: the simultaneous testing of hundreds or thousands of hypotheses to determine which, if any, show statistical significance warranting follow-on research. The now-common practice of multiple testing in high dimensional experiment (HDE) settings has generated new methods for detecting statistically significant results. Although such methods have heretofore been subject to comparative performance analysis using simulated data, simulating data that realistically reflect data from an actual HDE remains a challenge. We describe a simulation procedure using actual data from an HDE where some truth regarding parameters of interest is known. We use the procedure to compare estimates for the proportion of true null hypotheses, the false discovery rate (FDR), and a local version of FDR obtained from 15 different statistical methods.

Evolution of Mammals and Their Gut Microbes

Ruth Ley — 2008-06-20T11:27:07-00:00

Science, Vol. 320, No. 5883. (20 June 2008), pp. 1647-1651.

Mammals are metagenomic in that they are composed of not only their own gene complements but also those of all of their associated microbes. To understand the coevolution of the mammals and their indigenous microbial communities, we conducted a network-based analysis of bacterial 16S ribosomal RNA gene sequences from the fecal microbiota of humans and 59 other mammalian species living in two zoos and in the wild. The results indicate that host diet and phylogeny both influence bacterial diversity, which increases from carnivory to omnivory to herbivory; that bacterial communities codiversified with their hosts; and that the gut microbiota of humans living a modern life-style is typical of omnivorous primates. 10.1126/science.1155725

Proliferating Cells Express mRNAs with Shortened 3' Untranslated Regions and Fewer MicroRNA Target Sites

Rickard Sandberg — 2008-06-20T15:33:43-00:00

Science, Vol. 320, No. 5883. (20 June 2008), pp. 1643-1647.

Messenger RNA (mRNA) stability, localization, and translation are largely determined by sequences in the 3' untranslated region (3'UTR). We found a conserved increase in expression of mRNAs terminating at upstream polyadenylation sites after activation of primary murine CD4+ T lymphocytes. This program, resulting in shorter 3'UTRs, is a characteristic of gene expression during immune cell activation and correlates with proliferation across diverse cell types and tissues. Forced expression of full-length 3'UTRs conferred reduced protein expression. In some cases the reduction in protein expression could be reversed by deletion of predicted microRNA target sites in the variably included region. Our data indicate that gene expression is coordinately regulated, such that states of increased proliferation are associated with widespread reductions in the 3'UTR-based regulatory capacity of mRNAs. 10.1126/science.1155390

Natural Selection Shapes Genome-Wide Patterns of Copy-Number Polymorphism in Drosophila melanogaster

JJ Emerson — 2008-06-20T11:15:27-00:00

Science, Vol. 320, No. 5883. (20 June 2008), pp. 1629-1631.

The role that natural selection plays in governing the locations and early evolution of copy-number mutations remains largely unexplored. We used high-density full-genome tiling arrays to create a fine-scale genomic map of copy-number polymorphisms (CNPs) in Drosophila melanogaster. We inferred a total of 2658 independent CNPs, 56% of which overlap genes. These include CNPs that are likely to be under positive selection, most notably high-frequency duplications encompassing toxin-response genes. The locations and frequencies of CNPs are strongly shaped by purifying selection, with deletions under stronger purifying selection than duplications. Among duplications, those overlapping exons or introns, as well as those falling on the X chromosome, seem to be subject to stronger purifying selection. 10.1126/science.1158078

Phylogeny-Aware Gap Placement Prevents Errors in Sequence Alignment and Evolutionary Analysis

Ari Loytynoja — 2008-06-20T03:07:52-00:00

Science, Vol. 320, No. 5883. (20 June 2008), pp. 1632-1635.

Genetic sequence alignment is the basis of many evolutionary and comparative studies, and errors in alignments lead to errors in the interpretation of evolutionary information in genomes. Traditional multiple sequence alignment methods disregard the phylogenetic implications of gap patterns that they create and infer systematically biased alignments with excess deletions and substitutions, too few insertions, and implausible insertion-deletion-event histories. We present a method that prevents these systematic errors by recognizing insertions and deletions as distinct evolutionary events. We show theoretically and practically that this improves the quality of sequence alignments and downstream analyses over a wide range of realistic alignment problems. These results suggest that insertions and sequence turnover are more common than is currently thought and challenge the conventional picture of sequence evolution and mechanisms of functional and structural changes. 10.1126/science.1158395

Pervasive positive selection on duplicated and non duplicated vertebrate protein coding genes

Romain Studer — 2008-06-19T16:38:40-00:00

Genome Res. (18 June 2008), gr.076992.108.

A stringent branch-site codon model was used to detect positive selection in vertebrate evolution. We show that the test is robust to the large evolutionary distances involved. Positive selection was detected in 77% of 884 genes studied. Most positive selection concerns a few sites on a single branch of the phylogenetic tree: less than 2.5% of sites are affected by positive selection. No functional category was over-represented among genes under positive selection. Surprisingly, whole genome duplication had no effect on the prevalence of positive selection, whether the fish specific genome duplication or the two rounds at the origin of vertebrates. Thus positive selection has not been limited to a few gene classes, nor to specific evolutionary events such as duplication, but has been pervasive during vertebrate evolution. 10.1101/gr.076992.108

From genes to functional classes in the study of biological systems

Fatima Al-Shahrour — 2007-04-04T03:54:52-00:00

BMC Bioinformatics, Vol. 8 (03 April 2007), 114.

A simple method for calculating the statistical power for detecting a QTL located in a marker interval

Z Hu — 2008-04-30T19:33:14-00:00

Heredity, Vol. aop, No. current.

Use and misuse of the gene ontology annotations.

Seung Yon Rhee — 2008-05-15T05:58:28-00:00

Nature reviews. Genetics (13 May 2008)

The Gene Ontology (GO) project is a collaboration among model organism databases to describe gene products from all organisms using a consistent and computable language. GO produces sets of explicitly defined, structured vocabularies that describe biological processes, molecular functions and cellular components of gene products in both a computer- and human-readable manner. Here we describe key aspects of GO, which, when overlooked, can cause erroneous results, and address how these pitfalls can be avoided.

Recracking the nucleosome positioning code

Mark Segal — 2008-06-18T18:01:45-00:00

Recurrent Deletion and Gene Presence/Absence Polymorphism: Telomere Dynamics Dominate Evolution at the Tip of 3L in Drosophila melanogaster and D. simulans

Andrew Kern — 2008-06-18T17:53:23-00:00

Genetics, Vol. 179, No. 2. (1 June 2008), pp. 1021-1027.

Although Drosophila melanogaster has been the subject of intensive analysis of polymorphism and divergence, little is known about the distribution of variation at the most distal regions of chromosomes arms. Here we report a survey of genetic variation on the tip of 3L in D. melanogaster and D. simulans. Levels of single nucleotide polymorphism in the most distal euchromatic sequence are approximately one order of magnitude less than that typically observed in genomic regions of normal crossing over, consistent with what might be expected under models of linked selection in regions of low crossing over. However, despite this reduced level of nucleotide variation, we found abundant deletion polymorphism. These deletions create at least three gene presence/absence polymorphisms within D. melanogaster: the putative G-protein coupled receptor mthl-8 (which is the most distal known or predicted gene on 3L) and the unannotated mRNAs AY060886 and BT006009. Strikingly, D. simulans is also segregating deletions that cause mthl8 presence/absence polymorphism. Breakpoint sequencing and tests of correlations with segregating SNPs in D. melanogaster suggest that each deletion is unique. Cloned breakpoint sequences revealed the presence of Het-A elements just distal to unique, canonical euchromatic sequences. This pattern suggests a model in which repeated telomeric deficiencies cause deletions of euchromatic sequence followed by subsequent "healing" by retrotranposition of Het-A elements. These data reveal the dominance of telomeric dynamics on the evolution of closely linked sequences in Drosophila. 10.1534/genetics.107.078345

Levels of Selection on Threshold Characters

Jacob Moorad — 2008-06-18T17:49:42-00:00

Genetics, Vol. 179, No. 2. (1 June 2008), pp. 899-905.

Threshold models are useful for understanding the evolution of dimorphic traits with polygenic bases. Selection for threshold characters on individuals is expected to be frequency dependent because of the peculiar way that selection views underlying genetic and environmental factors. Selection among individuals is inefficient because individual phenotypes fall into only two discrete categories that map imperfectly to the underlying genes. Incidence, however, can be continuously distributed among groups, making among-group selection relatively more efficient. Differently put, the group-mean phenotype can be a better predictor of an individual's genotype than that individual's own phenotype. Because evolution in group-structured populations is governed by the balance of selection within and between groups, we can expect threshold traits to evolve in fundamentally different ways when group mean fitness is a function of morph frequency. We extend the theory of selection on threshold traits to include group selection using contextual analysis. For the simple case of linear group-fitness functions, we show that the group-level component of selection, like the individual-level component, is frequency dependent. However, the conditions that determine which component dominates when levels of selection are in conflict (as described by Hamilton's rule) are not frequency dependent. Thus, enhanced group selection is not an inherent property of threshold characters. Nevertheless, we show that predicting the effects of multiple levels of selection on dimorphic traits requires special considerations of the threshold model. 10.1534/genetics.108.086959

Complementary hierarchical clustering

Gen Nowak — 2008-06-18T17:43:11-00:00

Biostat, Vol. 9, No. 3. (1 July 2008), pp. 467-483.

When applying hierarchical clustering algorithms to cluster patient samples from microarray data, the clustering patterns generated by most algorithms tend to be dominated by groups of highly differentially expressed genes that have closely related expression patterns. Sometimes, these genes may not be relevant to the biological process under study or their functions may already be known. The problem is that these genes can potentially drown out the effects of other genes that are relevant or have novel functions. We propose a procedure called complementary hierarchical clustering that is designed to uncover the structures arising from these novel genes that are not as highly expressed. Simulation studies show that the procedure is effective when applied to a variety of examples. We also define a concept called relative gene importance that can be used to identify the influential genes in a given clustering. Finally, we analyze a microarray data set from 295 breast cancer patients, using clustering with the correlation-based distance measure. The complementary clustering reveals a grouping of the patients which is uncorrelated with a number of known prognostic signatures and significantly differing distant metastasis-free probabilities. 10.1093/biostatistics/kxm046

Significance levels for studies with correlated test statistics.

Jianxin Shi — 2008-03-03T10:24:44-00:00

Biostatistics (18 December 2007)

When testing large numbers of null hypotheses, one needs to assess the evidence against the global null hypothesis that none of the hypotheses is false. Such evidence typically is based on the test statistic of the largest magnitude, whose statistical significance is evaluated by permuting the sample units to simulate its null distribution. Efron (2007) has noted that correlation among the test statistics can induce substantial interstudy variation in the shapes of their histograms, which may cause misleading tail counts. Here, we show that permutation-based estimates of the overall significance level also can be misleading when the test statistics are correlated. We propose that such estimates be conditioned on a simple measure of the spread of the observed histogram, and we provide a method for obtaining conditional significance levels. We justify this conditioning using the conditionality principle described by Cox and Hinkley (1974). Application of the method to gene expression data illustrates the circumstances when conditional significance levels are needed.

Mixture models with multiple levels, with application to the analysis of multifactor gene expression data.

Rebecka Jörnsten — 2008-03-24T06:03:38-00:00

Biostatistics (5 February 2008)

Model-based clustering is a popular tool for summarizing high-dimensional data. With the number of high-throughput large-scale gene expression studies still on the rise, the need for effective data- summarizing tools has never been greater. By grouping genes according to a common experimental expression profile, we may gain new insight into the biological pathways that steer biological processes of interest. Clustering of gene profiles can also assist in assigning functions to genes that have not yet been functionally annotated. In this paper, we propose 2 model selection procedures for model-based clustering. Model selection in model-based clustering has to date focused on the identification of data dimensions that are relevant for clustering. However, in more complex data structures, with multiple experimental factors, such an approach does not provide easily interpreted clustering outcomes. We propose a mixture model with multiple levels, , that provides sparse representations both "within" and "between" cluster profiles. We explore various flexible "within-cluster" parameterizations and discuss how efficient parameterizations can greatly enhance the objective interpretability of the generated clusters. Moreover, we allow for a sparse "between-cluster" representation with a different number of clusters at different levels of an experimental factor of interest. This enhances interpretability of clusters generated in multiple-factor contexts. Interpretable cluster profiles can assist in detecting biologically relevant groups of genes that may be missed with less efficient parameterizations. We use our multilevel mixture model to mine a proliferating cell line expression data set for annotational context and regulatory motifs. We also investigate the performance of the multilevel clustering approach on several simulated data sets.

Linkage disequilibrium — understanding the evolutionary past and mapping the medical future

Montgomery Slatkin — 2008-05-17T12:26:03-00:00

Nature Reviews Genetics, Vol. 9, No. 6., pp. 477-485.

Dynamics and Design Principles of a Basic Regulatory Architecture Controlling Metabolic Pathways

Chen-Shan Chin — 2008-06-17T20:37:14-00:00

PLoS Biology, Vol. 6, No. 6. (1 June 2008), e146.

The dynamic features of a genetic network's response to environmental fluctuations represent essential functional specifications and thus may constrain the possible choices of network architecture and kinetic parameters. To explore the connection between dynamics and network design, we have analyzed a general regulatory architecture that is commonly found in many metabolic pathways. Such architecture is characterized by a dual control mechanism, with end product feedback inhibition and transcriptional regulation mediated by an intermediate metabolite. As a case study, we measured with high temporal resolution the induction profiles of the enzymes in the leucine biosynthetic pathway in response to leucine depletion, using an automated system for monitoring protein expression levels in single cells. All the genes in the pathway are known to be coregulated by the same transcription factors, but we observed drastically different dynamic responses for enzymes upstream and immediately downstream of the key control point—the intermediate metabolite α-isopropylmalate (αIPM), which couples metabolic activity to transcriptional regulation. Analysis based on genetic perturbations suggests that the observed dynamics are due to differential regulation by the leucine branch-specific transcription factor Leu3, and that the downstream enzymes are strictly controlled and highly expressed only when αIPM is available. These observations allow us to build a simplified mathematical model that accounts for the observed dynamics and can correctly predict the pathway's response to new perturbations. Our model also suggests that transient dynamics and steady state can be separately tuned and that the high induction levels of the downstream enzymes are necessary for fast leucine recovery. It is likely that principles emerging from this work can reveal how gene regulation has evolved to optimize performance in other metabolic pathways with similar architecture.

Gene Duplication: A Drive for Phenotypic Diversity and Cause of Human Disease.

Bernard Conrad — 2007-04-19T17:12:06-00:00

Annu Rev Genomics Hum Genet (26 March 2007)

Gene duplication is one of the key factors driving genetic innovation, i.e., producing novel genetic variants. Although the contribution of whole-genome and segmental duplications to phenotypic diversity across species is widely appreciated, the phenotypic spectrum and potential pathogenicity of small-scale duplications in individual genomes are less well explored. This review discusses the nature of small-scale duplications and the phenotypes produced by such duplications. Phenotypic variation and disease phenotypes induced by duplications are more diverse and widespread than previously anticipated, and duplications are a major class of disease-related genomic variation. Pathogenic duplications particularly involve dosage-sensitive genes with both similar and dissimilar over- and underexpression phenotypes, and genes encoding proteins with a propensity to aggregate. Phenotypes related to human-specific copy number variation in genes regulating environmental responses and immunity are increasingly recognized. Small genomic duplications containing defense-related genes also contribute to complex common phenotypes. Expected online publication date for the Annual Review of Genomics and Human Genetics Volume 8 is August 30, 2007. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

Trends in Selenium Utilization in Marine Microbial World Revealed through the Analysis of the Global Ocean Sampling (GOS) Project

Yan Zhang — 2008-06-13T19:06:39-00:00

PLoS Genet, Vol. 4, No. 6. (13 June 2008), e1000095.

Selenium is an important trace element that occurs in proteins in the form of selenocysteine (Sec) and in tRNAs in the form of selenouridine. Recent large-scale metagenomics projects provide an opportunity for understanding global trends in trace element utilization. Herein, we characterized the selenoproteome of the microbial marine community derived from the Global Ocean Sampling (GOS) expedition. More than 3,600 selenoprotein gene sequences belonging to 58 protein families were detected, including sequences representing 7 newly identified selenoprotein families, such as homologs of ferredoxin–thioredoxin reductase and serine protease. In addition, a new eukaryotic selenoprotein family, thiol reductase GILT, was identified. Most GOS selenoprotein families originated from Cys-containing thiol oxidoreductases. In both Pacific and Atlantic microbial communities, SelW-like and SelD were the most widespread selenoproteins. Geographic location had little influence on Sec utilization as measured by selenoprotein variety and the number of selenoprotein genes detected; however, both higher temperature and marine (as opposed to freshwater and other aquatic) environment were associated with increased use of this amino acid. Selenoproteins were also detected with preference for either environment. We identified novel fusion forms of several selenoproteins that highlight redox activities of these proteins. Almost half of Cys-containing SelDs were fused with NADH dehydrogenase, whereas such SelD forms were rare in terrestrial organisms. The selenouridine utilization trait was also analyzed and showed an independent evolutionary relationship with Sec utilization. Overall, our study provides insights into global trends in microbial selenium utilization in marine environments.

Positive selection drives a correlation between nonsynonymous/ synonymous divergence and functional divergence.

Jacob A Tennessen — 2008-05-01T10:54:48-00:00

Bioinformatics (Oxford, England) (28 April 2008)

MOTIVATION: Functional divergence among proteins is often assumed to be strongly influenced by natural selection, as inferred from the ratio of nonsynonymous nucleotide divergence (d(N)) to synonymous nucleotide divergence (d(S)). That is, the more a mutation changes protein function, the more likely it is to be either selected against or selectively favored, and because the d(N)/d(S) ratio is a measure of natural selection, this ratio can be used to predict the degree of functional divergence (d(F)). However, these hypotheses have rarely been experimentally tested. RESULTS: I present a novel method to address this issue, and demonstrate that divergence in bacteria-killing activity among animal antimicrobial peptides is positively correlated with the log of the d(N)/d(S) ratio. The primary cause of this pattern appears to be that positively selected substitutions change protein function more than neutral substitutions do. Thus, the d(N)/d(S) ratio is an accurate estimator of adaptive functional divergence. CONTACT: tennessj@science.oregonstate.edu SUPPLEMENTARY INFORMATION: Supplementary data, including GenBank Accession numbers, are available at Bioinformatics Online.

The Transcriptional Landscape of the Yeast Genome Defined by RNA Sequencing

Ugrappa Nagalakshmi — 2008-05-01T22:47:26-00:00

Science (1 May 2008), 1158441.

The identification of untranslated regions (UTRs), introns, and coding regions within an organism remains challenging. We developed a quantitative sequencing-based method for mapping transcribed regions called RNA-Seq in which cDNA fragments are subjected to high throughput sequencing and mapped to the genome. We applied RNA-Seq to generate a high-resolution transcriptome map of the yeast genome and demonstrated that most (74.5%) of the nonrepetitive sequence of the yeast genome is transcribed. We confirmed many known and predicted introns and demonstrated that others are not actively used. Alternative initiation codons and upstream open reading frames were also identified for many yeast genes. We also found unexpected 3' end heterogeneity and the presence of many overlapping genes. These results indicate that the yeast transcriptome is more complex than previously appreciated. 10.1126/science.1158441

Anticipatory Behavior Within Microbial Genetic Networks

Ilias Tagkopoulos — 2008-05-08T21:24:02-00:00

Science (8 May 2008), 1154456.

We question whether homeostasis alone adequately explains microbial responses to environmental stimuli, and explore the capacity of intra-cellular networks for predictive behavior in a fashion similar to metazoan nervous systems. We show that in silico biochemical networks, evolving randomly under precisely defined complex habitats, capture the dynamical, multi-dimensional structure of diverse environments by forming internal models that allow prediction of environmental change. We provide evidence for such anticipatory behavior by revealing striking correlations of Escherichia coli transcriptional responses to temperature and oxygen perturbations--precisely mirroring the co-variation of these parameters upon transitions between the outside world and the mammalian gastrointestinal-tract. We further show that these internal correlations reflect a true associative learning paradigm, since they show rapid de-coupling upon exposure to novel environments. 10.1126/science.1154456

Birth and Rapid Subcellular Adaptation of a Hominoid-Specific CDC14 Protein

Lia Rosso — 2008-06-10T19:41:00-00:00

PLoS Biology, Vol. 6, No. 6. (1 June 2008), e140.

Gene duplication was prevalent during hominoid evolution, yet little is known about the functional fate of new ape gene copies. We characterized the CDC14B cell cycle gene and the functional evolution of its hominoid-specific daughter gene, CDC14Bretro. We found that CDC14B encodes four different splice isoforms that show different subcellular localizations (nucleus or microtubule-associated) and functional properties. A microtubular CDC14B variant spawned CDC14Bretro through retroposition in the hominoid ancestor 18–25 million years ago (Mya). CDC14Bretro evolved brain-/testis-specific expression after the duplication event and experienced a short period of intense positive selection in the African ape ancestor 7–12 Mya. Using resurrected ancestral protein variants, we demonstrate that by virtue of amino acid substitutions in distinct protein regions during this time, the subcellular localization of CDC14Bretro progressively shifted from the association with microtubules (stabilizing them) to an association with the endoplasmic reticulum. CDC14Bretro evolution represents a paradigm example of rapid, selectively driven subcellular relocalization, thus revealing a novel mode for the emergence of new gene function.

CSMET: Comparative Genomic Motif Detection via Multi-Resolution Phylogenetic Shadowing

Pradipta Ray — 2008-06-07T18:41:30-00:00

PLoS Comput Biol, Vol. 4, No. 6. (6 June 2008), e1000090.

Functional turnover of transcription factor binding sites (TFBSs), such as whole-motif loss or gain, are common events during genome evolution. Conventional probabilistic phylogenetic shadowing methods model the evolution of genomes only at nucleotide level, and lack the ability to capture the evolutionary dynamics of functional turnover of aligned sequence entities. As a result, comparative genomic search of non-conserved motifs across evolutionarily related taxa remains a difficult challenge, especially in higher eukaryotes, where the cis-regulatory regions containing motifs can be long and divergent; existing methods rely heavily on specialized pattern-driven heuristic search or sampling algorithms, which can be difficult to generalize and hard to interpret based on phylogenetic principles. We propose a new method: Conditional Shadowing via Multi-resolution Evolutionary Trees, or CSMET, which uses a context-dependent probabilistic graphical model that allows aligned sites from different taxa in a multiple alignment to be modeled by either a background or an appropriate motif phylogeny conditioning on the functional specifications of each taxon. The functional specifications themselves are the output of a phylogeny which models the evolution not of individual nucleotides, but of the overall functionality (e.g., functional retention or loss) of the aligned sequence segments over lineages. Combining this method with a hidden Markov model that autocorrelates evolutionary rates on successive sites in the genome, CSMET offers a principled way to take into consideration lineage-specific evolution of TFBSs during motif detection, and a readily computable analytical form of the posterior distribution of motifs under TFBS turnover. On both simulated and real Drosophila cis-regulatory modules, CSMET outperforms other state-of-the-art comparative genomic motif finders.

Genome-Wide Analysis Reveals a Complex Pattern of Genomic Imprinting in Mice

Jason Wolf — 2008-06-07T18:38:18-00:00

PLoS Genet, Vol. 4, No. 6. (6 June 2008), e1000091.

Parent-of-origin–dependent gene expression resulting from genomic imprinting plays an important role in modulating complex traits ranging from developmental processes to cognitive abilities and associated disorders. However, while gene-targeting techniques have allowed for the identification of imprinted loci, very little is known about the contribution of imprinting to quantitative variation in complex traits. Most studies, furthermore, assume a simple pattern of imprinting, resulting in either paternal or maternal gene expression; yet, more complex patterns of effects also exist. As a result, the distribution and number of different imprinting patterns across the genome remain largely unexplored. We address these unresolved issues using a genome-wide scan for imprinted quantitative trait loci (iQTL) affecting body weight and growth in mice using a novel three-generation design. We identified ten iQTL that display much more complex and diverse effect patterns than previously assumed, including four loci with effects similar to the callipyge mutation found in sheep. Three loci display a new phenotypic pattern that we refer to as bipolar dominance, where the two heterozygotes are different from each other while the two homozygotes are identical to each other. Our study furthermore detected a paternally expressed iQTL on Chromosome 7 in a region containing a known imprinting cluster with many paternally expressed genes. Surprisingly, the effects of the iQTL were mostly restricted to traits expressed after weaning. Our results imply that the quantitative effects of an imprinted allele at a locus depend both on its parent of origin and the allele it is paired with. Our findings also show that the imprinting pattern of a locus can be variable over ontogenetic time and, in contrast to current views, may often be stronger at later stages in life.

The Evolution of the DLK1-DIO3 Imprinted Domain in Mammals

Carol Edwards — 2008-06-04T01:22:45-00:00

PLoS Biology, Vol. 6, No. 6. (1 June 2008), e135.

A comprehensive, domain-wide comparative analysis of genomic imprinting between mammals that imprint and those that do not can provide valuable information about how and why imprinting evolved. The imprinting status, DNA methylation, and genomic landscape of the Dlk1-Dio3 cluster were determined in eutherian, metatherian, and prototherian mammals including tammar wallaby and platypus. Imprinting across the whole domain evolved after the divergence of eutherian from marsupial mammals and in eutherians is under strong purifying selection. The marsupial locus at 1.6 megabases, is double that of eutherians due to the accumulation of LINE repeats. Comparative sequence analysis of the domain in seven vertebrates determined evolutionary conserved regions common to particular sub-groups and to all vertebrates. The emergence of Dlk1-Dio3 imprinting in eutherians has occurred on the maternally inherited chromosome and is associated with region-specific resistance to expansion by repetitive elements and the local introduction of noncoding transcripts including microRNAs and C/D small nucleolar RNAs. A recent mammal-specific retrotransposition event led to the formation of a completely new gene only in the eutherian domain, which may have driven imprinting at the cluster.

Identification of active transcriptional regulatory modules by the functional assay of DNA from nucleosome-free regions.

Mahesh Yaragatti — 2008-05-01T09:02:43-00:00

Genome research (25 April 2008)

The identification of transcriptional regulatory modules within mammalian genomes is a prerequisite to understanding the mechanisms controlling regulated gene expression. While high-throughput microarray- and sequencing-based approaches have been used to map the genomic locations of sites of nuclease hypersensitivity or target DNA sequences bound by specific protein factors, the identification of regulatory elements using functional assays, which would provide important complementary data, has been relatively rare. Here we present a method that permits the functional identification of active transcriptional regulatory modules using a simple procedure for the isolation and analysis of DNA derived from nucleosome-free regions (NFRs), the 2% of the cellular genome that contains these elements. The more than 100 new active regulatory DNAs identified in this manner from F9 cells correspond to both promoter-proximal and distal elements, and display several features predicted for endogenous transcriptional regulators, including localization within DNase-accessible chromatin and CpG islands, and proximity to expressed genes. Furthermore, comparison with published ChIP-seq data of ES-cell chromatin shows that the functional elements we identified correspond with genomic regions enriched for H3K4me3, a histone modification associated with active transcriptional regulatory elements, and that the correspondence of H3K4me3 with our promoter-distal elements is largely ES-cell specific. The majority of the distal elements exhibit enhancer activity. Importantly, these functional DNA fragments are an average 149 bp in length, greatly facilitating future applications to identify transcription factor binding sites mediating their activity. Thus, this approach provides a tool for the high-resolution identification of the functional components of active promoters and enhancers.

Genetic determinants of phenotypic diversity in humans

Nazli Rahim — 2008-04-24T19:33:41-00:00

Genome Biology, Vol. 9 (24 April 2008), 215.

A Probabilistic Model of Local Sequence Alignment That Simplifies Statistical Significance Estimation

Sean Eddy — 2008-05-30T23:44:58-00:00

Assessing the Evolutionary Impact of Amino Acid Mutations in the Human Genome

2008-05-30T21:29:18-00:00

Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation

Yutaka Kondo — 2008-05-29T14:31:27-00:00

Nature Genetics, Vol. 40, No. 6. (18 May 2008), pp. 741-750.