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Host Biology in Light of the Microbiome: Ten Principles of Holobionts and Hologenomes.
Bordenstein SR, Theis KR
(2015) PLoS Biol 13: e1002226
MeSH Terms: Animals, Biological Evolution, Humans, Metagenome, Microbiota, Mutation, Plants, Selection, Genetic, Symbiosis
Show Abstract · Added October 8, 2015
Groundbreaking research on the universality and diversity of microorganisms is now challenging the life sciences to upgrade fundamental theories that once seemed untouchable. To fully appreciate the change that the field is now undergoing, one has to place the epochs and foundational principles of Darwin, Mendel, and the modern synthesis in light of the current advances that are enabling a new vision for the central importance of microbiology. Animals and plants are no longer heralded as autonomous entities but rather as biomolecular networks composed of the host plus its associated microbes, i.e., "holobionts." As such, their collective genomes forge a "hologenome," and models of animal and plant biology that do not account for these intergenomic associations are incomplete. Here, we integrate these concepts into historical and contemporary visions of biology and summarize a predictive and refutable framework for their evaluation. Specifically, we present ten principles that clarify and append what these concepts are and are not, explain how they both support and extend existing theory in the life sciences, and discuss their potential ramifications for the multifaceted approaches of zoology and botany. We anticipate that the conceptual and evidence-based foundation provided in this essay will serve as a roadmap for hypothesis-driven, experimentally validated research on holobionts and their hologenomes, thereby catalyzing the continued fusion of biology's subdisciplines. At a time when symbiotic microbes are recognized as fundamental to all aspects of animal and plant biology, the holobiont and hologenome concepts afford a holistic view of biological complexity that is consistent with the generally reductionist approaches of biology.
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9 MeSH Terms
Fine Time Scaling of Purifying Selection on Human Nonsynonymous mtDNA Mutations Based on the Worldwide Population Tree and Mother-Child Pairs.
Cavadas B, Soares P, Camacho R, Brandão A, Costa MD, Fernandes V, Pereira JB, Rito T, Samuels DC, Pereira L
(2015) Hum Mutat 36: 1100-11
MeSH Terms: Alleles, Computational Biology, DNA, Mitochondrial, Evolution, Molecular, Family, Female, Genetics, Population, Humans, Male, Mutation, Phylogeny, Selection, Genetic
Show Abstract · Added February 15, 2016
A high-resolution mtDNA phylogenetic tree allowed us to look backward in time to investigate purifying selection. Purifying selection was very strong in the last 2,500 years, continuously eliminating pathogenic mutations back until the end of the Younger Dryas (∼11,000 years ago), when a large population expansion likely relaxed selection pressure. This was preceded by a phase of stable selection until another relaxation occurred in the out-of-Africa migration. Demography and selection are closely related: expansions led to relaxation of selection and higher pathogenicity mutations significantly decreased the growth of descendants. The only detectible positive selection was the recurrence of highly pathogenic nonsynonymous mutations (m.3394T>C-m.3397A>G-m.3398T>C) at interior branches of the tree, preventing the formation of a dinucleotide STR (TATATA) in the MT-ND1 gene. At the most recent time scale in 124 mother-children transmissions, purifying selection was detectable through the loss of mtDNA variants with high predicted pathogenicity. A few haplogroup-defining sites were also heteroplasmic, agreeing with a significant propensity in 349 positions in the phylogenetic tree to revert back to the ancestral variant. This nonrandom mutation property explains the observation of heteroplasmic mutations at some haplogroup-defining sites in sequencing datasets, which may not indicate poor quality as has been claimed.
© 2015 WILEY PERIODICALS, INC.
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12 MeSH Terms
Shared Selective Pressures on Fungal and Human Metabolic Pathways Lead to Divergent yet Analogous Genetic Responses.
Eidem HR, McGary KL, Rokas A
(2015) Mol Biol Evol 32: 1449-55
MeSH Terms: Evolution, Molecular, Fungi, Gene Expression Regulation, Fungal, Genes, Fungal, Genetic Linkage, Humans, Metabolic Networks and Pathways, Selection, Genetic
Show Abstract · Added February 19, 2015
Reduced metabolic efficiency, toxic intermediate accumulation, and deficits of molecular building blocks, which all stem from disruptions of flux through metabolic pathways, reduce organismal fitness. Although these represent shared selection pressures across organisms, the genetic signatures of the responses to them may differ. In fungi, a frequently observed signature is the physical linkage of genes from the same metabolic pathway. In contrast, human metabolic genes are rarely tightly linked; rather, they tend to show tissue-specific coexpression. We hypothesized that the physical linkage of fungal metabolic genes and the tissue-specific coexpression of human metabolic genes are divergent yet analogous responses to the range of selective pressures imposed by disruptions of flux. To test this, we examined the degree to which the human homologs of physically linked metabolic genes in fungi (fungal linked homologs or FLOs) are coexpressed across six human tissues. We found that FLOs are significantly more correlated in their expression profiles across human tissues than other metabolic genes. We obtained similar results in analyses of the same six tissues from chimps, gorillas, orangutans, and macaques. We suggest that when selective pressures remain stable across large evolutionary distances, evidence of selection in a given evolutionary lineage can become a highly reliable predictor of the signature of selection in another, even though the specific adaptive response in each lineage is markedly different.
© The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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8 MeSH Terms
The contrasting phylodynamics of human influenza B viruses.
Vijaykrishna D, Holmes EC, Joseph U, Fourment M, Su YC, Halpin R, Lee RT, Deng YM, Gunalan V, Lin X, Stockwell TB, Fedorova NB, Zhou B, Spirason N, Kühnert D, Bošková V, Stadler T, Costa AM, Dwyer DE, Huang QS, Jennings LC, Rawlinson W, Sullivan SG, Hurt AC, Maurer-Stroh S, Wentworth DE, Smith GJ, Barr IG
(2015) Elife 4: e05055
MeSH Terms: Age Distribution, Animals, Antigens, Viral, Asparagine, Dogs, Evolution, Molecular, Genetic Variation, Genome, Viral, Glycosylation, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Influenza A virus, Influenza B virus, Influenza, Human, Madin Darby Canine Kidney Cells, Models, Molecular, New Zealand, Phylogeny, Reassortant Viruses, Selection, Genetic, Time Factors, Victoria
Show Abstract · Added January 20, 2015
A complex interplay of viral, host, and ecological factors shapes the spatio-temporal incidence and evolution of human influenza viruses. Although considerable attention has been paid to influenza A viruses, a lack of equivalent data means that an integrated evolutionary and epidemiological framework has until now not been available for influenza B viruses, despite their significant disease burden. Through the analysis of over 900 full genomes from an epidemiological collection of more than 26,000 strains from Australia and New Zealand, we reveal fundamental differences in the phylodynamics of the two co-circulating lineages of influenza B virus (Victoria and Yamagata), showing that their individual dynamics are determined by a complex relationship between virus transmission, age of infection, and receptor binding preference. In sum, this work identifies new factors that are important determinants of influenza B evolution and epidemiology.
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22 MeSH Terms
Compensatory substitutions in the HIV-1 capsid reduce the fitness cost associated with resistance to a capsid-targeting small-molecule inhibitor.
Shi J, Zhou J, Halambage UD, Shah VB, Burse MJ, Wu H, Blair WS, Butler SL, Aiken C
(2015) J Virol 89: 208-19
MeSH Terms: Amino Acid Substitution, Anti-HIV Agents, Cells, Cultured, Drug Resistance, Viral, HIV Core Protein p24, HIV-1, Humans, Indoles, Macrophages, Mutant Proteins, Mutation, Missense, Phenylalanine, Selection, Genetic, Suppression, Genetic, Virus Replication
Show Abstract · Added February 19, 2015
UNLABELLED - The HIV-1 capsid plays multiple roles in infection and is an emerging therapeutic target. The small-molecule HIV-1 inhibitor PF-3450074 (PF74) blocks HIV-1 at an early postentry stage by binding the viral capsid and interfering with its function. Selection for resistance resulted in accumulation of five amino acid changes in the viral CA protein, which collectively reduced binding of the compound to HIV-1 particles. In the present study, we dissected the individual and combinatorial contributions of each of the five substitutions Q67H, K70R, H87P, T107N, and L111I to PF74 resistance, PF74 binding, and HIV-1 infectivity. Q67H, K70R, and T107N each conferred low-level resistance to PF74 and collectively conferred strong resistance. The substitutions K70R and L111I impaired HIV-1 infectivity, which was partially restored by the other substitutions at positions 67 and 107. PF74 binding to HIV-1 particles was reduced by the Q67H, K70R, and T107N substitutions, consistent with the location of these positions in the inhibitor-binding pocket. Replication of the 5Mut virus was markedly impaired in cultured macrophages, reminiscent of the previously reported N74D CA mutant. 5Mut substitutions also reduced the binding of the host protein CPSF6 to assembled CA complexes in vitro and permitted infection of cells expressing the inhibitory protein CPSF6-358. Our results demonstrate that strong resistance to PF74 requires accumulation of multiple substitutions in CA to inhibit PF74 binding and compensate for fitness impairments associated with some of the sequence changes.
IMPORTANCE - The HIV-1 capsid is an emerging drug target, and several small-molecule compounds have been reported to inhibit HIV-1 infection by targeting the capsid. Here we show that resistance to the capsid-targeting inhibitor PF74 requires multiple amino acid substitutions in the binding pocket of the CA protein. Three changes in CA were necessary to inhibit binding of PF74 while maintaining viral infectivity. Replication of the PF74-resistant HIV-1 mutant was impaired in macrophages, likely owing to altered interactions with host cell factors. Our results suggest that HIV-1 resistance to capsid-targeting inhibitors will be limited by functional constraints on the viral capsid protein. Therefore, this work enhances the attractiveness of the HIV-1 capsid as a therapeutic target.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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15 MeSH Terms
A model-based analysis of GC-biased gene conversion in the human and chimpanzee genomes.
Capra JA, Hubisz MJ, Kostka D, Pollard KS, Siepel A
(2013) PLoS Genet 9: e1003684
MeSH Terms: Animals, Base Sequence, Chromosome Mapping, Evolution, Molecular, Gene Conversion, Genome, Humans, Mammals, Models, Theoretical, Pan troglodytes, Phylogeny, Recombination, Genetic, Selection, Genetic, Sequence Alignment
Show Abstract · Added April 18, 2017
GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional consequences remain poorly understood. gBGC is difficult to incorporate into models of molecular evolution and so far has primarily been studied using summary statistics from genomic comparisons. Here, we introduce a new probabilistic model that captures the joint effects of natural selection and gBGC on nucleotide substitution patterns, while allowing for correlations along the genome in these effects. We implemented our model in a computer program, called phastBias, that can accurately detect gBGC tracts about 1 kilobase or longer in simulated sequence alignments. When applied to real primate genome sequences, phastBias predicts gBGC tracts that cover roughly 0.3% of the human and chimpanzee genomes and account for 1.2% of human-chimpanzee nucleotide differences. These tracts fall in clusters, particularly in subtelomeric regions; they are enriched for recombination hotspots and fast-evolving sequences; and they display an ongoing fixation preference for G and C alleles. They are also significantly enriched for disease-associated polymorphisms, suggesting that they contribute to the fixation of deleterious alleles. The gBGC tracts provide a unique window into historical recombination processes along the human and chimpanzee lineages. They supply additional evidence of long-term conservation of megabase-scale recombination rates accompanied by rapid turnover of hotspots. Together, these findings shed new light on the evolutionary, functional, and disease implications of gBGC. The phastBias program and our predicted tracts are freely available.
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14 MeSH Terms
Putting pleiotropy and selection into context defines a new paradigm for interpreting genetic data.
Predazzi IM, Rokas A, Deinard A, Schnetz-Boutaud N, Williams ND, Bush WS, Tacconelli A, Friedrich K, Fazio S, Novelli G, Haines JL, Sirugo G, Williams SM
(2013) Circ Cardiovasc Genet 6: 299-307
MeSH Terms: Alleles, Animals, Data Mining, Evolution, Molecular, Genetic Pleiotropy, Genetics, Population, Humans, Introns, Phylogeny, Polymorphism, Single Nucleotide, Primates, Scavenger Receptors, Class E, Selection, Genetic
Show Abstract · Added May 30, 2014
BACKGROUND - Natural selection shapes many human genes, including some related to complex diseases. Understanding how selection affects genes, especially pleiotropic ones, may be important in evaluating disease associations and the role played by environmental variation. This may be of particular interest for genes with antagonistic roles that cause divergent patterns of selection. The lectin-like low-density lipoprotein 1 receptor, encoded by OLR1, is exemplary. It has antagonistic functions in the cardiovascular and immune systems because the same protein domain binds oxidized low-density lipoprotein and bacterial cell wall proteins, the former contributing to atherosclerosis and the latter presumably protecting from infection. We studied patterns of selection in this gene, in humans and nonhuman primates, to determine whether variable selection can lead to conflicting results in cardiovascular disease association studies.
METHODS AND RESULTS - We analyzed sequences from 11 nonhuman primate species, as well as single-nucleotide polymorphisms and sequence data from multiple human populations. Results indicate that the derived allele is favored across primate lineages (probably because of recent positive selection). However, both the derived and ancestral alleles were maintained in human populations, especially European ones (possibly because of balancing selection derived from dual roles of LOX-1). Balancing selection likely reflects response to diverse environmental pressures among humans.
CONCLUSIONS - These data indicate that differential selection patterns, within and between species, in OLR1 render association studies difficult to replicate even if the gene is etiologically connected to cardiovascular disease. Selection analyses can identify genes exhibiting gene-environment interactions critical for unraveling disease association.
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13 MeSH Terms
Non-optimal codon usage is a mechanism to achieve circadian clock conditionality.
Xu Y, Ma P, Shah P, Rokas A, Liu Y, Johnson CH
(2013) Nature 495: 116-20
MeSH Terms: Bacterial Proteins, Circadian Clocks, Circadian Rhythm, Circadian Rhythm Signaling Peptides and Proteins, Codon, Gene Expression Regulation, Bacterial, Genes, Bacterial, Multigene Family, Phenotype, Selection, Genetic, Synechococcus, Temperature
Show Abstract · Added May 30, 2014
Circadian rhythms are oscillations in biological processes that function as a key adaptation to the daily rhythms of most environments. In the model cyanobacterial circadian clock system, the core oscillator proteins are encoded by the gene cluster kaiABC. Genes with high expression and functional importance, such as the kai genes, are usually encoded by optimal codons, yet the codon-usage bias of the kaiBC genes is not optimized for translational efficiency. We discovered a relationship between codon usage and a general property of circadian rhythms called conditionality; namely, that endogenous rhythmicity is robustly expressed under some environmental conditions but not others. Despite the generality of circadian conditionality, however, its molecular basis is unknown for any system. Here we show that in the cyanobacterium Synechococcus elongate, non-optimal codon usage was selected as a post-transcriptional mechanism to switch between circadian and non-circadian regulation of gene expression as an adaptive response to environmental conditions. When the kaiBC sequence was experimentally optimized to enhance expression of the KaiB and KaiC proteins, intrinsic rhythmicity was enhanced at cool temperatures that are experienced by this organism in its natural habitat. However, fitness at those temperatures was highest in cells in which the endogenous rhythms were suppressed at cool temperatures as compared with cells exhibiting high-amplitude rhythmicity. These results indicate natural selection against circadian systems in cyanobacteria that are intrinsically robust at cool temperatures. Modulation of circadian amplitude is therefore crucial to its adaptive significance. Moreover, these results show the direct effects of codon usage on a complex phenotype and organismal fitness. Our work also challenges the long-standing view of directional selection towards optimal codons, and provides a key example of natural selection against optimal codons to achieve adaptive responses to environmental changes.
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12 MeSH Terms
Comparative genomic analysis of East Asian and non-Asian Helicobacter pylori strains identifies rapidly evolving genes.
Duncan SS, Valk PL, McClain MS, Shaffer CL, Metcalf JA, Bordenstein SR, Cover TL
(2013) PLoS One 8: e55120
MeSH Terms: Alleles, Bacterial Proteins, Bacterial Typing Techniques, DNA, Bacterial, Evolution, Molecular, Far East, Genes, Bacterial, Genetic Markers, Genetic Variation, Genomics, Helicobacter pylori, Multilocus Sequence Typing, Phylogeny, Selection, Genetic, Species Specificity, Stomach Neoplasms
Show Abstract · Added March 5, 2014
Helicobacter pylori infection is a risk factor for the development of gastric adenocarcinoma, a disease that has a high incidence in East Asia. Genes that are highly divergent in East Asian H. pylori strains compared to non-Asian strains are predicted to encode proteins that differ in functional activity and could represent novel determinants of virulence. To identify such proteins, we undertook a comparative analysis of sixteen H. pylori genomes, selected equally from strains classified as East Asian or non-Asian. As expected, the deduced sequences of two known virulence determinants (CagA and VacA) are highly divergent, with 77% and 87% mean amino acid sequence identities between East Asian and non-Asian groups, respectively. In total, we identified 57 protein sequences that are highly divergent between East Asian and non-Asian strains, but relatively conserved within East Asian strains. The most highly represented functional groups are hypothetical proteins, cell envelope proteins and proteins involved in DNA metabolism. Among the divergent genes with known or predicted functions, population genetic analyses indicate that 86% exhibit evidence of positive selection. McDonald-Kreitman tests further indicate that about one third of these highly divergent genes, including cagA and vacA, are under diversifying selection. We conclude that, similar to cagA and vacA, most of the divergent genes identified in this study evolved under positive selection, and represent candidate factors that may account for the disproportionately high incidence of gastric cancer associated with East Asian H. pylori strains. Moreover, these divergent genes represent robust biomarkers that can be used to differentiate East Asian and non-Asian H. pylori strains.
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16 MeSH Terms
The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers.
Diaz LA, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, Nowak MA, Kinzler KW, Oliner KS, Vogelstein B
(2012) Nature 486: 537-40
MeSH Terms: Antibodies, Monoclonal, Colorectal Neoplasms, DNA, Neoplasm, Drug Resistance, Neoplasm, ErbB Receptors, Evolution, Molecular, Genes, ras, Humans, Mutation, Panitumumab, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Selection, Genetic, Time Factors, ras Proteins
Show Abstract · Added March 20, 2014
Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy. The mechanisms underlying this acquired resistance to anti-EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs. The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion.
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15 MeSH Terms