Sequence variability and protein domain architectures for bovine Toll-like receptors 1, 5, and 10.
(1/545)
The mammalian Toll-like receptors (TLRs) play an important role in the recognition of invading pathogens and the modulation of innate immune responses. The primary objective of this study was to characterize single nucleotide polymorphisms (SNPs) and insertion-deletion polymorphisms (indels) within bovine TLRs 1, 5, and 10, thereby facilitating future TLR signaling and association studies relevant to bovine innate immunity. Comparative sequence analysis for 10 bovine breeds derived from Bos taurus and Bos indicus revealed 98 polymorphisms (92 SNPs and 6 indels), with at least 14 nonsynonymous SNPs located within predicted TLR domains considered to be of functional significance. Of the 98 polymorphisms detected, 94 are reported here for the first time. Notably, 2 nonsynonymous SNPs were determined to modulate the prediction of a novel leucine-rich repeat (LRR) domain within B. indicusTLR5. Prediction and comparison of TLR protein domain architectures for multiple species revealed seven conserved regions of LRR patterning associated with the three genes investigated. (+info)
The diploid genome sequence of an individual human.
(2/545)
Presented here is a genome sequence of an individual human. It was produced from approximately 32 million random DNA fragments, sequenced by Sanger dideoxy technology and assembled into 4,528 scaffolds, comprising 2,810 million bases (Mb) of contiguous sequence with approximately 7.5-fold coverage for any given region. We developed a modified version of the Celera assembler to facilitate the identification and comparison of alternate alleles within this individual diploid genome. Comparison of this genome and the National Center for Biotechnology Information human reference assembly revealed more than 4.1 million DNA variants, encompassing 12.3 Mb. These variants (of which 1,288,319 were novel) included 3,213,401 single nucleotide polymorphisms (SNPs), 53,823 block substitutions (2-206 bp), 292,102 heterozygous insertion/deletion events (indels)(1-571 bp), 559,473 homozygous indels (1-82,711 bp), 90 inversions, as well as numerous segmental duplications and copy number variation regions. Non-SNP DNA variation accounts for 22% of all events identified in the donor, however they involve 74% of all variant bases. This suggests an important role for non-SNP genetic alterations in defining the diploid genome structure. Moreover, 44% of genes were heterozygous for one or more variants. Using a novel haplotype assembly strategy, we were able to span 1.5 Gb of genome sequence in segments >200 kb, providing further precision to the diploid nature of the genome. These data depict a definitive molecular portrait of a diploid human genome that provides a starting point for future genome comparisons and enables an era of individualized genomic information. (+info)
Phylocomposer and phylodirector: analysis and visualization of transducer indel models.
(3/545)
Finite-state string transducers are probabilistic tools similar to Hidden Markov Models that can be systematically extended to large number of sequences related by indel and substitution processes on phylogenetic trees. The number of states in such models grows exponentially with the number of nodes in the tree, with the consequence that even quite small trees can be difficult to analyze or visualize. Here, we present two tools, phylocomposer and phylodirector, for working with string transducers. The former tool implements previously described composition algorithms for extending transducers to arbitrary tree topologies, while the latter generates short animations for arbitrary input alignments and phylogenetic trees, illustrating the state path through the composed transducer. AVAILABILITY: Phylocomposer and phylodirector are freely available at http://biowiki.org/PhyloComposer and http://biowiki.org/PhyloDirector (+info)
Evaluation of fetal and maternal genetic variation in the progesterone receptor gene for contributions to preterm birth.
(4/545)
Progesterone plays a critical role in the maintenance of pregnancy and has been effectively used to prevent recurrences of preterm labor. We investigated the role of genetic variation in the progesterone receptor (PGR) gene in modulating risks for preterm labor by examining both maternal and fetal effects. Cases were infants delivered prematurely at the University of Iowa. DNA was collected from the mother, infant, and father. Seventeen single nucleotide polymorphisms (SNP) and an insertion deletion variant in PGR were studied in 415 families. Results were then analyzed using transmission disequilibrium tests and log-linear-model-based analysis. DNA sequencing of the PGR gene was also carried out in 92 mothers of preterm infants. We identified significant associations between SNP in the PGR for both mother and preterm infant. No etiologic sequence variants were found in the coding sequence of the PGR gene. This study suggests that genetic variation in the PGR gene of either the mother or the fetus may trigger preterm labor. (+info)
An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases.
(5/545)
The interferon regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune responses. The IRF5 gene has been shown to be associated with systemic lupus erythematosus and rheumatoid arthritis. We studied whether the IRF5 gene is also associated with inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC). Twelve polymorphisms in the IRF5 gene were genotyped in a cohort of 1007 IBD patients (748 CD and 254 UC) and 241 controls from Wallonia, Belgium. The same polymorphisms were genotyped in a confirmatory cohort of 311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven, Belgium. A strong signal of association [P = 1.9 x 10(-5), odds ratio (OR) 1.81 (1.37-2.39)] with IBD was observed for a 5 bp indel (CGGGG) polymorphism in the promoter region of the IRF5 gene. The association was detectable also in CD patients (P = 6.8 x 10(-4)) and was particularly strong among the UC patients [P = 5.3 x 10(-8), OR = 2.42 (1.76-3.34)]. The association of the CGGGG indel was confirmed in the second cohort [P = 3.2 x 10(-5), OR = 1.59 (1.28-1.98)]. The insertion of one CGGGG unit is predicted to create an additional binding site for the transcription factor SP1. Using an electrophoretic mobility shift assay, we show allele-specific differences in protein binding to this repetitive DNA-stretch, which suggest a potential function role for the CGGGG indel. (+info)
Evolution of two distinct phylogenetic lineages of the emerging human pathogen Mycobacterium ulcerans.
(6/545)
BACKGROUND: Comparative genomics has greatly improved our understanding of the evolution of pathogenic mycobacteria such as Mycobacterium tuberculosis. Here we have used data from a genome microarray analysis to explore insertion-deletion (InDel) polymorphism among a diverse strain collection of Mycobacterium ulcerans, the causative agent of the devastating skin disease, Buruli ulcer. Detailed analysis of large sequence polymorphisms in twelve regions of difference (RDs), comprising irreversible genetic markers, enabled us to refine the phylogenetic succession within M. ulcerans, to define features of a hypothetical M. ulcerans most recent common ancestor and to confirm its origin from Mycobacterium marinum. RESULTS: M. ulcerans has evolved into five InDel haplotypes that separate into two distinct lineages: (i) the "classical" lineage including the most pathogenic genotypes - those that come from Africa, Australia and South East Asia; and (ii) an "ancestral" M. ulcerans lineage comprising strains from Asia (China/Japan), South America and Mexico. The ancestral lineage is genetically closer to the progenitor M. marinum in both RD composition and DNA sequence identity, whereas the classical lineage has undergone major genomic rearrangements. CONCLUSION: Results of the InDel analysis are in complete accord with recent multi-locus sequence analysis and indicate that M. ulcerans has passed through at least two major evolutionary bottlenecks since divergence from M. marinum. The classical lineage shows more pronounced reductive evolution than the ancestral lineage, suggesting that there may be differences in the ecology between the two lineages. These findings improve the understanding of the adaptive evolution and virulence of M. ulcerans and pathogenic mycobacteria in general and will facilitate the development of new tools for improved diagnostics and molecular epidemiology. (+info)
Waves of genomic hitchhikers shed light on the evolution of gamebirds (Aves: Galliformes).
(7/545)
BACKGROUND: The phylogenetic tree of Galliformes (gamebirds, including megapodes, currassows, guinea fowl, New and Old World quails, chicken, pheasants, grouse, and turkeys) has been considerably remodeled over the last decades as new data and analytical methods became available. Analyzing presence/absence patterns of retroposed elements avoids the problems of homoplastic characters inherent in other methodologies. In gamebirds, chicken repeats 1 (CR1) are the most prevalent retroposed elements, but little is known about the activity of their various subtypes over time. Ascertaining the fixation patterns of CR1 elements would help unravel the phylogeny of gamebirds and other poorly resolved avian clades. RESULTS: We analyzed 1,978 nested CR1 elements and developed a multidimensional approach taking advantage of their transposition in transposition character (TinT) to characterize the fixation patterns of all 22 known chicken CR1 subtypes. The presence/absence patterns of those elements that were active at different periods of gamebird evolution provided evidence for a clade (Cracidae + (Numididae + (Odontophoridae + Phasianidae))) not including Megapodiidae; and for Rollulus as the sister taxon of the other analyzed Phasianidae. Genomic trace sequences of the turkey genome further demonstrated that the endangered African Congo Peafowl (Afropavo congensis) is the sister taxon of the Asian Peafowl (Pavo), rejecting other predominantly morphology-based groupings, and that phasianids are monophyletic, including the sister taxa Tetraoninae and Meleagridinae. CONCLUSION: The TinT information concerning relative fixation times of CR1 subtypes enabled us to efficiently investigate gamebird phylogeny and to reconstruct an unambiguous tree topology. This method should provide a useful tool for investigations in other taxonomic groups as well. (+info)
Improvement in protein sequence-structure alignment using insertion/deletion frequency arrays.
(8/545)
As a protein evolves, not every part of the amino acid sequence has an equal probability of being deleted or for allowing insertions, because not every amino acid plays an equally important role in maintaining the protein structure. However the most prevalent models in fold recognition methods treat every amino acid deletion and insertion as equally probable events. We have analyzed the alignment patterns for homologous and analogous sequences to determine patterns of insertion and deletions, and used that information to determine the statistics of insertions and deletions for different amino acids of a target sequence. We define these patterns as Insertion/Deletion (Indel) Frequency Arrays (IFA). By applying IFA to the protein threading problem, we have been able to improve the alignment accuracy, especially for proteins with low sequence identity. (+info)