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Somatic mitochondrial DNA mutations in cancer escape purifying selection and high pathogenicity mutations lead to the oncocytic phenotype: pathogenicity analysis of reported somatic mtDNA mutations in tumors.
Pereira L, Soares P, Máximo V, Samuels DC
(2012) BMC Cancer 12: 53
MeSH Terms: DNA, Mitochondrial, Electron Transport Complex I, Humans, Mitochondrial Proteins, Mutation, Neoplasms, Phenotype, Phylogeny, Selection, Genetic
Show Abstract · Added December 12, 2013
BACKGROUND - The presence of somatic mitochondrial DNA (mtDNA) mutations in cancer cells has been interpreted in controversial ways, ranging from random neutral accumulation of mutations, to positive selection for high pathogenicity, or conversely to purifying selection against high pathogenicity variants as occurs at the population level.
METHODS - Here we evaluated the predicted pathogenicity of somatic mtDNA mutations described in cancer and compare these to the distribution of variations observed in the global human population and all possible protein variations that could occur in human mtDNA. We focus on oncocytic tumors, which are clearly associated with mitochondrial dysfunction. The protein variant pathogenicity was predicted using two computational methods, MutPred and SNPs&GO.
RESULTS - The pathogenicity score of the somatic mtDNA variants were significantly higher in oncocytic tumors compared to non-oncocytic tumors. Variations in subunits of Complex I of the electron transfer chain were significantly more common in tumors with the oncocytic phenotype, while variations in Complex V subunits were significantly more common in non-oncocytic tumors.
CONCLUSIONS - Our results show that the somatic mtDNA mutations reported over all tumors are indistinguishable from a random selection from the set of all possible amino acid variations, and have therefore escaped the effects of purifying selection that act strongly at the population level. We show that the pathogenicity of somatic mtDNA mutations is a determining factor for the oncocytic phenotype. The opposite associations of the Complex I and Complex V variants with the oncocytic and non-oncocytic tumors implies that low mitochondrial membrane potential may play an important role in determining the oncocytic phenotype.
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9 MeSH Terms
Evolutionary genomics of a temperate bacteriophage in an obligate intracellular bacteria (Wolbachia).
Kent BN, Funkhouser LJ, Setia S, Bordenstein SR
(2011) PLoS One 6: e24984
MeSH Terms: Bacteriophages, Evolution, Molecular, Genes, Bacterial, Genome, Bacterial, Genomics, Lysogeny, Phylogeny, Recombination, Genetic, Selection, Genetic, Wolbachia
Show Abstract · Added February 8, 2016
Genome evolution of bacteria is usually influenced by ecology, such that bacteria with a free-living stage have large genomes and high rates of horizontal gene transfer, while obligate intracellular bacteria have small genomes with typically low amounts of gene exchange. However, recent studies indicate that obligate intracellular species that host-switch frequently harbor agents of horizontal transfer such as mobile elements. For example, the temperate double-stranded DNA bacteriophage WO in Wolbachia persistently transfers between bacterial coinfections in the same host. Here we show that despite the phage's rampant mobility between coinfections, the prophage's genome displays features of constraint related to its intracellular niche. First, there is always at least one intact prophage WO and usually several degenerate, independently-acquired WO prophages in each Wolbachia genome. Second, while the prophage genomes are modular in composition with genes of similar function grouping together, the modules are generally not interchangeable with other unrelated phages and thus do not evolve by the Modular Theory. Third, there is an unusual core genome that strictly consists of head and baseplate genes; other gene modules are frequently deleted. Fourth, the prophage recombinases are diverse and there is no conserved integration sequence. Finally, the molecular evolutionary forces acting on prophage WO are point mutation, intragenic recombination, deletion, and purifying selection. Taken together, these analyses indicate that while lateral transfer of phage WO is pervasive between Wolbachia with occasional new gene uptake, constraints of the intracellular niche obstruct extensive mixture between WO and the global phage population. Although the Modular Theory has long been considered the paradigm of temperate bacteriophage evolution in free-living bacteria, it appears irrelevant in phages of obligate intracellular bacteria.
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10 MeSH Terms
Comparing phylogeny and the predicted pathogenicity of protein variations reveals equal purifying selection across the global human mtDNA diversity.
Pereira L, Soares P, Radivojac P, Li B, Samuels DC
(2011) Am J Hum Genet 88: 433-9
MeSH Terms: Amino Acid Substitution, DNA, Mitochondrial, Evolution, Molecular, Female, Genes, Mitochondrial, Genetic Variation, Humans, Male, Mitochondrial Proteins, Mutation, Phylogeny, Selection, Genetic
Show Abstract · Added December 12, 2013
We used detailed phylogenetic trees for human mtDNA, combined with pathogenicity predictions for each amino acid change, to evaluate selection on mtDNA-encoded protein variants. Protein variants with high pathogenicity scores were significantly rarer in the older branches of the tree. Variants that have formed and survived multiple times in the human phylogenetics tree had significantly lower pathogenicity scores than those that only appear once in the tree. We compared the distribution of pathogenicity scores observed on the human phylogenetic tree to the distribution of all possible protein variations to define a measure of the effect of selection on these protein variations. The measured effect of selection increased exponentially with increasing pathogenicity score. We found no measurable difference in this measure of purifying selection in mtDNA across the global population, represented by the macrohaplogroups L, M, and N. We provide a list of all possible single amino acid variations for the human mtDNA-encoded proteins with their predicted pathogenicity scores and our measured selection effect as a tool for assessing novel protein variations that are often reported in patients with mitochondrial disease of unknown origin or for assessing somatic mutations acquired through aging or detected in tumors.
Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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12 MeSH Terms
Targeted resequencing of a genomic region influencing tameness and aggression reveals multiple signals of positive selection.
Albert FW, Hodges E, Jensen JD, Besnier F, Xuan Z, Rooks M, Bhattacharjee A, Brizuela L, Good JM, Green RE, Burbano HA, Plyusnina IZ, Trut L, Andersson L, Schöneberg T, Carlborg O, Hannon GJ, Pääbo S
(2011) Heredity (Edinb) 107: 205-14
MeSH Terms: Aggression, Alleles, Animals, Base Sequence, Female, Genetic Variation, Genome, High-Throughput Nucleotide Sequencing, Male, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Rats, Selection, Genetic, Sequence Analysis, DNA
Show Abstract · Added February 15, 2016
The identification of the causative genetic variants in quantitative trait loci (QTL) influencing phenotypic traits is challenging, especially in crosses between outbred strains. We have previously identified several QTL influencing tameness and aggression in a cross between two lines of wild-derived, outbred rats (Rattus norvegicus) selected for their behavior towards humans. Here, we use targeted sequence capture and massively parallel sequencing of all genes in the strongest QTL in the founder animals of the cross. We identify many novel sequence variants, several of which are potentially functionally relevant. The QTL contains several regions where either the tame or the aggressive founders contain no sequence variation, and two regions where alternative haplotypes are fixed between the founders. A re-analysis of the QTL signal showed that the causative site is likely to be fixed among the tame founder animals, but that several causative alleles may segregate among the aggressive founder animals. Using a formal test for the detection of positive selection, we find 10 putative positively selected regions, some of which are close to genes known to influence behavior. Together, these results show that the QTL is probably not caused by a single selected site, but may instead represent the joint effects of several sites that were targets of polygenic selection.
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16 MeSH Terms
Dual selection mechanisms drive efficient single-gene reverse genetics for rotavirus.
Trask SD, Taraporewala ZF, Boehme KW, Dermody TS, Patton JT
(2010) Proc Natl Acad Sci U S A 107: 18652-7
MeSH Terms: Amino Acid Sequence, Base Sequence, Cell Line, DNA, Viral, Genes, Viral, Genetic Engineering, Humans, Molecular Sequence Data, Mutation, RNA Interference, RNA-Binding Proteins, Recombinant Proteins, Recombination, Genetic, Rotavirus, Selection, Genetic, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Temperature, Viral Nonstructural Proteins
Show Abstract · Added December 10, 2013
Current methods for engineering the segmented double-stranded RNA genome of rotavirus (RV) are limited by inefficient recovery of the recombinant virus. In an effort to expand the utility of RV reverse genetics, we developed a method to recover recombinant viruses in which independent selection strategies are used to engineer single-gene replacements. We coupled a mutant SA11 RV encoding a temperature-sensitive (ts) defect in the NSP2 protein with RNAi-mediated degradation of NSP2 mRNAs to isolate a virus containing a single recombinant gene that evades both selection mechanisms. Recovery is rapid and simple; after two rounds of selective passage the recombinant virus reaches titers of ≥10(4) pfu/mL. We used this reverse genetics method to generate a panel of viruses with chimeric NSP2 genes. For one of the chimeric viruses, the introduced NSP2 sequence was obtained from a pathogenic, noncultivated human RV isolate, demonstrating that this reverse genetics system can be used to study the molecular biology of circulating RVs. Combining characterized RV ts mutants and validated siRNA targets should permit the extension of this "two-hit" reverse genetics methodology to other RV genes. Furthermore, application of a dual selection strategy to previously reported reverse genetics methods for RV may enhance the efficiency of recombinant virus recovery.
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19 MeSH Terms
A new lysozyme from the eastern oyster, Crassostrea virginica, and a possible evolutionary pathway for i-type lysozymes in bivalves from host defense to digestion.
Xue Q, Hellberg ME, Schey KL, Itoh N, Eytan RI, Cooper RK, La Peyre JF
(2010) BMC Evol Biol 10: 213
MeSH Terms: Amino Acid Sequence, Animals, Cloning, Molecular, Crassostrea, DNA, Complementary, Evolution, Molecular, Molecular Sequence Data, Molecular Weight, Muramidase, Phylogeny, Selection, Genetic, Sequence Alignment, Sequence Analysis, DNA
Show Abstract · Added May 27, 2014
BACKGROUND - Lysozymes are enzymes that lyse bacterial cell walls, an activity widely used for host defense but also modified in some instances for digestion. The biochemical and evolutionary changes between these different functional forms has been well-studied in the c-type lysozymes of vertebrates, but less so in the i-type lysozymes prevalent in most invertebrate animals. Some bivalve molluscs possess both defensive and digestive lysozymes.
RESULTS - We report a third lysozyme from the oyster Crassostrea virginica, cv-lysozyme 3. The chemical properties of cv-lysozyme 3 (including molecular weight, isoelectric point, basic amino acid residue number, and predicted protease cutting sites) suggest it represents a transitional form between lysozymes used for digestion and immunity. The cv-lysozyme 3 protein inhibited the growth of bacteria (consistent with a defensive function), but semi-quantitative RT-PCR suggested the gene was expressed mainly in digestive glands. Purified cv-lysozyme 3 expressed maximum muramidase activity within a range of pH (7.0 and 8.0) and ionic strength (I = 0.005-0.01) unfavorable for either cv-lysozyme 1 or cv-lysozyme 2 activities. The topology of a phylogenetic analysis of cv-lysozyme 3 cDNA (full length 663 bp, encoding an open reading frame of 187 amino acids) is also consistent with a transitional condition, as cv-lysozyme 3 falls at the base of a monophyletic clade of bivalve lysozymes identified from digestive glands. Rates of nonsynonymous substitution are significantly high at the base of this clade, consistent with an episode of positive selection associated with the functional transition from defense to digestion.
CONCLUSION - The pattern of molecular evolution accompanying the shift from defensive to digestive function in the i-type lysozymes of bivalves parallels those seen for c-type lysozymes in mammals and suggests that the lysozyme paralogs that enhance the range of physiological conditions for lysozyme activity may provide stepping stones between defensive and digestive forms.
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13 MeSH Terms
Evolutionary flux of canonical microRNAs and mirtrons in Drosophila.
Berezikov E, Liu N, Flynt AS, Hodges E, Rooks M, Hannon GJ, Lai EC
(2010) Nat Genet 42: 6-9; author reply 9-10
MeSH Terms: Animals, Base Sequence, Conserved Sequence, Drosophila, Evolution, Molecular, Gene Expression Profiling, Genes, Insect, Genome, Insect, MicroRNAs, Molecular Sequence Data, Nucleic Acid Conformation, Phylogeny, Selection, Genetic, Sequence Homology, Nucleic Acid
Added February 15, 2016
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14 MeSH Terms
The ontogeny of delta-like protein 1 messenger ribonucleic acid expression during muscle development and regeneration: comparison of broiler and Leghorn chickens.
Shin J, Velleman SG, Latshaw JD, Wick MP, Suh Y, Lee K
(2009) Poult Sci 88: 1427-37
MeSH Terms: Animals, Chick Embryo, Chickens, Female, Gene Expression Regulation, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Muscle, Skeletal, RNA, Messenger, Selection, Genetic
Show Abstract · Added March 3, 2014
Delta-like protein 1 (DLK1) has been implicated in the muscle hypertrophy observed in DLK1 transgenic mice, callipyge sheep, and mouse paternal uniparental disomy 12 and human paternal uniparental disomy 14 syndromes. The current study was aimed to determine chicken DLK1 (gDLK1) mRNA expression during primary muscle cell differentiation and during muscle regeneration after cold injury and to compare gDLK1 mRNA expression during skeletal muscle development in layers and broilers. In chicken primary muscle cell culture, gDLK1 mRNA expression was significantly increased from 12 to 48 h (P < or = 0.05) when the nascent myotubes were actively formed at d 2 to 3. Myogenin, a late myogenic marker gene, mRNA expression peaked at 36 to 48 h. Myogenic differentiation 1 (MyoD) and paired box gene 7 (Pax7), early myogenic marker genes, mRNA expression gradually decreased during myogenic differentiation. During muscle regeneration, the expression of MyoD and Pax7 peaked at d 2 (P < or = 0.05), and myogenin mRNA expression peaked at d 4 (P < or = 0.05). The induction of gDLK1 gene appeared between d 7 to 10 postinjury (P < or = 0.05) when myotubes were actively formed as also demonstrated in histological sections. The expression of gDLK1 was slowly downregulated to the control levels at d 14 when the damaged muscle appeared nearly healed. These data suggest that gDLK1 may be involved in the late myogenic stages of primary muscle cell differentiation and muscle regeneration. The gDLK1 mRNA in the muscle tissues was very abundant at embryonic ages but decreased after hatching in both broiler and layer chickens. Compared with layers, broiler muscle at embryonic d 13 had a 3-fold greater expression of DLK1 (P < or = 0.01). In addition, the gDLK1 mRNA expression at d 1, 11, and 33 post-hatch was significantly higher in broilers than layers (P < or = 0.05). Therefore, the relatively greater expression of the gDLK1 gene in muscles of broilers compared with layers suggests that gDLK1 may serve as a new selection marker for high muscle growth in chickens. These findings may provide new insight into chicken muscle development and regeneration.
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11 MeSH Terms
Evidence for variable selective pressures at a large secondary structure of the human mitochondrial DNA control region.
Pereira F, Soares P, Carneiro J, Pereira L, Richards MB, Samuels DC, Amorim A
(2008) Mol Biol Evol 25: 2759-70
MeSH Terms: Animals, Base Composition, DNA, Mitochondrial, Gene Deletion, Humans, Locus Control Region, Mitochondria, Nucleic Acid Conformation, Primates, Selection, Genetic
Show Abstract · Added December 12, 2013
A combined effect of functional constraints and random mutational events is responsible for the sequence evolution of the human mitochondrial DNA (mtDNA) control region. Most studies targeting this noncoding segment usually focus on its primary sequence information disregarding other informative levels such as secondary or tertiary DNA conformations. In this work, we combined the most recent developments in DNA folding calculations with a phylogenetic comparative approach in order to investigate the formation of intrastrand secondary structures in the human mtDNA control region. Our most striking results are those regarding a new cloverleaf-like secondary structure predicted for a 93-bp stretch of the control region 5'-peripheral domain. Randomized sequences indicated that this structure has a more negative folding energy than the average of random sequences with the same nucleotide composition. In addition, a sliding window scan across the complete mitochondrial genome revealed that it stands out as having one of the highest folding potential. Moreover, we detected several lines of evidence of both negative and positive selection on this structure with high levels of conservation at the structure-relevant stem regions and the occurrence of compensatory base changes in the primate lineage. In the light of previous data, we discuss the possible involvement of this structure in mtDNA replication and/or transcription. We conclude that maintenance of this structure is responsible for the observed heterogeneity in the rate of substitution among sites in part of the human hypervariable region I and that it is a hot spot for the 3' end of human mtDNA deletions.
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Selection against pathogenic mtDNA mutations in a stem cell population leads to the loss of the 3243A-->G mutation in blood.
Rajasimha HK, Chinnery PF, Samuels DC
(2008) Am J Hum Genet 82: 333-43
MeSH Terms: Age Factors, Computer Simulation, DNA, Mitochondrial, Hematopoietic Stem Cells, Humans, Mitochondrial Diseases, Models, Biological, Mutation, RNA, Transfer, Amino Acyl, RNA, Transfer, Lys, Selection, Genetic
Show Abstract · Added December 12, 2013
The mutation 3243A-->G is the most common heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutation in humans, but it is not understood why the proportion of this mutation decreases in blood during life. Changing levels of mtDNA heteroplasmy are fundamentally related to the pathophysiology of the mitochondrial disease and correlate with clinical progression. To understand this process, we simulated the segregation of mtDNA in hematopoietic stem cells and leukocyte precursors. Our observations show that the percentage of mutant mtDNA in blood decreases exponentially over time. This is consistent with the existence of a selective process acting at the stem cell level and explains why the level of mutant mtDNA in blood is almost invariably lower than in nondividing (postmitotic) tissues such as skeletal muscle. By using this approach, we derived a formula from human data to correct for the change in heteroplasmy over time. A comparison of age-corrected blood heteroplasmy levels with skeletal muscle, an embryologically distinct postmitotic tissue, provides independent confirmation of the model. These findings indicate that selection against pathogenic mtDNA mutations occurs in a stem cell population.
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11 MeSH Terms