text:
Human genomic regions with exceptionally high levels of population differentiation identified from 911 whole-genome sequences
DOI: 10.1186/gb-2014-15-6-r88
© Colonna et al.; licensee BioMed Central Ltd. 2014
Received: 3 May 2014
Accepted: 30 June 2014
Published: 30 June 2014
Population differentiation has proved to be effective for identifying loci under geographically localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes.
We demonstrate that while sites with low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively.
We identify known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research.
The environment, acting through selective processes, is one of the main forces that shapes the genomes of species on an evolutionary timescale [1]. A population carries a certain level of genetic variation, known as 'standing variation'; most of these variants are neutral and have no appreciable effect on fitness, but some do influence fitness. When the environment changes, natural selection acts on these non-neutral variants (and indirectly on linked variants), and over subsequent generations their frequencies may change in response. Genetic influences on fitness are typically small, and many variants usually affect the same trait, so adaptation is generally the result of small changes in frequency of multiple alleles: a 'soft sweep' [2]. Occasionally, a single new mutation has a major advantageous effect and can dominate the selective response, leading to a 'hard sweep' [2]. In addition, sexual selection provides an additional force on the genome [3], with consequences for patterns of genetic variation in the population that are difficult to distinguish from those resulting from natural selection, although hard sweeps based on the perceived attractiveness of a new observable variant may be more frequent. In other circumstances, natural selection may favor more than one allele at a particular site in the genome - for example, if the heterozygote has the highest fitness, or the rarer allele is generally at an advantage - and this can lead to similar allele frequencies in different populations, sometimes maintained for long periods [4]. Thus, allele frequency comparisons between different populations can potentially be informative about several forms of selection.
Humans have a worldwide distribution, but this is, evolutionarily, recent. Human populations outside Africa originated from migration out of Africa 50 to 70 thousand years ago, with low levels of admixture with archaic hominins, that reached all inhabitable continents by about 15 thousand years ago [5]. Our ancestors have thus been exposed to a diverse range of environments over this time period, experiencing different temperatures, altitudes, ultra-violet radiation levels, foods and pathogens; and with the development of farming and livestock domestication in some places within the last 10 thousand years, additional changes in lifestyles. The common variants in our genomes are mostly older than the out-of-Africa expansion, and thus their frequencies are potentially informative about adaptations to these environmental changes. Indeed, both general correlations between climatic variables and the frequencies of classes of functionally related single nucleotide polymorphisms (SNPs) [6], and specific examples of variants showing both frequency differences between populations and relevant functional effects have been reported. Examples of this second class are the A allele at rs1426654 within SLC24A5 contributing to light skin color in Europeans [7], and the T allele at rs4988235 near the lactase gene (LCT) leading to the ability to digest lactose as an adult in Western Asia and Europe [8]. In contrast, rs1129740 at DQA1 in the HLA locus shows similar frequencies of the two alleles (coding for cysteine and tyrosine, respectively) in many populations, linked to both increased susceptibility and protection against conditions such as hepatitis, leprosy and AIDS, possibly as a result of balancing selection [5]. Of course, apparent allele frequency patterns of these kinds are not necessarily the result of adaptation: they can also arise as a consequence of genetic drift, background selection or genotyping error [9–11], and the relative contributions of these different processes remain to be determined.
Genetic investigations of the selective forces that have shaped the human genome have mostly been based on limited genetic information: either genotyping of known variable sites using SNP arrays, or studies focused on regions of prior interest. The ability to sequence whole human genomes on a population scale has allowed analyses to be performed using more complete datasets less biased by prior expectations [12, 13]. Within the 1000 Genomes Project, we have previously identified, validated and reported SNPs with unusually high levels of population differentiation between continents, and also between populations within continents (HighD sites) [13]. These analyses revealed that no variants in the genome were fixed for one allele in one continent/population and for the other allele in another continent/population; they also re-discovered the known examples mentioned above, and identified many additional highly differentiated alleles. We have also explored the functional annotations of these HighD sites, showing that they are enriched for categories such as non-synonymous variants, DNase hypersensitive sites and site-specific transcription factor binding sites, supporting the idea that they are functionally important [14].
In the current study, we have extended these analyses in three ways. First, we have included additional types of variant from the same set of samples (indel calls and large deletions from the integrated callset [13] and additional indel calls from the exome dataset); second, we have explored the properties of the most extremely low-differentiated variants (LowD sites); and third, we have further analyzed the most highly differentiated variants to investigate the extent to which they are likely to result from selection of different kinds, or other processes. In this way, we have identified many novel candidates for geographically restricted positive selection, and suggest several directions for further research.
Identification of regions of unusually high and low differentiation among human populations
We systematically investigated the pattern of genomic differentiation among 911 individuals from the 1000 Genomes Project. We considered 36.8 million genomic variants (35,587,323 SNPs; 1,244,127 small insertion/deletions (INDELs); 13,110 large deletions or structural variants (SVs) from the 1000 Genomes phase I integrated dataset [13] and 7,210 additional previously unreported high quality exomic INDELs from the same samples (Materials and methods). We restricted our analysis to the 911 individuals belonging to the three major continental groups; populations with small sample size (IBS) and known extensive admixture (CLM, MXL, PUR) were excluded from this analysis (Table S1 in Additional file 1).
We also identified regions of low differentiation among continents, and among populations within continents. In addition to the factors taken into account for HighD sites, we considered two additional features. Rare sites inevitably show low differentiation, but this is a consequence of their rarity rather than of possible balancing selection, and such sites were therefore excluded. We also observed a class of sites with allele frequency 0.5 in all populations, which are likely to represent miscalled paralogous variants. For these reasons, we restricted our analysis to approximately two million sites (1,835,365 SNPs, 172,191 INDELs, 285 SVs) with 0.40 ≤ DAF ≤ 0.60 (in the entire sample of 911), excluding sites with 0.45 < DAF < 0.55. As a measure of low differentiation, we calculated the coefficient of variation of derived allele frequencies among populations (cvDAF). We ranked cvDAF genome-wide and again assigned an empirical P-value, with the lowest P-value corresponding to the smallest cvDAF. As with HighD sites, LowD sites also tended to cluster in the genome (Figure S4 in Additional file 2) and thus we explored a range of combinations of cvDAF and window size (Figure S5 in Additional file 2) to retain variants with the lowest cvDAF, conditioning on cvDAF <0.01 in non-overlapping windows of 100 variants. We identified 236 variants that met these criteria (213 SNPs and 23 INDELs; Table S3 in Additional file 1).
Most HighD variants are SNPs (85%) and the INDEL/SNP ratio in HighD sites with good genotype quality (genotype imputation quality from MaCH/Thunder >0.8) [16, 17] is similar to that in matched controls (0.10 in HighD, 0.12 in controls; Fisher exact test P-value = 0.25). We validated the HighD and LowD sites with several approaches, in addition to the Sequenom genotyping reported previously [13]. First, we observed high genotype concordance at 808 sites that were independently genotyped in 112 individuals in both phase I and complete genomics [18] datasets (0.99 for one lowD INDEL; medians of 0.98 for 629 HighD SNPs, 0.94 for 8 HighD INDELs, and 0.99 for 170 lowD SNPs). Second, we compared allele frequencies between the phase I populations and 255 independent individuals from the same populations genotyped on a different platform [19]. While we observed a high correlation of allele frequencies and ΔDAF values for HighD sites (r = 0.82 to 0.97, P-value <2.0 × 10-10), the correlation of the coefficient of variation for LowD sites was poor (r = 0.13, P-value = 0.278), despite a good correlation in allele frequencies (r = 0.94 to 0.98 and r = 0.77 to 0.96 in HighD and lowD sites, respectively; Figure S6 in Additional file 2). Thus, while both sets of genotypes are reliable and the high levels of population differentiation measured by the ΔDAF value were replicated in independent samples, the low levels of population differentiation measured by the cvDAF value were specific to the phase I samples and are not a more general feature of the populations that the samples are derived from. We have therefore not analyzed the LowD sites further, and concentrate below on the HighD sites.
Do HighD sites result from selection or drift?
Do HighD selected sites represent cases of hard or soft sweeps?
HighD sites are enriched in genes and other functional elements
Having established the likelihood of positive selection acting on a proportion of HighD sites, probably via both hard and soft sweeps, we turned to an investigation of the probable functional targets of this selection. We first considered HighD site association with annotated genes coding for either proteins or RNAs. There was a strong enrichment for genic sites compared to frequency-matched controls (odds ratio = 6.9, Fisher exact test P-value <1 × 10-10). We did not find enrichment for HighD sites with reported expression quantitative trait loci [32], but have previously reported their enrichment in nonsynonymous SNPs and UTRs among coding sequences, and DNase hypersensitive sites and binding sites of some classes of transcription factors among non-coding regulatory regions [14]. These findings suggest that changes in both amino acid sequences and regulatory elements may have been selected.
In order to determine whether or not specific classes of genes were enriched for HighD sites, two approaches were used. Functional annotation clustering was carried out using the Database for Annotation, Visualization, and Integrated Discovery (DAVID v.6.7) [33]. Using the highest classification stringency with a Bonferroni correction for multiple comparisons, no significant enrichment of any Gene Ontology term associated with any biological process, cellular compartment, or molecular function was found. However, using medium classification stringency, a significant enrichment was observed for transcription factor binding sites at the continental and all population levels. In addition, we analyzed the same sites by Ingenuity Pathway Analysis. Here, also, no significant associations were observed after applying a Bonferroni correction for multiple comparisons. Thus, HighD sites, and by implication the local adaptations that underlie a proportion of them, involve diverse biological pathways, none of which predominates at our level of sensitivity.
Novel insights into individual genomic candidates for population- or continent-specific positive selection
At the continental level, 58% (65% when restricting to protein coding) of the HighD variants are in genes previously reported to be under positive selection. Within continents, 24% (30% when restricting to protein coding) of the HighD genes belong to lists of genes putatively under positive selection. We have thus discovered a large number of HighD sites that appear to represent novel candidates for selection. Confirmation of this possibility would require functional investigations, which are beyond the scope of the current study. However, we note that while this manuscript was under review, one of our candidates, rs1871534 in ZIP4, was the subject of such a detailed study, and strong functional support for positive selection acting on altered zinc transport was obtained [34]. Encouraged by this, we now present a number of other candidates that illustrate a range of features.
Among the within-continent comparisons, the C > T intronic polymorphism rs77943343 is located in the caldesmon 1 (CALD1) gene, which encodes a calmodulin- and actin-binding protein regulating smooth muscle and non-muscle contraction. Almost half of the JPT sample carries the derived allele at rs77943343 (DAF = 0.49), which is less frequent in the other Asian (CHB = 0.15, CHS = 0.18) and continental populations in general (AFR = 0.18, EUR = 0.05). This variant lies immediately adjacent to another polymorphism, rs77994671, which, however, appears to reflect an independent mutation whose derived allele has frequency 0.024 in AFR and 0.002 in EUR but is absent in ASN. rs77943343 lies in a candidate enhancer region and in a site for histone H3 acetylation in skeletal muscle myoblasts, 497 bp downstream of an inactive promoter and 11.5 kb upstream of the active promoter (11.6 kb from the gene's first codon) and thus might be relevant to the regulation of this gene (Figure S16 in Additional file 2). CALD1 is implicated in Ca++-dependent smooth muscle contraction. Knockout of CALD1 paralogs in zebrafish results in altered intestinal peristalsis [35]and in humans CALD1 has been associated with gastric cancer [36] and endometriosis [34]. Network analysis of haplotypes surrounding rs77943343 in the ASN populations shows the increased frequency of a core haplotype specific to the JPT population and six rare single-step derivatives also carrying the derived allele, all also present in the JPT population, and five specific to this population (Figure S16 in Additional file 2). We speculate that the derived allele could have improved the efficiency of the use of Ca++ in conditions of low dietary calcium intake, such as the Japanese diet [37, 38].
We observed two other examples of HighD sites located in genes related to calcium metabolism, both with high DAF in the LWK: rs7818866 in VDAC3 and rs6578434 in STIM1 (DAF = 0.67 and 0.63, respectively, compared with DAF <5% in other populations). VDAC3 is a voltage-dependent anion channel type 3, essential for sperm mobility, while STIM1 generates the Ca++ ions in oocytes during fertilization and is essential for this process. These three examples together highlight the potential importance of calcium metabolism in human adaptation.
Second, the derived allele at an exomic INDEL (a novel variant; chromosome 2, position 185802211; Table S2 in Additional file 1) is an insertion of 3 bp (ACA), which adds a threonine residue at amino acid position 697, within the first exon of the zinc finger protein 804A gene (ZNF804A). This variant is present at high frequency in the ASN population (DAF = 0.83 versus 0.58 and 0.07 in EUR and AFR, respectively). ZNF804A acts as a transcription factor and regulates the transcription of genes related to schizophrenia [45]. An intronic polymorphism (rs1344706) in this gene has been associated with schizophrenia [46] and a third variant, rs4667001 in the fourth exon, changes both an amino acid and mRNA levels [47]. The ACA insertion is in strong linkage disequilibrium (LD) with rs4667001 (r2 = 0.96) but less so with rs1344706 (r2 = 0.45). Because of the threonine insertion, the protein has an additional site for post-translational modifications such as glycosylation and phosphorylation. Phosphorylation of other proteins (for example, the deubiquitinating enzyme OTUB1) has been demonstrated to regulate susceptibility to pathogens of the Yersinia family [48], of which some members probably evolved in China [49], and thus we speculate that the insertion may have been selected in relation to pathogen resistance.
Positive selection acts through several mechanisms, and the predominant ones in human populations remain to be clarified. Population differentiation is one of the most straightforward ways to identify a subset of variants experiencing this form of selection, and indeed some of the resulting phenotypes have been recognized and studied by physical anthropologists for over a century, while the genes and specific variants that underlie them are now being identified by geneticists [5]. Whole-genome sequences from population samples provide a powerful starting resource for this, and are now available from the 1000 Genomes Project [12, 13]. In the current study, we have examined a near-complete catalog of the accessible sites in the genome that represent extreme differentiation between and within the African, European and East Asian population groups participating in the project. In doing this, we have rediscovered known examples of classic selective sweeps, and also encountered a large number of novel sites, and have thus been able to both characterize the general features of this mode of selection and obtain new insights into some specific examples.While our validation studies confirm that the vast majority of the HighD sites we have listed are indeed highly differentiated between continents or populations, rather than being artifacts arising from genotyping errors, it is more difficult to assess the proportions that result from random genetic drift compared to positive selection. A major underlying limitation is the paucity of positively selected variants supported by direct functional evidence. HighD sites are undoubtedly enriched for positive selection (Figures 3 and 4), and overlap with genes previously reported as positively selected. This 34% overlap, divided into 58% for comparisons between continents and 24% for comparisons between populations, provides one estimate of the proportion that are selected, albeit one that ignores the novel events. The lower proportion in population comparisons could reflect, among other factors, the higher noise contributed by drift and the greater difficulty of detecting selection by other approaches at less complete sweeps.
This study is more comprehensive than previous surveys of highly differentiated variants, which in large-scale studies have been limited to examining the SNPs included on genotyping arrays [11, 50] or SNPs in protein-coding genes discovered by resequencing three populations [12]. Our strategy of choosing the highest ΔDAF value from a fixed window expands the range of signals we can discover, but will nevertheless exclude weaker but still potentially interesting selection signals from the windows with a strong signal, and future studies could use more sophisticated approaches to identifying peak signals. A level of population differentiation higher than that at the DARC gene has sometimes been used as a criterion, and here we observe novel ΔDAF values greater than DARC at three positions: rs6014096 in DOCK5, rs1596930 in EXOC6B and rs12903208 in PRTG (Figure 5b), all in introns. In addition, HighD sites in genes such as CALD1, ABCA12 and ZNF804A provide intriguing examples for follow-up in model organisms, the last also illustrating the importance of considering variants other than SNPs.
Our data throw light on two topics of current debate about selection in humans. First, some but not all studies [22] have found more evidence for recent positive selection outside Africa than inside. It has been difficult to interpret the results of tests that incorporate haplotype structure, because recombination differs between populations, with lower levels of LD and different PRDM9 alleles and recombination hotspots in Africa [51]. Similarly, SNP ascertainment in African populations has been less thorough than in European populations, and so analyses based on known SNPs have been biased against discovering highly differentiated sites in Africans. The identification of HighD sites from full sequence data, however, is unaffected by recombination or ascertainment, and the lower number of HighD sites in Africa (25 versus 110 each in EUR and ASN) supports the hypothesis of less positive selection of this type, despite the larger effective population size, which should make selection more efficient.
Second, our identification of a large sample of likely positive selection events allows us to consider the relative importance of classic sweeps compared with selection on standing variation in humans. To do this, we need to know the proportion of HighD sites that result from positive selection rather than drift, and the proportion that result from classic sweeps. If we took the proportion of HighD sites that overlap genes with published evidence of positive selection as a minimum estimate of the proportion of selective events (58% for continental comparisons), and the proportion of inter-continental HighD sites with low Levenshtein distances (see Results) as a minimum estimate of the proportion of classic sweeps (30%), we would estimate about one-half. Both of these proportions are likely to be under-estimates - DARC would be excluded from the classic sweep numbers, for example - and thus this estimate is highly uncertain, but in contrast to some other analyses [52], emphasizes an important role for classic sweeps.
This study has established a comprehensive catalog of most of the variants, including SNPs, INDELS and SVs, that are highly differentiated between the major populations of sub-Saharan Africa, Europe and East Asia. Remarkably, this simple approach, when applied to whole-genome sequences from large population samples, usually seems to lead directly to the functional variant responsible for the differentiated phenotype. Several of the most highly differentiated variants and their associated phenotypes were known long before this work, testifying to the high visibility of the phenotypes, but the remaining catalog should be a rich source of starting points for investigations of phenotypes that should be equally important and fascinating.
Materials and methods
We used genotype calls from two sources: the 1000 Genomes Phase I integrated callset [53] and 7,210 additional, previously unreported high quality exonic INDELs from the same samples. In each case, we restricted our analyses to 911 individuals from 10 populations with ancestry from Africa, Europe or East Asia (Table S1 in Additional file 1). Allele frequencies were calculated using vcffixup from Vcflib [54] and used to identify HighD sites. We determined distance from the nearest annotated gene using information from Ensembl v72 and subsequently generated sets of sites used in various analyses as matched random genomic sites by matching allele frequency and distance from gene start site (Figure S10 in Additional file 2), taking into account the population to which the HighD site was assigned. Occurrence of HighD and matched sites among expression quantitative trait loci was estimated using the GeneVar database [32].
Weir and Cockerham's FST[49] was calculated using vcftools [50]. FST values were used to evaluate correlation with ΔDAF values for the same variants in chosen regions.
Using COSI [20], we simulated the evolution of 600 kb regions under a published demographic model [20] for three continental populations, namely AFR, EUR and ASN. We generated 3,000 replicates of neutral evolution (that is, without any selected variant) as well as 3 × 100 replicates of 30 selective sweep scenarios as described [24], within each of the three populations. Each of these selective scenarios has a selective sweep acting on a new variant located at the center of the simulated region, that is, at position 300,000 bp. The selective sweep lasts from 200 to 1,200 generations and always ends 401 generations ago. The selective coefficient was set to drive the selected allele up to a frequency of 0.2, 0.4, 0.6, 0.8 or 1. For each replicate, we ran iHS [25], XP-EHH [15], FST[55] and ΔDAF [13] using a pipeline described previously [56]. For cross-population statistics, we considered all the six pairwise comparisons. We then inferred the sensitivity (true positive rate) of those four methods by (i) calculating the 95th percentile of the score distributions obtained across the 3,000 neutral replicates, hence inferring the threshold corresponding to a 5% false discovery rate, and (ii) counting the proportion of replicates under a given sweep scenario with a score for the selected variant above this threshold. For each population, we performed the sensitivity analysis for five different sweep scenarios by grouping the replicates where the final allele frequency of the selected variant was the same, as well as an 'overall' sweep scenario grouping all the replicates with selection in a given population.
Genotype concordance of HighD and LowD sites between phase I data and publicly available complete genomics data was calculated as the proportion of concordant calls among 112 overlapping individuals averaged across loci. Allele frequency concordance was calculated between phase I EUR, AFR, and ASN populations and three non-overlapping sets of individuals from the same continents from the HapMap3 study [15] (total of 255 individuals: 24 EUR (18 CEU, 6 TSI); 166 ASN (101 CHD, 31 JPT, 34 CHB); 65 AFR (22 LWK, 43 YRI)) genotyped on a different platform (Illumina BeadArray genotypes at 1,456,587 sites [19]). Because overlap of sites on the chip with HighD and LowD sites was poor (100 HighD and 29 LowD sites), we also included comparisons at sites in high LD (r2 > 0.8) with HighD and LowD sites (255 and 202 sites, respectively). LD was calculated using Vcftools [57]. Concordance was assessed using a Spearman correlation coefficient.
In order to estimate the expectation for number of HighD sites under neutrality, we simulated 100 replicates of 500 Mb DNA sequence data (subdivided into 10 chromosomes of the same size) from 911 diploid genomes from three populations according to two published demographic models [20, 21] for the three continental populations AFR, ASN and EUR using MaCS [58]; we included variable recombination rates by incorporating information from random regions from HapMap phase 3 recombination maps [19]. Because all models led to similar conclusions, we only report results from [21]. We estimated the number of HighD sites in 500 Mb of simulated data as for the phase 1 data, and then scaled this number to the size of the accessible genome (2,526,390,487 base pairs [13]).
We summarized from the literature a list of 3,467 genes that have been previously identified in genomic scans for positive selection [22–24] and compiled the occurrence of non-redundant genes hosting HighD sites (HighD-genes; n = 542) in it. To obtain estimates of random expectation we calculated the occurrence of 100 sets of control genes in the list of positively selected genes. Control genes were randomly selected to match the number of HighD-genes or fractions of this set based on ΔDAF quartiles (n = 247 and n = 146 for third and fourth quartiles, respectively). A one-sided t-test was used to assess the significance of the differences in overlap.
We estimated genome-wide statistics informative about selection from sequence data of the phase I data set. These statistics were based on 10 kb windows and include three allele frequency spectrum-based tests, Tajima's D, Fay and Wu's H, and Nielsen et al.'s composite likelihood ratio, calculated and combined to give a single P-value as described previously [26]. We also estimated the haplotype-based statistics iHS [25]and XP-EHH [15] using Selscan [59] at sites for which recombination maps and ancestral allele information were available. In order to make the continent and population level analyses comparable, in each group we restricted the analysis to a set of 30 randomly chosen individuals. The iHS and XP-EHH scores obtained for each SNP in each population/continent were divided into allele frequency classes and, within each class, normalized following standard procedures [25, 44]. Similarly, we calculated iHS and XP-EHH for a set of genomic sizes matched to HighD sites for allele frequency in the combined sample and distance from gene start site. A two-sample Kolmogorov-Smirnov test was used to evaluate differences between the HighD and matched site iHS distributions.
The Database for Annotation, Visualization, and Integrated Discovery (DAVID v.6.7 [33, 60]) was used for functional characterization of the highly differentiated variants that lay within genes. The Functional Annotation Clustering option was used by adding Panther and Reactome to Pathways, Panther to Protein Domains and Reactome and UCSC TFBS to Protein Interactions to the default settings. In another approach, Ingenuity Pathway Analysis (IPA, Ingenuity Systems, Redwood City, CA, USA) was carried out for the same set of variants. Ensembl gene identifiers were uploaded and core analyses was carried out for the differentiated variants at the continental (CON) and population levels (AFR, ASN and EUR). The analyses generated networks based on their connectivity in the Ingenuity Knowledge Base (IKB), which includes experimental data from human, mouse and rat models. The core analyses selected only those interactions that have been experimentally observed and included pathways based on (i) diseases and disorders, (ii) molecular and cellular functions and (iii) physiological system development and function. The significance of the association between the dataset and the pathways was tabulated by estimating a ratio between the number of genes from the dataset that met the expression value cutoff and map to the pathway, and the total number of molecules present in the pathway. A conservative Bonferroni P-value threshold was used to account for multiple testing.
Median-joining networks for haplotype visualization and analysis were generated using Network 18.104.22.168 [61]. Since this version of the software can display only 100 chromosomes per circle, we selected each time 300 random chromosomes. The CALD1 and ABCA12 haplotypes were based on all the SNPs in D' = 1 within 10 kb of the HighD site in the population with the highest DAF; for the networks in Figure 7 and Figure S16 in Additional file 2, haplotypes were derived from polymorphisms within 2 kb surrounding the HighD site.
Data availability
The 1000 Genomes phase I integrated callset used in this study is publicly available at [53]. For a list of samples used in this study, refer to Table S1 in Additional file 1.
- bp:
Base pair
Derived allele frequency
Linkage disequilibrium
Single-nucleotide polymorphism
Structural variant
untranslated region.
We thank Danny Challis, Fuli Yu, Donna Muzny and Richard Gibbs for contributing the exomic indel data set and Goo Jun for helping with the Complete Genomics data set. We thank Tsun-Po Yang for assistance with Genevar. This work was supported by The Wellcome Trust (098051), an Italian National Research Council (CNR) short-term mobility fellowship from the 2013 program to VC, and an EMBO Short Term Fellowship ASTF 324–2010 to VC. A full list of participants and institutions is available in Additional file 3.
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Answer:If you damaged a library material you will need to pay for its repair or its replacement. Cost is determined by type of damage, amount of damage, and replacement cost is determined by subject matter. Damage includes any underlining and sticky notes of all kinds. Please contact the Libraries' Borrowing Privileges & Fines Department for price and billing information. Please do not attempt to repair the material. Return to the Fines FAQ

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More Videos...
How to Improve Your Old Car's Performance - Part 2/3
The Smoking Tire gets down and dirty on their Jetta Project Car, trying to improve the car's performance with just a factory service, performed at home by Matt Farah, a first time mechanic.
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The Smoking Tire takes to the track and Dyno to find out just how much performance can be gained after doing a factory service on our 166,000 mile VW Jetta
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We really shouldn't be surprised that a Prius would eventually be here. This one has the full kit of suspension upgrades, a drive control module, and some JDM accessories. Check out Jay's Prius on Wheelwell! https://www.wheelwell.com/profile/557d90b357b98cb82a392da8/vehicles/557d990 557b98cb82a392dbe/specs/


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A Honor Roll
Did you know that refund and exchange policies are not required by law? In fact, retailers offer refund policies as a voluntary practice. There are no laws that require merchants to offer refunds, exchanges or credit on merchandise they sell, although laws do protect consumers from misrepresented or defective products.
A Honor Rolls
Third grade: Azad Akhtar, Lily Kate Best, Michael Browning, Rylee Cliatt, Milwa Davy, Rylan Driesen, Jayla Fevrine, Kaitlyn Freeman, Eylaaf Garman, Ryan Hill, Robert Innacone, Campbell King, Raleigh Long, Ethan Manning, Georgia Morris, Cecilia Muro, Erin Nichols, Kai Okoh, Alyshia Olson, Andrew Phillips, Andrew Pye, Christopher Reiter, Jose Rosalaes, Milo Rosengrant, Riya Sondhi, Julian Sosa, Alayna Stephens, Aubrey Taylor, Hannah Thomas, Marilla Vernon
Tax Aide volunteers
Tax Aide volunteers are needed for tax season. No experience is necessary. Visit www.aarp.org/taxaide or call Jim Roberts at (706) 726-3101. www.aarp.org/taxaide.
Festival applications
Applications are due Nov. 29 for those interested in participating in the Grovetown Christmas Festival, Dec. 3 from 4 - 8 p.m. at Liberty Park Community Center. Email email@example.com; http://www.cityofgrovetown.com/calendar.aspx?EID=108
Lightwire Theater
Rotarians from around the country gathered at the Centers for Disease Control in Atlanta for a live broadcast with CDC Director Tom Frieden, Rotary International President John Germ, End Polio Ambassador and Paralympian Dennis Ogbe for World Polio Day. Visit www.endpolio.org for the broadcast. Pictured from left: Rotary International Director 2014-2016 Robert Hall, District Governor Pam Lightsey of Martinez, Barry and Cynde Covington and District Governor Marshall Butler.
Pets shown have been adopted. To browse adoptable pets, visit columbiacountyga.gov.
Tax Aide volunteers are are needed for tax season. No experience is necessary. Visit www.aarp.org/taxaide or call Jim Roberts at (706) 726-3101. www.aarp.org/taxaide.
Pioneer lifestyles
Children ages 6 and older can explore the past with activities based on pioneer life from 9:30 a.m. to 2 p.m. Monday, Nov. 21, or Tuesday, Nov. 22, at Mistletoe State Park, 3725 Mistletoe Road, Appling. The cost is $25 per child plus $5 parking; lunch is included. Call (706) 541-0321 or visit gastateparks.org.
Support group
Thomas George Treadwell Jr. and Kayla Marie Blitchington applied for a marriage license Oct. 26 and were married Oct. 29 in Appling
Ethan Alexander Booth and Jaylynn Ann Dearing applied for a marriage license Oct. 31 and were married Nov. 2 in Grovetown
Andrew Eugene Howard and Michelle Blackstone Pope applied for a marriage license Nov. 1 and were married Nov. 1 in Grovetown
Jennifer Catherine Meyer and Darien Brie Dearth applied for a marriage license Nov. 2 and were married Nov. 9 in Evans
Wells Fargo Bank, N.A. to Secretary of Veterans Affairs, an officer of the United States of America, successors and assigns; 8028 Battle St.; $175,665; Government/nonprofit public corp.
Kimberly H. Barker to Louis R. Barker; 572 Tudor Branch; $0; Divorce based transfer
Jeanette G. Pate to Jeannette G. Pate and Ronald C. Smith as joint tenants with right of survivorship; Map & Parcel number: 030 004, 030 004B; $0; Deed of gift
Tevis Hoffman and Gary Oxton to Berry Payton Bidetto; Map & Parcel number: 082A002; $202,000
Columbia County News-Times ©2017. All Rights Reserved.


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All Agencies (A-Z) » Support Agencies, Legislative » Other, Department of Health and Human Services, Executive
Other, Department of Health and Human Services, Executive (1 - 10 of 21 items)
Mental Health and Substance Use: Treatment Exclusions in Employers' Health Insurance Coverage
GAO-12-761R: Published: May 31, 2012. Publicly Released: May 31, 2012.
In summary, this report provides information on the incidence of treatment exclusions for MH/SU for the 2011 or 2010 plan year and the 2008 plan year for employers that responded to our survey. In total, for the 2011 or 2010 plan year, of the 96 employers that responded to our question about whether their most popular plan excluded coverage for any specific treatments related to MH/SU, 39 employer...
Pre-Existing Condition Insurance Plan: Comparison of Implementation and Early Enrollment with the Children's Health Insurance Program
GAO-12-62R: Published: Nov 10, 2011. Publicly Released: Dec 13, 2011.
The federal Pre-Existing Condition Insurance Plan (PCIP) was created in 2010 to provide access to insurance for individuals previously unable to acquire coverage due to pre-existing conditions. Eligibility is limited to those who have been uninsured for at least 6 months prior to application, thus focusing the program on those who have been locked out of the private insurance market. The Patient P...
Nursing Homes: Private Investment Homes Sometimes Differed from Others in Deficiencies, Staffing, and Financial Performance
GAO-11-571: Published: Jul 15, 2011. Publicly Released: Aug 15, 2011.
Private investment (PI) firms' acquisition of several large nursing home chains led to concerns that the quality of care may have been adversely affected. These concerns may have been in part due to PI firms' business strategies and their lack of financial transparency compared to publicly traded companies. In September 2010, GAO reported on the extent of PI ownership of nursing homes and firms' i...
Head Start: Undercover Testing Finds Fraud and Abuse at Selected Head Start Centers
GAO-10-733T: Published: May 18, 2010. Publicly Released: May 18, 2010.
The Head Start program, overseen by the Department of Health and Human Services and administered by the Office of Head Start, provides child development services primarily to low-income families and their children. Federal law allows up to 10 percent of enrolled families to have incomes above 130 percent of the poverty line--GAO refers to them as "over-income." Families with incomes below 130 perc...
Hurricane Katrina: Federal Grants Have Helped Health Care Organizations Provide Primary Care, but Sustaining Services Will Be a Challenge
GAO-10-273T: Published: Dec 3, 2009. Publicly Released: Dec 3, 2009.
The greater New Orleans area--Jefferson, Orleans, Plaquemines, and St. Bernard parishes--continues to face challenges in restoring health care services disrupted by Hurricane Katrina which made landfall in August 2005. In 2007, the Department of Health and Human Services (HHS) awarded the $100 million Primary Care Access and Stabilization Grant (PCASG) to Louisiana to help restore primary care ser...
Federal Tort Claims Act: Information Related to Implications of Extending Coverage to Volunteers at HRSA-Funded Health Centers
GAO-09-693R: Published: Jun 24, 2009. Publicly Released: Jun 24, 2009.
The Federal Tort Claims Act (FTCA) was enacted in 1946 and permits individuals injured by the wrongful or negligent acts or omissions of federal employees, including medical malpractice, to seek and receive compensation from the federal government through an administrative process and, ultimately, through the federal courts. The FTCA, with few exceptions, provides the exclusive means by which indi...
Long-Term Care Insurance: Partnership Programs Include Benefits That Protect Policyholders and Are Unlikely to Result in Medicaid Savings
GAO-07-231: Published: May 11, 2007. Publicly Released: Jun 11, 2007.
Partnership programs allow individuals who purchase Partnership long-term care insurance policies to exempt at least some of their personal assets from Medicaid eligibility requirements. In response to a congressional request, GAO examined (1) the benefits and premium requirements of Partnership policies as compared with those of traditional long-term care insurance policies; (2) the demographics...
Medicare: CMS's Proposed Approach to Set Hospital Inpatient Payment Appears Promising
GAO-06-880: Published: Jul 28, 2006. Publicly Released: Jul 28, 2006.
Under Medicare's inpatient prospective payment system (IPPS), hospitals generally receive fixed payments for hospital stays based on diagnosis-related groups (DRG), a system that classifies stays by patient diagnosis and procedures. CMS is required to at least annually update DRG payments to address changes in the cost of inpatient care. CMS uses charge-based weights to update these payments. Cost...
Medicare Dialysis Facilities: Beneficiary Access Stable and Problems in Payment System Being Addressed
GAO-04-450: Published: Jun 25, 2004. Publicly Released: Jun 25, 2004.
Medicare covers about 90 percent of patients with end-stage renal disease (ESRD), the permanent loss of kidney function. Most ESRD patients receive regular hemodialysis treatments, a process that removes toxins from the blood, at a dialysis facility. A small percentage dialyzes-at home. From 1991 through 2001, the ESRD patient population more than doubled, from about 201,000 to 406,000. As the nee...
Medical Malpractice: Implications of Rising Premiums on Access to Health Care
GAO-03-836: Published: Aug 8, 2003. Publicly Released: Aug 29, 2003.
The recent rising cost of medical malpractice insurance premiums in many states has reportedly influenced some physicians to move or close practices, reduce high-risk services, or alter their practices to preclude potential lawsuits (known as defensive medicine practices). States have revised tort laws under which malpractice lawsuits are litigated to help constrain malpractice premium and claims...


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They should either forgive them all or forget them all.
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They should either forgive them all or forget them all.
There's a big difference between steroids and betting on baseball
Guys on the juice will eventually get in
Pete may never get in, and if he does he won't be alive when it happens
Rose was not banned from baseball or the HOF because he cheated.
He bet on baseball. By betting on baseball he became indebted to people who had a vested interest in the outcome of baseball games. He did all of this while in a position to directly effect the outcome of many, many baseball games. Connect the dots and try and understand why it is MUCH more serious than taking PEDS (including greenies), doctoring a bat, doctoring baseball, rubbing out the batter's box, running outside the baseline, peeking at the catcher, deking a baserunner, or stealing signs.
As long as Gaylord Perry is in the Hall of Fame, the doors can remain open to nearly anyone who can put the proper numbers on the back of his baseball card. Anything else is hypocrisy.
I think Rose will be voted in by the Veteran's Committee long after he dies. Probably Jackson will, too, maybe at the same time.
I think the steroid era guys will eventually all walk free, grandfathered in.
Just my opinion.
Put in Shoeless Joe and then we can talk about the rest of them.
this again?
Pete Rose is not only the hit king he's the games most famous liar and Cincinnati's favorite son.
Let'em all in, I say. Just give an accurate history. Pete Rose's entry should say banned from baseball for gambling. ARod's should say "admitted steriod user."
Someone on ESPN radio this morning said the Hall of Fame "is a museum, not the Vatican." How can you have a museum about the history of the game without the hits leader, HR leader, etc.?
What about other cheaters? The guys who used speed in the 60s and 70s and 80s?
Scuffers, spitballers and admitted cheaters like Gaylord Perry?
Ty Cobb is one of the vilest people on the planet, yet he is celebrated in the HOF.
This is perhaps the best sumnation of my feelings on the subject;
I don't know exactly where steroid use should sit on the hierarchy of sins against the game: I think it's worse than throwing spitballs and not as bad as throwing games, but how much worse and how much less noxious I'm not entirely sure. But I do know that to date, the only otherwise-deserving players who've been denied entry to the Hall - Rose and Shoeless Joe Jackson - have been those who were guilty of infractions that got them banned them from the game for life. Now perhaps steroid users should be banned for life, but the fact remains that A-Rod and others stand accused of violating a rule that carried no penalty save treatment at the time that they (and dozens if not hundreds of other players whose names haven't been leaked) broke it, and that today only gets you banned outright if you're a three-time offender. And I think it's a good rule of thumb that if you're allowed to continue playing major league baseball after committing a given infraction, you shouldn't be disqualified - informally or formally - from its Hall of Fame.
Let them all in. You're honoring their on the field accomplishments. Yes, Pete bet on baseball. And yes, Barry and Big Mac and A-Rod and the Rocket and so on altered themselves to gain an edge. But it is what it is. Put them in the all and acknowledge their errors. But to leave them out is silly, IMO. I respect the opinion of the people that think they shouldn't get in, because I thought that way at one point in time. But as Jayson Stark said, the all time hit leader will be out of the Hall, the all time home run leader, one of the greatest right-handed pitchers of all time... etc. etc. I want to be able to take my kids there 20 years from now and say "This is who they are, this is what they did, and here's what they accomplished." We can't pretend that it never happened. It can be a good learning tool, IMO. "See this guy? HE screwed up. Don't let the same happen to you."
I won't vote in this poll, because i would let Rose in and not the steroid users.
What Rose did, betting on baseball while managing the Reds, was wrong and should keep him out of the game for good. Why should we ever take a chance that he is again violating the betting rules while in uniform?
However, to me the Hall of Fame is not about the players character or morals, it is about whether that player was one of the best of his era. Ty Cobb was a nasty man in most respects, and was hated by his peers. There was one fairly credible allegation involving Cobb being involved in a scandal where a game was actually thrown. However, he was also one of the best players of all time.
I feel that Rose fits in the category of one of the best players ever. I know, he is a liar and a compulsive gambler. But to me, his accomplishments while playing justify inclusion in the HOF.
The steroid guys put up stats that I simply don't trust. Some, like Bonds , would be HOF worthy based on what they did before they were on performance enhancing drugs. Others, like ARod, may have also accomplished much after they quit. But how can we ever know what portion of their records were tainted?
With Rose, we know that his gambling and lying did not taint his actual playing baseball, or the resulting records. We cannot say the same about Bonds, Canseco, McGuire, or ARod.
Do we really?Quote:
With Rose, we know that his gambling and lying did not taint his actual playing baseball, or the resulting records
MLB started investigating Rose and Gambling in 1970, that's a long time before he was manager.
Shoeless Joe Jackson was given a lifetime ban for his infractions (real or perceived) and his life is over. I would induct him now.
Pete Rose knew what he was doing when he bet on baseball and he signed an agreement to his lifetime ban. I would induct him in the Hall of Fame the first year after his passing.
As far as I can tell, one of the reasons (probably not the MAIN reason) behind using steroids is to attain numbers sufficient for Hall of Fame induction. I would not want to encourage such actions and so would subject them to the same treatment...posthumous induction.
So basically, you don't give up the right to be in the Hall, you just give up the right to be there at the celebration.


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Wymondham, Norfolk
Peter Graham Wines sell wholesale wine to the trade in East Anglia Soon after returning to Norwich Peter Graham Wines was born and started life in a beautiful 16th century building in the cobbled streets of Elm…
London, Greater London
Top UK Fine wine merchant and trader of First growths, en primeur, Bordeaux, Champagne, Burgundy and fine wines online. Learn about wine investment, online wine storage, wine tastings, wine events and wine school
Great Yarmouth, Norfolk
We pride ourselves on our large selection of quality Wines and Champagnes and are proud to be members of the Society of Vintners, The Society of Vintners is a consortium that has 28 members covering the whole of the…
Bradford, West Yorkshire
Our strong links with manufacturers and suppliers, coupled with our own transport division, our extensive warehouse facilities, our keen eye for marketing, in house design, dedicated customer service representatives…
Elgin, MORAYSHIRE
Our iconic retail shop on South Street, Elgin still thrives today on the site where the business began in 1895. Since those early days the company has grown and has a number of business interests. We are a bottler of whi…
We are the largest composite independent drinks distributor in the South East and home counties Our delivery areas now cover all of Essex, East and North Hertfordshire, parts of Suffolk, Middlesex and Kent and …
Hastings, East Sussex
Welcome to Gunson Fine Wines Limited vintage cellar list We have brought together a dedicated site for our range of Fine, Rare and Esoteric wines in a concise and easy to use format
Wholesale of wine, beer and spirits, Wholesale of alcoholic and other beverages
Suppliers of fosters john, smiths smooth, carling, Carlsberg,stella and many more we are Barnsley`s longest running beer wholesaler with over a decade of experience under our belts. We`ve seen beer wholesalers in Barnsle…
North Kensington, London
Salisbury, Wiltshire
Shop online for quality fine wines from Swallow Fine Wines. Huge selection of wines from France, Italy, Australia and the new world
Saffron Walden, Essex
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Find Cash Advance, Debt Consolidation and more at Bonawines.com. Get the best of Insurance or Free Credit Report, browse our section on Cell Phones or learn about Life Insurance. Bonawines.com is the site for Cash Advanc…
Sittingbourne, Kent
Wolverhampton, WEST MIDLANDS
The UK's leading independent and pub retailing business, Marston's PLC is at the heart of thriving local communities
South Ruislip, London
SKV Wholesalers Ltd : Wholesaler of Alcoholic & Non-alcoholic Drinks,Confectionery,Snacks & Crisps
Nelson, Lancashire
Jersey, Channel Islands
In an age when the friendly and personal family business is fast disappearing, we're proud of the fact that Gallie's World of Wines is still very much an independent family wine merchant, established in 1948 , who gua…
Barton, Cambridgeshire
Independent wine merchant Cambridge Cozzi and Boffa, Cambridge wine merchants
One of London's last remaining traditional wine trading companies
Tonbridge, Kent
Oxford, Oxfordshire
We represent a broad range of global brands including those from our parent company
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Hereford, Herefordshire
Linlithgow, West Lothian
Cheap Spirits, Wholesale Discount Cheap Wine Wines and Spirits Supplier Suppliers Distributor UK Wholesalers of Cheap and Discount Wines, Wine and Spirits at Wholesale Prices UK
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Seaview, Isle of Wight
Our wines are selected with a rigid and strict criteria that the taste, feel and character are better than the price allows
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Mill Creek Real Estate
Mill Creek is located in Pennsylvania. Mill Creek, Pennsylvania 17060 has a population of 398. Mill Creek 17060 is more family-centric than the surrounding county with 29.48% of the households containing married families with children. The county average for households married with children is 28.22%.
The median household income in Mill Creek, Pennsylvania 17060 is $38,750. The median household income for the surrounding county is $44,455 compared to the national median of $53,046. The median age of people living in Mill Creek 17060 is 30.6 years.
Mill Creek Weather
The average high temperature in July is 86 degrees, with an average low temperature in January of 19.9 degrees. The average rainfall is approximately 37.5 inches per year, with 27.8 inches of snow per year. No weather information available.
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(based on 1 review)
Ratings Distribution
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Perfect Gift
By M Lewis
from New Orleans, Louisiana
About Me Budget Shopper
Best Uses
Comments about Personalized Princess Castle Pillowcase:
Purchased product for my grandgirls and their parents were very impressed and pleased with the quality of your product especially the monogram will be using until they wear out this is a product I should have ordered much more just in case of discontinuing this particular product.
Bottom Line Yes, I would recommend this to a friend
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Internet guy who believes in the triumph of humanity with a little help from technology. Yadda, yadda, yadda.
I took this photo with my camera phone just as we arrived at the San Francisco Opera a few weeks ago. We're going again later this month because its a good time.
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Search On For Suspect Who Stabbed, Slashed Men In Chinatown FightPolice on Friday were searching for a suspect who stabbed a teen and slashed another man in Chinatown, in a fight over a broken gaming machine.
Police: Burglars Targeted Restaurants, Bars On Lower East Side, In ChinatownPolice late Monday were searching for two suspects in a string of burglaries targeting Lower Manhattan restaurants and bars.
Shopper's Guide To San FranciscoGuide to best neighborhoods for shopping in San Francisco
Manhattan's 5 Best Late-Night EatsNew York is the city that never sleeps. Head to these Manhattan restaurants for these quality late-night eats after a night on the town.
Police: Man Attacks Woman In Chinatown With Metal ObjectJust before 5 a.m. a woman in her 40s was sitting outside a closed produce store on Mott Street off Grand Street.
Police: 83-Year-Old Man Struck, Killed By Truck In ChinatownThe driver, 24-year-old Maykel Felix-Tejada, was arrested and charged with aggravated unlicensed driving.
Group Home Worker Arrested After Teens Escape And Allegedly Raped WomanHe is expected to appear in court later Thursday.
2 Suspects Arraigned In Chinatown Rape, Robbery CaseEric Pek and Emanuel Burrows, both 16, were each ordered held on $100,000 bail.
Police: 3 Teens Arrested In Chinatown Sex Assault, RobberyPolice have arrested three Brooklyn teenagers in connection with a sex assault and robbery of a woman in Chinatown.
Chinatown Tenants Claim Landlord Is Letting Building Fall Apart To Force Them OutAbout 30 tenants of a six-story building in Chinatown claim their health and safety are in jeopardy, and they are looking to the city for help.
NYPD Releases Video Of Man Wanted In Chinatown Groping IncidentThe suspect followed a 27-year-old woman as she was walking on Mulberry Street and groped her, police said.
New York City Celebrates Start Of Lunar New YearThe celebration is about family and food -- fruits, nuts and fish are considered good luck.


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Rib mignon on a fresh ratatouille stack drizzled with a tomato coulis.
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- Serves:1
- Degree of difficulty:Low
1x250g rib fillet
(Wrapped in bacon with one skewer to hold bacon onto rib fillet)
Ratatouille stack ingredients
1/2 egg plant (cut into thick slicers)
1/2 zucchini (cut into long length slices)
1/2 red capsicum (cut into long length slices)
2 knobs of garlic (roasted) - cook in a hot oven 170 degrees with a drizzle of oil for 5 to 6 minutes until coloured and smells sweet.
Feta, half hand full for garnish
Coulis ingredients:
2 large roman tomatoes
2 cherry tomatoes
1 knob of roasted garlic
1/2 bunch basil
Salt and pepper to taste
Place all ingredients for the coulis in a big bowl and blend up with a small hand mixer or just cut ingredients nice and fine and mash them up with a hand potato masher.
The mix should become a nice thick sauce. Once sauce is made cool in a cold fridge for ten minutes.
Seal and cook all the ingredients of the ratatouille stack on a hot char grill fry pan. Just use a normal fry pan with a drizzle of oil over the vegetables and salt and pepper to taste.
Place a little bit of feta on one of the slices of egg plant and place under a hot grill to get some nice colour.
At the same time cook the rib fillet to your liking.
Once the rib is cooked and the stack ingredients are ready to go its time for the fun part.
The fun part, plating up time:
Drizzle coulis around the plate and place the steak on the side. Arrange the stack with different colours and the slice of egg plant with the grilled feta cheese on top. Place that slice as the main garnish of the stack and spread a little bit of broken up feta over the top.


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Rate ProFibe
Verified Purchase
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My blood pressure was the lowest it has been in years this week when I donated blood.ProFibe is the only thing I did different. Charlotte
Rate ProFibe
My blood pressure was the lowest it has been in years this week when I donated blood.ProFibe is the only thing I did different. Charlotte
CerlBurg, ProFibe, 454 g ---Recommended
Posted by Reviewer1892861 on Dec 02, 2008
I have been using this product for about a year now and my cholesterol numbers have improved. Latest (11/08) were 173/50. I recommend trying the product for a reasonable period (8 months to a year) and see if it works for you. In my opinion, preferable to going on statins, if it works for you.
CerBurg Profibe is Great
Posted by Reviewer1918851 on Oct 10, 2007
I have used CerBurg Profibe for several years and believe it made a major contribution to bringing my cholesterol count into a very healthy range and keeping it there. Before beginning to use it I ordered copies of the research studies that are available from Cerburg.
CerBurg, Profibe
Posted by Reviewer1737777 on Dec 08, 2007
I tried Profibe a few years ago and lowered my cholesterol 71 points. That was the only change I made to my diet. My doctor was astounded. I got lazy and let it run out and my cholesterol began to climb again. I'm back on it now and much prefer this to messing around with my liver as statin drugs allegedly do. It also seems to help the lower GI tract. This is going to a permanent part of my regimen.
Mr. Zenon Ulczak
Posted by Reviewer1230235 on Apr 02, 2008
Wonderful product..I have more energy..Gums feels good..I have more of a bounce...Just a really good it. I just need to go to the Doc and check out the insides. I explained to my my co-worker of it's benefits and passed on this web-site.
Posted by Reviewer2087474 on Jul 29, 2008
Has lowered my cholesterol effectively and naturally.
Posted by Reviewer2253831 on Jan 02, 2009
great for lowering cholesterol. I eat oatmeal in the morning and add a teaspoon of Profibe for extra fiber. Great for the colon also.
Great Product at Great Price
Posted by Reviewer1363943 on Nov 16, 2007
This is an extremely good product at the best price on the internet. Keep up the good work.
Posted by Reviewer2142158 on Nov 21, 2007
This is a really good source of fiber and easy to take. Thanks iherb for the great price!
CerBurg ProFibe
Posted by Reviewer1197583 on Aug 11, 2009
This is an excellent product and continues to effectively lower my cloresterol and maintain the lower level after several years use! I am greatly pleased with this product and I am also highly pleased with the excellent prices through iHerb.


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Jordan Carter is once again putting himself forward for the policy council of Labour.
Here is his email begging for a vote and here is his CV/brochure.
So here we have Jordan Carter campaigning on an explicitly left ticket.
Let's take a closer look…
"I've held that role for the past three years"
Yeah, and how did policy work out at the last election, Jordan? Was that a triumph you're seeking to better this time around.
"we need bold, left wing policy in 2014".
Really, that's his pitch? Understand clearly that a vote for Carter on policy council is a vote for Labour to shift further left than it was last year.
"I also want us to be, and become, a party that welcomes debate about ideas and the future."
"Be and become" eh? I think I see what you're trying to fudge there Jordan. How about you think about being a party that welcomes debate.
No doubt Chris Trotter and Martyn "DBD" Bradbury will blog forth in support.
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I plant all my geraniums in pots and containers and I do try to winter over
some of the plants that are smaller or the ones I couldn't get many cuttings
from. I put these larger plants under the lights with the cuttings. I prune
them back about a third and water them maybe once a week. For most of my
plants though I do rely on the cuttings. I can usually start potting up and
setting the plants outside in April. They grow outside until the first hard
frost which is usually October or November. I add fertilizer like Osmicote
to the soil when I plant the geraniums. So during the summer growing season
all I do is water them. During some of the hottest months I have to water
them twice a day.
Dayton, OH


text:
Students have been using iTunes University to search, download and play educational content for several years, but some educators at the college level say they are using the site as a source for for homework assignments and classroom lessons. One educator called the site, which has about 200,000 education files, a "fantastic tool" that allows teachers to see how their colleagues are teaching a particular topic.
Full Story:eSchool News (free registration)


text:
Apartment Alger Centre Totally New
- Airport Shuttle
- Breakfast
- Gym
- Parking
- Pets Allowed
- Swimming Pool
- Wifi
- Smoking Allowed
Apartment in perfect condition, refurbished and decorated with care. It is located in a hewn stone building, 3rd floor, it is quiet and the neighbors are very friendly. It can accommodate 4 to 5 people (with extra bed in the living room) is equipped with a television and a TV, a washing machine and everything needed for a pleasant stay (microwave, coffee maker , oven, fridge-freezer, cookware compète, linens, sheets, comforters, and pillows provided) It is also equipped with internet and with air conditioning (cold and hot) nearby, a car park open 7 days 7, paid and monitored. The metro is just steps away. The shops and market are close to the apartment.


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Budget Minded,
Go Green,
Off The Beaten Path,
Travelers Rest RV Resort and Golf Course is the perfect place to stop in central Florida. Just 3 easy miles from I-75, and conveniently located to many major attractions and events.
www.travelersrestresort.com. 100 Activities in season, November to April. Beautiful park with great amenities. Come for a day or stay for a lifetime, this park has something for everyone.
29129 Johnston Road Dade City, FL 33523
(352) 588-2013
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Buzz! Master Quiz
| |
Release Date: September 23, 2008
Buzz! Master Quiz Cheats & Codes
| Cheats | Unlockables | Hints | Easter Eggs | Achievements
Be the first to submit a cheat for Buzz! Master Quiz.
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Game Details
Published by: Sony Computer Entertainment
Developed by: Relentless Software, Curve Digital
Genre: Trivia
Release Date:
United States: September 23, 2008
Also Available On:
Games You May Like
- Trivia
- PlayStation Portable
This trivia game challenges players to recognize familiar musical sounds. Questions can involve recognizing which instrument, musical note,…
This trivia game challenges players to identify animals from all over the world via a series of split-up pictures.
Buzz! Quiz World provides an ultra-realistic quiz show experience, putting you and your friends in the contestants' seats.
A member of an elite military team, Squall is forced into a conflict beyond imagination in Final Fantasy VIII, no on the PSN.
All Jill Valentine wants to do is go home but the zombies, hellhounds, and blood hunters are making it really tough. Each time you meet up…
The operations are set to continue in the sequel to the hit PSP title, Metal Gear Solid: Portable Ops.


text:
Green schools aren't only effective at helping the environment—they can also produce kids who are more knowledgeable about environmental issues.
"The idea is that by being exposed to this innovative design every day at school, along with a sustainable school culture fostered by educators, students will inherently learn and appreciate the importance of green buildings," says Laura Cole, a professor of architectural studies in the University of Missouri's College of Human Environmental Sciences.
A study, led by Cole, set out to test whether "Teaching Green" middle schools actually made a difference to the kids taught in them. She defines the schools as "places where architects and educators have aspired to use the school building to amplify student understanding of environmental sustainability," and notes that, until now, the efficacy of these schools has not been well examined.
The results show that kids, as we already know, learn by mimicking what we do, and not what we tell them to do. Students taught in green schools "had much higher levels of environmentally friendly behaviors while at school, such as recycling and turning off lights," says Cole. They also showed much better knowledge of environmentally friendly practices in general.
The schools include obvious features like easy-to-use recycling facilities, plus less obvious ones like open-air hallways (which don't need to be heated or cooled), repurposed construction materials, and exposed beams and other architectural features that let kids see how the places are put together.
While purpose-designed schools are great, ripping all our schools out to replace them with greener buildings is impractical, and more than a little environmentally dodgy itself. But existing schools can participate at lower levels by introducing greener practices. "Anything educators can do to utilize existing space can help their students' green building literacy," says Cole.
Around 50% of all fossil fuels burned in the U.S. go to heat up buildings, cool them down again, and power their lights and appliances. Teaching future and current generations of kids to turn out the lights, or not leave the faucet running, or to maybe put on a damn sweater instead of cranking the heating could some day have an impact on future energy use.


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Ocean View Real Estate
Ocean View is located in Delaware. Ocean View, Delaware 19970 has a population of 1,968. Ocean View 19970 is less family-centric than the surrounding county with 12.08% of the households containing married families with children. The county average for households married with children is 21.34%.
The median household income in Ocean View, Delaware 19970 is $70,333. The median household income for the surrounding county is $52,692 compared to the national median of $53,046. The median age of people living in Ocean View 19970 is 61.4 years.
Ocean View Weather
The average high temperature in July is 85 degrees, with an average low temperature in January of 27.6 degrees. The average rainfall is approximately 45.5 inches per year, with 12.4 inches of snow per year. No weather information available.
Ocean View Map
Ocean View real estate offices
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Jordan Hill to start against Pelicans
EL SEGUNDO – Lakers' coach Mike D'Antoni has been hesitant to disrupt the continuity of his second unit. But as lackluster starts piled up, by Tuesday he felt like he was out of choices.
The coach will turn to his sixth starting lineup in nine games Tuesday against the New Orleans Pelicans, making Jordan Hill the third player to start at power forward.
Hill will join a lineup of Steve Blake, Jodie Meeks, Pau Gasol and Nick Young. Meeks will start for the third time this season due to the absence of Steve Nash, who will be out at least two weeks due to nerve root irritation that stems back to his broken leg last season.
Hill is averaging 6.3 points and 6.6 rebounds in 16.1 minutes per game. He has become a familiar presence at the end of games, playing alongside Gasol.
"I love playing with Pau," Hill said. "Definitely keep my eyes open, expect the pass from him. Both great rebounders, we definitely should be on the boards a lot more."
For D'Antoni, starting Hill was a risk-reward proposition.
"I'm going to look at Jordan Hill and see if we can start off with his energy," he said. "I hate to lose it off the bench, but then again, right now … the blanket's a little short, we're trying to figure out how to make the blanket a little bit longer."
Playing without Nash is just an added obstacle for a season already battered by inconsistency and the elephant in the room – the absence of Kobe Bryant.
"We knew that the first of the year was going to be tough," D'Antoni said, "getting Steve back after a long layoff, trying to get Kobe back, trying to get Pau over his operation this summer. We knew at first it could be some ups and downs. Our focus is just to stay focused, get the energy right, win as many as we can, get our guys healthy and then see what we can do."
Nash was already being used sparingly, sitting out the second game of back-to-backs and playing limited minutes. He was pulled at halftime of Sunday's loss to Minnesota.
"It's disappointing," D'Antoni said. "I'm sure for him above all. Just something we'll have to deal with and hopefully in two weeks he'll come back and feel better."
D'Antoni said Nash will not travel with the Lakers to Denver for Wednesday's game against the Nuggets, but will likely be with them for longer road trips.
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The list you're viewing contains actors like Anthony Quinn and Gregory Peck.
If you want to answer the questions, "Who starred in the movie The Guns of Navarone?" and "What is the full cast list of The Guns of Navarone?" then this page has got you covered.
This cast list of who was in The Guns of Navarone includes both lead and minor roles. (18 items)
- 1
Marcello Mastroianni Cinema Paradiso, 8½, La Dolce Vita
- 2
Richard Harris Gladiator, Harry Potter and the Philosopher's Stone, Harry Potter and the ...
- 3
Gregory Peck To Kill a Mockingbird, Cape Fear, The Omen
- 4
Anthony Quinn Lawrence of Arabia, The Ox-Bow Incident, Last Action Hero
- 5
David Niven The Pink Panther, Mutiny on the Bounty, Murder by Death
- 6
Olivia de Havilland Gone with the Wind, The Adventures of Robin Hood, Cinema Paradiso
- 7
Anthony Quayle Lawrence of Arabia, The Guns of Navarone, The Fall of the Roman Empire
- 8
Telly Savalas The Muppet Movie, The Dirty Dozen, On Her Majesty's Secret Service
- 9
James Robertson Justice Chitty Chitty Bang Bang, The Guns of Navarone, Moby Dick
- 10
Stanley Baker Zulu, The Guns of Navarone, Richard III
- 11
James Darren The Guns of Navarone, Venus in Furs, Gidget
- 12
Percy Herbert The Bridge on the River Kwai, The Guns of Navarone, Mysterious Island
- 13
Bryan Forbes The Guns of Navarone, King Rat, International Velvet
- 14
Irene Papas The Guns of Navarone, Z, Zorba the Greek
- 15
Allan Cuthbertson The Guns of Navarone, Performance, Ice Cold in Alex
- 16
Gia Scala The Guns of Navarone, Ride a Crooked Trail, The Two-Headed Spy
- 17
Michael Trubshawe The Pink Panther, The Guns of Navarone, Bedazzled
- 18
George Mikell The Great Escape, The Guns of Navarone, The Spy Who Came in from the Cold ...


text:
Auto Partes Balcania, C.A.
Reserves and accessories for cars and trucks
Reclaim business
Address and Phones Auto Partes Balcania, C.A.
Carrera 19, Entre Calle 43 y 44, Edf. Cesidio, Loc. 4 y 5, Carrera 19, Barquisimeto, Lara - Venezuela
How to get?
How to get?
Contact person: Hidden
Days and Hours of Service Auto Partes Balcania, C.A.
Monday, Tuesday, Wednesday, Thursday, Friday
Morning: 08:00 am - 12:00 am
Afternoon: 01:00 pm - 5:00 pm
Afternoon: 01:00 pm - 5:00 pm
E-mail and Web Site
Download the information to the mobile
Share your experiences!


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track list
Album Inside the Dream Syndicate, Vol. 2: Dream Interpretation
Label Table Of The Elements
Released January 08, 2002
This site contains content from artists, fans, and writers from around the internet in it's natural form. Such content is not representative of Viacom Media Networks.
©2017 Viacom International Inc. All Rights Reserved. MTV and all related titles and logos are trademarks of Viacom International Inc.


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Callum Turner
Actors Olivia Woodward
+44 (0)20 7393 4484
Email Olivia Woodward
Callum Turner played Eli with a tremendous damaged energy throughout the series. It's very difficult for an actor to portray so many different facets of a character at once, and in showing the many shades of Eli Bray's possessiveness and skewed nobility (culminating in that mesmerising scene on the hill), Turner pulled it off.
Jonathan McAloon
The Telegraph on Glue