101 research outputs found
Globular Cluster Distance Determinations
The present status of the distance scale to Galactic globular clusters is
reviewed. Six distance determination techniques which are deemed to be most
reliable are discussed in depth. These different techniques are used to
calibrate the absolute magnitude of the RR Lyrae stars. The various
calibrations fall into three groups. Main sequence fitting using Hipparcos
parallaxes, theoretical HB models and the RR Lyrae in the LMC all favor a
bright calibration, implying a `long' globular cluster distance scale. White
dwarf fitting and the astrometric distances yield a somewhat fainter RR Lyrae
calibration, while the statistical parallax solution yields faint RR Lyrae
stars implying a `short' distance scale to globular clusters. Various secondary
distance indicators discussed all favor the long distance scale. The `long' and
`short' distance scales differ by (0.31+/-0.16) mag. Averaging together all of
the different distance determinations yields Mv(RR) = (0.23+/-0.04)([Fe/H] +
1.6) + (0.56+/-0.12) mag.Comment: Invited review article to appear in: `Post-Hipparcos Cosmic Candles',
A. Heck & F. Caputo (Eds), Kluwer Academic Publ., Dordrecht, in pres
Recombination rate and selection strength in HIV intra-patient evolution
The evolutionary dynamics of HIV during the chronic phase of infection is
driven by the host immune response and by selective pressures exerted through
drug treatment. To understand and model the evolution of HIV quantitatively,
the parameters governing genetic diversification and the strength of selection
need to be known. While mutation rates can be measured in single replication
cycles, the relevant effective recombination rate depends on the probability of
coinfection of a cell with more than one virus and can only be inferred from
population data. However, most population genetic estimators for recombination
rates assume absence of selection and are hence of limited applicability to
HIV, since positive and purifying selection are important in HIV evolution.
Here, we estimate the rate of recombination and the distribution of selection
coefficients from time-resolved sequence data tracking the evolution of HIV
within single patients. By examining temporal changes in the genetic
composition of the population, we estimate the effective recombination to be
r=1.4e-5 recombinations per site and generation. Furthermore, we provide
evidence that selection coefficients of at least 15% of the observed
non-synonymous polymorphisms exceed 0.8% per generation. These results provide
a basis for a more detailed understanding of the evolution of HIV. A
particularly interesting case is evolution in response to drug treatment, where
recombination can facilitate the rapid acquisition of multiple resistance
mutations. With the methods developed here, more precise and more detailed
studies will be possible, as soon as data with higher time resolution and
greater sample sizes is available.Comment: to appear in PLoS Computational Biolog
Genomics of Divergence along a Continuum of Parapatric Population Differentiation
MM received funding from the Max Planck innovation funds for this project. PGDF was supported by a Marie Curie European Reintegration Grant (proposal nr 270891). CE was supported by German Science Foundation grants (DFG, EI 841/4-1 and EI 841/6-1)
Inference of population splits and mixtures from genome-wide allele frequency data
Many aspects of the historical relationships between populations in a species
are reflected in genetic data. Inferring these relationships from genetic data,
however, remains a challenging task. In this paper, we present a statistical
model for inferring the patterns of population splits and mixtures in multiple
populations. In this model, the sampled populations in a species are related to
their common ancestor through a graph of ancestral populations. Using
genome-wide allele frequency data and a Gaussian approximation to genetic
drift, we infer the structure of this graph. We applied this method to a set of
55 human populations and a set of 82 dog breeds and wild canids. In both
species, we show that a simple bifurcating tree does not fully describe the
data; in contrast, we infer many migration events. While some of the migration
events that we find have been detected previously, many have not. For example,
in the human data we infer that Cambodians trace approximately 16% of their
ancestry to a population ancestral to other extant East Asian populations. In
the dog data, we infer that both the boxer and basenji trace a considerable
fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to
domestication, and that East Asian toy breeds (the Shih Tzu and the Pekingese)
result from admixture between modern toy breeds and "ancient" Asian breeds.
Software implementing the model described here, called TreeMix, is available at
http://treemix.googlecode.comComment: 28 pages, 6 figures in main text. Attached supplement is 22 pages, 15
figures. This is an updated version of the preprint available at
http://precedings.nature.com/documents/6956/version/
Pervasive Hitchhiking at Coding and Regulatory Sites in Humans
Much effort and interest have focused on assessing the importance of natural
selection, particularly positive natural selection, in shaping the human genome.
Although scans for positive selection have identified candidate loci that may be
associated with positive selection in humans, such scans do not indicate whether
adaptation is frequent in general in humans. Studies based on the reasoning of
the MacDonaldβKreitman test, which, in principle, can be used to
evaluate the extent of positive selection, suggested that adaptation is
detectable in the human genome but that it is less common than in Drosophila or
Escherichia coli. Both positive and purifying natural
selection at functional sites should affect levels and patterns of polymorphism
at linked nonfunctional sites. Here, we search for these effects by analyzing
patterns of neutral polymorphism in humans in relation to the rates of
recombination, functional density, and functional divergence with chimpanzees.
We find that the levels of neutral polymorphism are lower in the regions of
lower recombination and in the regions of higher functional density or
divergence. These correlations persist after controlling for the variation in GC
content, density of simple repeats, selective constraint, mutation rate, and
depth of sequencing coverage. We argue that these results are most plausibly
explained by the effects of natural selection at functional
sitesβeither recurrent selective sweeps or background
selectionβon the levels of linked neutral polymorphism. Natural
selection at both coding and regulatory sites appears to affect linked neutral
polymorphism, reducing neutral polymorphism by 6% genome-wide and by
11% in the gene-rich half of the human genome. These findings suggest
that the effects of natural selection at linked sites cannot be ignored in the
study of neutral human polymorphism
A Reservoir of Drug-Resistant Pathogenic Bacteria in Asymptomatic Hosts
The population genetics of pathogenic bacteria has been intensively studied in order to understand the spread of disease and the evolution of virulence and drug resistance. However, much less attention has been paid to bacterial carriage populations, which inhabit hosts without producing disease. Since new virulent strains that cause disease can be recruited from the carriage population of bacteria, our understanding of infectious disease is seriously incomplete without knowledge on the population structure of pathogenic bacteria living in an asymptomatic host. We report the first extensive survey of the abundance and diversity of a human pathogen in asymptomatic animal hosts. We have found that asymptomatic swine from livestock productions frequently carry populations of Salmonella enterica with a broad range of drug-resistant strains and genetic diversity greatly exceeding that previously described. This study shows how agricultural practice and human intervention may lead and influence the evolution of a hidden reservoir of pathogens, with important implications for human health
Global assessment of genomic variation in cattle by genome resequencing and high-throughput genotyping
<p>Abstract</p> <p>Background</p> <p>Integration of genomic variation with phenotypic information is an effective approach for uncovering genotype-phenotype associations. This requires an accurate identification of the different types of variation in individual genomes.</p> <p>Results</p> <p>We report the integration of the whole genome sequence of a single Holstein Friesian bull with data from single nucleotide polymorphism (SNP) and comparative genomic hybridization (CGH) array technologies to determine a comprehensive spectrum of genomic variation. The performance of resequencing SNP detection was assessed by combining SNPs that were identified to be either in identity by descent (IBD) or in copy number variation (CNV) with results from SNP array genotyping. Coding insertions and deletions (indels) were found to be enriched for size in multiples of 3 and were located near the N- and C-termini of proteins. For larger indels, a combination of split-read and read-pair approaches proved to be complementary in finding different signatures. CNVs were identified on the basis of the depth of sequenced reads, and by using SNP and CGH arrays.</p> <p>Conclusions</p> <p>Our results provide high resolution mapping of diverse classes of genomic variation in an individual bovine genome and demonstrate that structural variation surpasses sequence variation as the main component of genomic variability. Better accuracy of SNP detection was achieved with little loss of sensitivity when algorithms that implemented mapping quality were used. IBD regions were found to be instrumental for calculating resequencing SNP accuracy, while SNP detection within CNVs tended to be less reliable. CNV discovery was affected dramatically by platform resolution and coverage biases. The combined data for this study showed that at a moderate level of sequencing coverage, an ensemble of platforms and tools can be applied together to maximize the accurate detection of sequence and structural variants.</p
Inferring the joint demographic history of multiple populations from multidimensional SNP frequency data
Demographic models built from genetic data play important roles in
illuminating prehistorical events and serving as null models in genome scans
for selection. We introduce an inference method based on the joint frequency
spectrum of genetic variants within and between populations. For candidate
models we numerically compute the expected spectrum using a diffusion
approximation to the one-locus two-allele Wright-Fisher process, involving up
to three simultaneous populations. Our approach is a composite likelihood
scheme, since linkage between neutral loci alters the variance but not the
expectation of the frequency spectrum. We thus use bootstraps incorporating
linkage to estimate uncertainties for parameters and significance values for
hypothesis tests. Our method can also incorporate selection on single sites,
predicting the joint distribution of selected alleles among populations
experiencing a bevy of evolutionary forces, including expansions, contractions,
migrations, and admixture. As applications, we model human expansion out of
Africa and the settlement of the New World, using 5 Mb of noncoding DNA
resequenced in 68 individuals from 4 populations (YRI, CHB, CEU, and MXL) by
the Environmental Genome Project. We also combine our demographic model with a
previously estimated distribution of selective effects among newly arising
amino acid mutations to accurately predict the frequency spectrum of
nonsynonymous variants across three continental populations (YRI, CHB, CEU).Comment: 17 pages, 4 figures, supporting information included with sourc
Recessive mutations in SPTBN2 implicate Ξ²-III spectrin in both cognitive and motor development
Ξ²-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding Ξ²-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of Ξ²-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that Ξ²-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome
Chemotherapeutic Sensitization of Leptomycin B Resistant Lung Cancer Cells by Pretreatment with Doxorubicin
The development of novel targeted therapies has become an important research focus for lung cancer treatment. Our previous study has shown leptomycin B (LMB) significantly inhibited proliferation of lung cancer cells; however, p53 wild type lung cancer cells were resistant to LMB. Therefore, the objective of this study was to develop and evaluate a novel therapeutic strategy to sensitize LMB-resistant lung cancer cells by combining LMB and doxorubicin (DOX). Among the different treatment regimens, pretreatment with DOX (pre-DOX) and subsequent treatment with LMB to A549 cells significantly decreased the 50% inhibitory concentration (IC50) as compared to that of LMB alone (4.4 nM vs. 10.6 nM, P<0.05). Analysis of cell cycle and apoptosis by flow cytometry further confirmed the cytotoxic data. To investigate molecular mechanisms for this drug combination effects, p53 pathways were analyzed by Western blot, and nuclear proteome was evaluated by two dimensional-difference gel electrophoresis (2D-DIGE) and mass spectrometry. In comparison with control groups, the levels of p53, phospho-p53 (ser15), and p21 proteins were significantly increased while phospho-p53 (Thr55) and survivin were significantly decreased after treatments of pre-DOX and LMB (P<0.05). The 2D-DIGE/MS analysis identified that sequestosome 1 (SQSTM1/p62) had a significant increase in pre-DOX and LMB-treated cells (P<0.05). In conclusion, our results suggest that drug-resistant lung cancer cells with p53 wild type could be sensitized to cell death by scheduled combination treatment of DOX and LMB through activating and restoring p53 as well as potentially other signaling pathway(s) involving sequestosome 1
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