The newest version of MUMmer easily handles comparisons of large eukaryotic genomes at varying evolutionary distances, as demonstrated by applications to multiple genomes. Two new graphical viewing tools provide alternative ways to analyze genome alignments. The new system is the first version of MUMmer to be released as open-source software. This allows other developers to contribute to the code base and freely redistribute the code. The MUMmer sources are available at http://www.tigr.org/software/mummer.

/pdf/versatile-and-open-software-for-comparing-large-genomes-25wj2yhhq7.pdf

Versatile and open software for comparing large genomes

The world's oceans contain a complex mixture of micro-organisms that are for the most part, uncharacterized both genetically and biochemically. We report here a metagenomic study of the marine planktonic microbiota in which surface (mostly marine) water samples were analyzed as part of the Sorcerer II Global Ocean Sampling expedition. These samples, collected across a several-thousand km transect from the North Atlantic through the Panama Canal and ending in the South Pacific yielded an extensive dataset consisting of 7.7 million sequencing reads (6.3 billion bp). Though a few major microbial clades dominate the planktonic marine niche, the dataset contains great diversity with 85% of the assembled sequence and 57% of the unassembled data being unique at a 98% sequence identity cutoff. Using the metadata associated with each sample and sequencing library, we developed new comparative genomic and assembly methods. One comparative genomic method, termed "fragment recruitment," addressed questions of genome structure, evolution, and taxonomic or phylogenetic diversity, as well as the biochemical diversity of genes and gene families. A second method, termed "extreme assembly," made possible the assembly and reconstruction of large segments of abundant but clearly nonclonal organisms. Within all abundant populations analyzed, we found extensive intra-ribotype diversity in several forms: (1) extensive sequence variation within orthologous regions throughout a given genome; despite coverage of individual ribotypes approaching 500-fold, most individual sequencing reads are unique; (2) numerous changes in gene content some with direct adaptive implications; and (3) hypervariable genomic islands that are too variable to assemble. The intra-ribotype diversity is organized into genetically isolated populations that have overlapping but independent distributions, implying distinct environmental preference. We present novel methods for measuring the genomic similarity between metagenomic samples and show how they may be grouped into several community types. Specific functional adaptations can be identified both within individual ribotypes and across the entire community, including proteorhodopsin spectral tuning and the presence or absence of the phosphate-binding gene PstS.

/pdf/the-sorcerer-ii-global-ocean-sampling-expedition-northwest-310cgsz0o9.pdf

The Sorcerer II Global Ocean Sampling Expedition: Northwest Atlantic through Eastern Tropical Pacific

Repetitive DNA sequences are abundant in a broad range of species, from bacteria to mammals, and they cover nearly half of the human genome. Repeats have always presented technical challenges for sequence alignment and assembly programs. Next-generation sequencing projects, with their short read lengths and high data volumes, have made these challenges more difficult. From a computational perspective, repeats create ambiguities in alignment and assembly, which, in turn, can produce biases and errors when interpreting results. Simply ignoring repeats is not an option, as this creates problems of its own and may mean that important biological phenomena are missed. We discuss the computational problems surrounding repeats and describe strategies used by current bioinformatics systems to solve them.

https://www.csie.ntu.edu.tw/~kmchao/bioinformatics12spr/presentation/Report_20120604%236.pdf

Repetitive DNA and next-generation sequencing: computational challenges and solutions.

Antibiotic resistance continues to plague antimicrobial chemotherapy of infectious disease. And while true biocide resistance is as yet unrealized, in vitro and in vivo episodes of reduced biocide susceptibility are common and the history of antibiotic resistance should not be ignored in the development and use of biocidal agents. Efflux mechanisms of resistance, both drug specific and multidrug, are important determinants of intrinsic and/or acquired resistance to these antimicrobials, with some accommodating both antibiotics and biocides. This latter raises the spectre (as yet generally unrealized) of biocide selection of multiple antibiotic-resistant organisms. Multidrug efflux mechanisms are broadly conserved in bacteria, are almost invariably chromosome-encoded and their expression in many instances results from mutations in regulatory genes. In contrast, drug-specific efflux mechanisms are generally encoded by plasmids and/or other mobile genetic elements (transposons, integrons) that carry additional resistance genes, and so their ready acquisition is compounded by their association with multidrug resistance. While there is some support for the latter efflux systems arising from efflux determinants of self-protection in antibiotic-producing Streptomyces spp. and, thus, intended as drug exporters, increasingly, chromosomal multidrug efflux determinants, at least in Gram-negative bacteria, appear not to be intended as drug exporters but as exporters with, perhaps, a variety of other roles in bacterial cells. Still, given the clinical significance of multidrug (and drug-specific) exporters, efflux must be considered in formulating strategies/approaches to treating drug-resistant infections, both in the development of new agents, for example, less impacted by efflux and in targeting efflux directly with efflux inhibitors.

/pdf/efflux-mediated-antimicrobial-resistance-2rhfe93zak.pdf

Efflux-mediated antimicrobial resistance

Studies of molecular evolutionary rates have yielded a wide range of rate estimates for various genes and taxa. Recent studies based on population-level and pedigree data have produced remarkably high estimates of mutation rate, which strongly contrast with substitution rates inferred in phylogenetic (species-level) studies. Using Bayesian analysis with a relaxed-clock model, we estimated rates for three groups of mitochondrial data: avian protein-coding genes, primate protein-coding genes, and primate d-loop sequences. In all three cases, we found a measurable transition between the high, short-term (<1–2 Myr) mutation rate and the low, long-term substitution rate. The relationship between the age of the calibration and the rate of change can be described by a vertically translated exponential decay curve, which may be used for correcting molecular date estimates. The phylogenetic substitution rates in mitochondria are approximately 0.5% per million years for avian protein-coding sequences and 1.5% per million years for primate protein-coding and d-loop sequences. Further analyses showed that purifying selection offers the most convincing explanation for the observed relationship between the estimated rate and the depth of the calibration. We rule out the possibility that it is a spurious result arising from sequence errors, and find it unlikely that the apparent decline in rates over time is caused by mutational saturation. Using a rate curve estimated from the d-loop data, several dates for last common ancestors were calculated: modern humans and Neandertals (354 ka; 222–705 ka), Neandertals (108 ka; 70–156 ka), and modern humans (76 ka; 47–110 ka). If the rate curve for a particular taxonomic group can be accurately estimated, it can be a useful tool for correcting divergence date estimates by taking the rate decay into account. Our results show that it is invalid to extrapolate molecular rates of change across different evolutionary timescales, which has important consequences for studies of populations, domestication, conservation genetics, and human evolution.

/pdf/time-dependency-of-molecular-rate-estimates-and-systematic-1toi2pp3bu.pdf

Time Dependency of Molecular Rate Estimates and Systematic Overestimation of Recent Divergence Times

Comparison of the whole-genome sequence of Bacillus anthracis isolated from a victim of a recent bioterrorist anthrax attack with a reference reveals 60 new markers that include single nucleotide polymorphisms (SNPs), inserted or deleted sequences, and tandem repeats. Genome comparison detected four high-quality SNPs between the two sequenced B. anthracis chromosomes and seven differences among different preparations of the reference genome. These markers have been tested on a collection of anthrax isolates and were found to divide these samples into distinct families. These results demonstrate that genome-based analysis of microbial pathogens will provide a powerful new tool for investigation of infectious disease outbreaks.

Comparative Genome Sequencing for Discovery of Novel Polymorphisms in Bacillus anthracis

<h3>Objective:</h3> We aim to determine whether a relationship exists between immunocompromise as defined by autoimmune disease or immunosuppressive and immunomodulatory medications in patients and incident HSVE. <h3>Background:</h3> Among infectious etiologies of encephalitis, herpes simplex virus type 1 (HSV-1) is commonest. The association between immune status and HSVE is unclear. Using a U.S. Medicaid database of 75.6 million persons, we evaluated the association between HSVE and autoimmune conditions, exposure to immunosuppressive and immunomodulatory medications, and other medical comorbidities. <h3>Design/Methods:</h3> We used the U.S. Medicaid Analytic eXtract Database between the years of 2007–2010 from the 29 most populated American states. We first examined the crude incidence of HSVE in the population. We then age- and sex-matched adult cases of HSVE with a sufficient enrolment period to a larger control population without HSVE. In a case-control analysis, we examined the association between HSVE and exposure to both autoimmune disease and immunosuppressive/immunomodulatory medications. Analyses were conducted with conditional logistic regression progressively adjusting for sociodemographic factors, Charlson comorbidity index, and non-autoimmune comorbidities. <h3>Results:</h3> Incidence of HSVE was ~3.01 per 10<sup>5</sup> person-years among adults. A total of 951 HSVE cases and 95,100 age- and sex-matched controls were compared. The HSVE population had higher rates of medical comorbidities than the control population. The association of HSVE and autoimmune conditions was strong, adjusted OR 2.6 (95% CI [2.2, 3.2]). The association of HSVE and immunomodulating medications had an OR of 2.2 [1.9, 2.6], also after covariate adjustment. When both exposures were included in regression models, the associations remained robust: 2.3 [1.9, 2.7] for autoimmune disease and 2.0 [1.7, 2.3] for immunosuppressive and immunomodulatory medications. <h3>Conclusions:</h3> In a large, national population, HSVE is strongly associated with pre-existing autoimmune disease and exposure to immunosuppressive and immunomodulatory medications. The role of antecedent immune-related dysregulation may have been underestimated to date. <b>Disclosure:</b> Dr. Tang has received personal compensation for serving as an employee of Third Rock Ventures. Dr. Bhattacharyya has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion Pharmaceuticals. Dr. Bhattacharyya has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Continuum. The institution of Dr. Bhattacharyya has received research support from Alexion Pharmaceuticals. The institution of Dr. Bhattacharyya has received research support from National Institute of Health. The institution of Dr. Bhattacharyya has received research support from UCB. Dr. Bhattacharyya has received publishing royalties from a publication relating to health care. Dr. Bhattacharyya has received publishing royalties from a publication relating to health care. Dr. Bhattacharyya has received publishing royalties from a publication relating to health care. Dr. Miyawaki has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Family Health, Inc.. Dr. Miyawaki has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Morrison and Mahoney. Dr. Miyawaki has stock in Cincinnati Bengals. Dr. Miyawaki has received publishing royalties from a publication relating to health care. Dr. Miyawaki has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant with US Department of Health and Human Services. Dr. Yoshida has received personal compensation for serving as an employee of OM1, Inc. Dr. Yoshida has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for OM1, Inc. Dr. Wilcox has nothing to disclose. Karen Costenbader has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Karen Costenbader has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Karen Costenbader has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Glaxo Smith Kline. Karen Costenbader has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for AstraZeneca Pharmaceuticals LP. Karen Costenbader has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Arthritis and Rheumatology. Karen Costenbader has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Uptodate. Karen Costenbader has stock in Neutrolis. The institution of Karen Costenbader has received research support from Gilead. The institution of Karen Costenbader has received research support from Exagen. The institution of Karen Costenbader has received research support from Merck. Karen Costenbader has received personal compensation in the range of $0-$499 for serving as a grant reviewer with NIH. Prof. Solomon has nothing to disclose. Mr. Guan has nothing to disclose. Miss Lahey has nothing to disclose. 

Immunocompromise and herpes simplex virus type 1 encephalitis (HSVE): a nationwide cohort and case-control study (S25.009)

Among infectious etiologies of encephalitis, herpes simplex virus type 1 (HSV-1) is most common, accounting for ∼15%-40% of adult encephalitis diagnoses. We aim to investigate the association between immune status and HSV encephalitis (HSVE). Using a US Medicaid database of 75.6 million persons, we evaluated the association between HSVE and autoimmune conditions, exposure to immunosuppressive and immunomodulatory medications, and other medical comorbidities. 

Herpes Simplex Virus Encephalitis in Patients With Autoimmune Conditions or Exposure to Immunomodulatory Medications.

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Comparative Genome Sequencing for Discovery of Novel Polymorphisms in Bacillus anthracis

Immunocompromise and herpes simplex virus type 1 encephalitis (HSVE): a nationwide cohort and case-control study (S25.009)

Herpes Simplex Virus Encephalitis in Patients With Autoimmune Conditions or Exposure to Immunomodulatory Medications.