Person:

Jordan, I. King

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https://hdl.handle.net/1853/71381

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School of Biological Sciences

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Now showing 1 - 10 of 18

Meningococcus genome informatics platform: a system for analyzing multilocus sequence typing data

(Georgia Institute of Technology, 2009-05-25) Katz, Lee S. ; Bolen, Chris R. ; Harcourt, Brian H. ; Schmink, Susanna ; Wang, Xin ; Kislyuk, Andrey ; Taylor, Robert T. ; Mayer, Leonard W. ; Jordan, I. King

The Meningococcus Genome Informatics Platform (MGIP) is a suite of computational tools for the analysis of multilocus sequence typing (MLST)data, at http://mgip.biology.gatech.edu. MLST is used to generate allelic profiles to characterize strains of Neisseria meningitidis, a major cause of bacterial meningitis worldwide. Neisseria meningitidis strains are characterized with MLST as specific sequence types (ST) and clonal complexes (CC) based on the DNA sequences at defined loci. These data are vital to molecular epidemiology studies of N. meningitidis, including outbreak investigations and population biology. MGIP analyzes DNA sequence trace files, returns individual allele calls and characterizes the STs and CCs. MGIP represents a substantial advance over existing software in several respects: (i) ease of use—MGIP is user friendly, intuitive and thoroughly documented; (ii) flexibility—because MGIP is a website, it is compatible with any computer with an internet connection, can be used from any geographic location, and there is no installation; (iii) speed—MGIP takes just over one minute to process a set of 96 trace files; and (iv) expandability—MGIP has the potential to expand to more loci than those used in MLST and even to other bacterial species.
Natural selection governs local, but not global, evolutionary gene coexpression networks in Caenorhabditis elegans

(Georgia Institute of Technology, 2008-11-13) Jordan, I. King ; Katz, Lee S. ; Denver, Dee R. ; Streelman, J. Todd

Background. Large-scale evaluation of gene expression variation among Caenorhabditis elegans lines that have diverged from a common ancestor allows for the analysis of a novel class of biological networks – evolutionary gene coexpression networks. Comparative analysis of these evolutionary networks has the potential to uncover the effects of natural selection in shaping coexpression network topologies since C. elegans mutation accumulation (MA) lines evolve essentially free from the effects of natural selection, whereas natural isolate (NI) populations are subject to selective constraints. Results. We compared evolutionary gene coexpression networks for C. elegans MA lines versus NI populations to evaluate the role that natural selection plays in shaping the evolution of network topologies. MA and NI evolutionary gene coexpression networks were found to have very similar global topological properties as measured by a number of network topological parameters. Observed MA and NI networks show node degree distributions and average values for node degree, clustering coefficient, path length, eccentricity and betweeness that are statistically indistinguishable from one another yet highly distinct from randomly simulated networks. On the other hand, at the local level the MA and NI coexpression networks are highly divergent; pairs of genes coexpressed in the MA versus NI lines are almost entirely different as are the connectivity and clustering properties of individual genes. Conclusion. It appears that selective forces shape how local patterns of coexpression change over time but do not control the global topology of C. elegans evolutionary gene coexpression networks. These results have implications for the evolutionary significance of global network topologies, which are known to be conserved across disparate complex systems.
Evolutionary rates and patterns for human transcription factor binding sites derived from repetitive DNA

(Georgia Institute of Technology, 2008-05-17) Polavarapu, Nalini ; Mariño-Ramírez, Leonardo ; Landsman, David ; McDonald, John F. ; Jordan, I. King

Background The majority of human non-protein-coding DNA is made up of repetitive sequences, mainly transposable elements (TEs). It is becoming increasingly apparent that many of these repetitive DNA sequence elements encode gene regulatory functions. This fact has important evolutionary implications, since repetitive DNA is the most dynamic part of the genome. We set out to assess the evolutionary rate and pattern of experimentally characterized human transcription factor binding sites (TFBS) that are derived from repetitive versus non-repetitive DNA to test whether repeat-derived TFBS are in fact rapidly evolving. We also evaluated the position-specific patterns of variation among TFBS to look for signs of functional constraint on TFBS derived from repetitive and non-repetitive DNA. Results We found numerous experimentally characterized TFBS in the human genome, 7–10% of all mapped sites, which are derived from repetitive DNA sequences including simple sequence repeats (SSRs) and TEs. TE-derived TFBS sequences are far less conserved between species than TFBS derived from SSRs and non-repetitive DNA. Despite their rapid evolution, several lines of evidence indicate that TE-derived TFBS are functionally constrained. First of all, ancient TE families, such as MIR and L2, are enriched for TFBS relative to younger families like Alu and L1. Secondly, functionally important positions in TE-derived TFBS, specifically those residues thought to physically interact with their cognate protein binding factors (TF), are more evolutionarily conserved than adjacent TFBS positions. Finally, TE-derived TFBS show position-specific patterns of sequence variation that are highly distinct from random patterns and similar to the variation seen for non-repeat derived sequences of the same TFBS. Conclusion The abundance of experimentally characterized human TFBS that are derived from repetitive DNA speaks to the substantial regulatory effects that this class of sequence has on the human genome. The unique evolutionary properties of repeat-derived TFBS are perhaps even more intriguing. TE-derived TFBS in particular, while clearly functionally constrained, evolve extremely rapidly relative to non-repeat derived sites. Such rapidly evolving TFBS are likely to confer species-specific regulatory phenotypes, i.e. divergent expression patterns, on the human evolutionary lineage. This result has practical implications with respect to the widespread use of evolutionary conservation as a surrogate for functionally relevant non-coding DNA. Most TE-derived TFBS would be missed using the kinds of sequence conservation-based screens, such as phylogenetic footprinting, that are used to help characterize non-coding DNA. Thus, the very TFBS that are most likely to yield human-specific characteristics will be neglected by the comparative genomic techniques that are currently de rigeur for the identification of novel regulatory sites.
Highly conserved regimes of neighbor-base-dependent mutation generated the background primary-structural heterogeneities along vertebrate chromosomes

(Georgia Institute of Technology, 2008-05-14) Antezana, Marcos A. ; Jordan, I. King

The content of guanine+cytosine varies markedly along the chromosomes of homeotherms and great effort has been devoted to studying this heterogeneity and its biological implications. Already before the DNA-sequencing era, however, it was established that the dinucleotides in the DNA of mammals in particular, and of most organisms in general, show striking over- and under-representations that cannot be explained by the base composition. Here we show that in the coding regions of vertebrates both GC content and codon occurrences are strongly correlated with such ‘‘motif preferences’’ even though we quantify the latter using an index that is not affected by the base composition, codon usage, and protein-sequence encoding. These correlations are likely to be the result of the long-term shaping of the primary structure of genic and non-genic DNA by a regime of mutation of which central features have been maintained by natural selection. We find indeed that these preferences are conserved in vertebrates even more rigidly than codon occurrences and we show that the occurrence-preference correlations are stronger in intronic and non-genic DNA, with the R2s reaching 99% when GC content is ,0.5. The mutation regime appears to be characterized by rates that depend markedly on the bases present at the site preceding and at that following each mutating site, because when we estimate such rates of neighbor-base-dependent mutation (NBDM) from substitutions retrieved from alignments of coding, intronic, and nongenic mammalian DNA sorted and grouped by GC content, they suffice to simulate DNA sequences in which motif occurrences and preferences as well as the correlations of motif preferences with GC content and with motif occurrences, are very similar to the mammalian ones. The best fit, however, is obtained with NBDM regimes lacking strand effects, which indicates that over the long term NBDM switches strands in the germline as one would expect for effects due to loosely contained background transcription. Finally, we show that human coding regions are less mutable under the estimated NBDM regimes than under matched context-independent mutation and that this entails marked differences between the spectra of amino-acid mutations that either mutation regime should generate. In the Discussion we examine the mechanisms likely to underlie NBDM heterogeneity along chromosomes and propose that it reflects how the diversity and activity of lesion-bypass polymerases (LBPs) track the landscapes of scheduled and non-scheduled genome repair, replication, and transcription during the cell cycle. We conclude that the primary structure of vertebrate genic DNA at and below the trinucleotide level has been governed over the long term by highly conserved regimes of NBDM which should be under direct natural selection because they alter drastically missense-mutation rates and hence the somatic and the germline mutational loads. Therefore, the non-coding DNA of vertebrates may have been shaped by NBDM only epiphenomenally, with non-genic DNA being affected mainly when found in the proximity of genes.
Endogenous retroviruses of the chicken genome

(Georgia Institute of Technology, 2008-03-24) Huda, Ahsan ; Polavarapu, Nalini ; Jordan, I. King ; McDonald, John F.

We analyzed the chicken (Gallus gallus) genome sequence to search for previously uncharacterized endogenous retrovirus (ERV) sequences using ab initio and combined evidence approaches. We discovered 11 novel families of ERVs that occupy more than 21 million base pairs, approximately 2%, of the chicken genome. These novel families include a number of recently active full-length elements possessing identical long terminal repeats (LTRs) as well as intact gag and pol open reading frames. The abundance and diversity of chicken ERVs we discovered underscore the utility of an approach that combines multiple methods for the identification of interspersed repeats in vertebrate genomes.
Dual coding of siRNAs and miRNAs by Plant Transposable Elements

(Georgia Institute of Technology, 2008-03) Piriyapongsa, Jittima ; Jordan, I. King

We recently proposed a specific model whereby miRNAs encoded from short nonautonomous DNA-type TEs known as MITEs evolved from corresponding ancestral full-length (autonomous) elements that originally encoded short interfering (siRNAs). Our miRNA-origins model predicts that evolutionary intermediates may exist as TEs that encode both siRNAs and miRNAs, and we analyzed Arabidopsis thaliana and Oryza sativa (rice) genomic sequence and expression data to test this prediction. We found a number of examples of individual plant TE insertions that encode both siRNAs and miRNAs. We show evidence that these dual coding TEs can be expressed as readthrough transcripts from the intronic regions of spliced RNA messages. These TE transcripts can fold to form the hairpin (stem–loop) structures characteristic of miRNA genes along with longer doublestranded RNA regions that typically are processed as siRNAs. Taken together with a recent study showing Drosha independent processing of miRNAs from Drosophila introns, our results indicate that ancestral miRNAs could have evolved from TEs prior to the full elaboration of the miRNA biogenesis pathway. Later, as the specific miRNA biogenesis pathway evolved, and numerous other expressed inverted repeat regions came to be recognized by the miRNA processing endonucleases, the host gene-related regulatory functions of miRNAs emerged. In this way, host genomes were afforded an additional level of regulatory complexity as a by-product of TE defense mechanisms. The siRNA-to-miRNA evolutionary transition is representative of a number of other regulatory mechanisms that evolved to silence TEs and were later co-opted to serve as regulators of host gene expression.
Evaluating the protein coding potential of exonized transposable element sequences

(Georgia Institute of Technology, 2007-11-26) Piriyapongsa, Jittima ; Rutledge, Mark T. ; Patel, Sanil ; Borodovsky, Mark ; Jordan, I. King

Background: Transposable element (TE) sequences, once thought to be merely selfish or parasitic members of the genomic community, have been shown to contribute a wide variety of functional sequences to their host genomes. Analysis of complete genome sequences have turned up numerous cases where TE sequences have been incorporated as exons into mRNAs, and it is widely assumed that such 'exonized' TEs encode protein sequences. However, the extent to which TE-derived sequences actually encode proteins is unknown and a matter of some controversy. We have tried to address this outstanding issue from two perspectives: i-by evaluating ascertainment biases related to the search methods used to uncover TE-derived protein coding sequences (CDS) and ii-through a probabilistic codon-frequency based analysis of the protein coding potential of TE-derived exons. Results: We compared the ability of three classes of sequence similarity search methods to detect TE-derived sequences among data sets of experimentally characterized proteins: 1-a profile-based hidden Markov model (HMM) approach, 2-BLAST methods and 3-RepeatMasker. Profile based methods are more sensitive and more selective than the other methods evaluated. However, the application of profile-based search methods to the detection of TE-derived sequences among well-curated experimentally characterized protein data sets did not turn up many more cases than had been previously detected and nowhere near as many cases as recent genome-wide searches have. We observed that the different search methods used were complementary in the sense that they yielded largely non-overlapping sets of hits and differed in their ability to recover known cases of TE-derived CDS. The probabilistic analysis of TE-derived exon sequences indicates that these sequences have low protein coding potential on average. In particular, non-autonomous TEs that do not encode protein sequences, such as Alu elements, are frequently exonized but unlikely to encode protein sequences. Conclusion: The exaptation of the numerous TE sequences found in exons as bona fide protein coding sequences may prove to be far less common than has been suggested by the analysis of complete genomes. We hypothesize that many exonized TE sequences actually function as post-transcriptional regulators of gene expression, rather than coding sequences, which may act through a variety of double stranded RNA related regulatory pathways. Indeed, their relatively high copy numbers and similarity to sequences dispersed throughout the genome suggests that exonized TE sequences could serve as master regulators with a wide scope of regulatory influence.
A family of human microRNA genes from miniature-inverted repeat transposable elements

(Georgia Institute of Technology, 2007-02-14) Piriyapongsa, Jittima ; Jordan, I. King

While hundreds of novel microRNA (miRNA) genes have been discovered in the last few years alone, the origin and evolution of these non-coding regulatory sequences remain largely obscure. In this report, we demonstrate that members of a recently discovered family of human miRNA genes, hsa-mir-548, are derived from Made1 transposable elements. Made1 elements are short miniature inverted-repeat transposable elements (MITEs), which consist of two 37 base pair (bp) terminal inverted repeats that flank 6 bp of internal sequence. Thus, Made1 elements are nearly perfect palindromes, and when expressed as RNA they form highly stable hairpin loops. Apparently, these Made1-related structures are recognized by the RNA interference enzymatic machinery and processed to form 22 bp mature miRNA sequences. Consistent with their origin from MITEs, hsa-mir- 548 genes are primate-specific and have many potential paralogs in the human genome. There are more than 3,500 putative hsa-mir-548 target genes; analysis of their expression profiles and functional affinities suggests cancer-related regulatory roles for hsa-mir-548. Taken together, the characteristics of Made1 elements, and MITEs in general, point to a specific mechanism for the generation of numerous small regulatory RNAs and target sites throughout the genome. The evolutionary lineage-specific nature of MITEs could also provide for the generation of novel regulatory phenotypes related to species diversification. Finally, we propose that MITEs may represent an evolutionary link between siRNAs and miRNAs.
Multiple independent evolutionary solutions to core histone gene regulation

(Georgia Institute of Technology, 2006-12-21) Mariño-Ramírez, Leonardo ; Jordan, I. King ; Landsman, David

Background: Core histone genes are periodically expressed along the cell cycle and peak during S phase. Core histone gene expression is deeply evolutionarily conserved from the yeast Saccharomyces cerevisiae to human. Results: We evaluated the evolutionary dynamics of the specific regulatory mechanisms that give rise to the conserved histone regulatory phenotype. In contrast to the conservation of core histone gene expression patterns, the core histone regulatory machinery is highly divergent between species. There has been substantial evolutionary turnover of cis-regulatory sequence motifs along with the transcription factors that bind them. The regulatory mechanisms employed by members of the four core histone families are more similar within species than within gene families. The presence of species-specific histone regulatory mechanisms is opposite to what is seen at the protein sequence level. Core histone proteins are more similar within families, irrespective of their species of origin, than between families, which is consistent with the shared common ancestry of the members of individual histone families. Structure and sequence comparisons between histone families reveal that H2A and H2B form one related group whereas H3 and H4 form a distinct group, which is consistent with the nucleosome assembly dynamics. Conclusion: The dissonance between the evolutionary conservation of the core histone gene regulatory phenotypes and the divergence of their regulatory mechanisms indicates a highly dynamic mode of regulatory evolution. This distinct mode of regulatory evolution is probably facilitated by a solution space for promoter sequences, in terms of functionally viable cis-regulatory sites, that is substantially greater than that of protein sequences.
Global similarity and local divergence in human and mouse gene co-expression networks

(Georgia Institute of Technology, 2006-09-12) Tsaparas Panayiotis ; Mariño-Ramírez, Leonardo ; Bodenreider, Olivier ; Koonin, Eugene V. ; Jordan, I. King

Background: A genome-wide comparative analysis of human and mouse gene expression patterns was performed in order to evaluate the evolutionary divergence of mammalian gene expression. Tissue-specific expression profiles were analyzed for 9,105 human-mouse orthologous gene pairs across 28 tissues. Expression profiles were resolved into species-specific coexpression networks, and the topological properties of the networks were compared between species. Results: At the global level, the topological properties of the human and mouse gene coexpression networks are, essentially, identical. For instance, both networks have topologies with small-world and scale-free properties as well as closely similar average node degrees, clustering coefficients, and path lengths. However, the human and mouse coexpression networks are highly divergent at the local level: only a small fraction (<10%) of coexpressed gene pair relationships are conserved between the two species. A series of controls for experimental and biological variance show that most of this divergence does not result from experimental noise. We further show that, while the expression divergence between species is genuinely rapid, expression does not evolve free from selective (functional) constraint. Indeed, the coexpression networks analyzed here are demonstrably functionally coherent as indicated by the functional similarity of coexpressed gene pairs, and this pattern is most pronounced in the conserved human-mouse intersection network. Numerous dense network clusters show evidence of dedicated functions, such as spermatogenesis and immune response, that are clearly consistent with the coherence of the expression patterns of their constituent gene members. Conclusion: The dissonance between global versus local network divergence suggests that the interspecies similarity of the global network properties is of limited biological significance, at best, and that the biologically relevant aspects of the architectures of gene coexpression are specific and particular, rather than universal. Nevertheless, there is substantial evolutionary conservation of the local network structure which is compatible with the notion that gene coexpression networks are subject to purifying selection.