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Methods of multiple comparisons were applied to linkage analysis in the case of genome scanning. Data for Problem 2A were used. p-Values were calculated for all 440,400 possible tests of linkage. Plots of distribution functions and false discovery rate are shown.
The radC102 mutation that sensitizes E. coli K-12 cells to ultraviolet light, ionizing radiations and alkylating agents was localized between the fpg and pyrE genes at 81.7 min on the bacterial chromosome. E. coli strain BH20 (radC+, fpg-1::KnR) has a 10.5-kb EcoRI/KpnI DNA fragment spanning the region from pyrE to the insertion mutation fpg-1::KnR. The proximity of the radC gene to this insertion mutation provided a strategy to isolate the radC+ gene based on the cloning of radC+ and fpg-1::KnR on the same DNA fragment using the resistance to kanamycin as a selector. A library of EcoRI/KpnI DNA fragments of E. coli strain BH20 was inserted into pUC19. One recombinant plasmid conferring resistance to kanamycin was selected and named pRCV10. The pRCV10 plasmid partially restores the resistance to UV-radiation when transformed into SR1187 (radC102), but sensitizes the wild-type strain to the same treatment. The radC102 complementing region was localized on a 1.2-kb BglII/BglII DNA fragment which was sequenced. The DNA sequence complementing the radC102 mutation contained an ATG translation start codon with an open reading frame of 297 base pairs which encodes a polypeptide of Mr 11,500. The order of the genes in this region of the E. coli chromosome is: fpg--rpmBG--radC--pyrE.
Spurious associations due to confounding factors are an often cited and intensely debated concern for genetic association studies. Great attention has been focused upon the specific threat of confounding due to population stratification. This emphasis has spurred the development of many statistical genetic methods to detect and correct for the potentially confounding effects of admixture. Unfortunately, this emphasis on admixture has led some authors to suggest that if ethnically homogenous populations are used, spurious associations are unlikely to occur. We show that under small and realistic degrees of assortative mating over time, spurious associations arise even in ethnically homogeneous populations. We demonstrate that structured association and genomic control tests can, under certain conditions, correct for these spurious associations. We conclude that investigators should not assume spurious associations will not occur in association studies using ethnically homogenous populations and recommend the use of genomic control methods and/or family-based association tests within genetic association studies.
It is the year 2025. In a leading teaching hospital, in London, New York, Paris, or Tokyo, a little girl is born. Her parents have elected to try an innovative new service that is being offered there--at a price--to all parents of newborns: whole genome analysis....
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The identification of transcription factor binding sites (TFBS) is an important initial step in determining the DNA signals that regulate transcription of the genome. We tested the performance of three distinct computational methods for the identification of TFBS applied to the human genome sequence, as judged by their ability to recover the location of experimentally determined, and uniquely mapped, TFBS taken from the TRANSFAC database. These identification methods all attempt to filter the quantity of TFBS identified by aligning positional weight matrices that describe the binding site and employ either (i) a P-value threshold for accepting a site, (ii) an over-representation measure of neighboring sites, or (iii) conservation with the mouse genome and application of P-value thresholds. The results show that the best recognition of TFBS is achieved by combining the identification of TFBS in regions of human-mouse conservation and also by applying a high stringency P-value to the TFBS identified in non-coding regions that are not conserved. Additionally, we find that only half of the 481 experimentally mapped sites can be found in sequence regions conserved with mouse, but the predictive power of the binding site identification method is up to threefold higher in the conserved regions.
We have studied the effect of some specific enzyme inhibitors on DNA repair and replication after UV damage in Chinese hamster ovary cells. The DNA repair was studied at the level of the average, overall genome and also in the active dihydrofolate reductase gene. Replication was measured in the overall genome. We tested inhibitors of DNA polymerase alpha and delta (aphidicolin), of poly(ADPr) polymerase (3-aminobenzamide), of ribonucleotide reductase (hydroxyurea), of topoisomerase I (camptothecin), and of topoisomerase II (merbarone, VP-16). In addition, we tested the effect of the potential topoisomerase I activator, beta-lapachone. All of these compounds inhibited genome replication and all topoisomerase inhibitors affected the overall genome repair; beta-lapachone stimulated it. None of these compounds had any effect on the gene-specific repair.
West Nile virus (WNV) is a priority pathogen that poses a high risk for public health emergencies of global concern. Although WNV is endemic to Africa, only few (n=63) whole genomic sequences are available from the continent. In this Review, we examined the status of the molecular testing and genomic sequencing of WNV across Africa and mapped its global spatiotemporal spread. WNV has been detected in 39 African countries, the Canary Islands, and Réunion Island. Although publications, including those with molecular data, originated from 24 of these countries, genomic sequences were available from only 16 countries. Our analysis identified regions with detected viral circulation but without molecular surveillance. The current literature has substantial knowledge gaps in terms of the disease burden, molecular epidemiology, and distribution of WNV in Africa. Addressing these gaps requires an integrated One Health surveillance approach, which is challenging to establish. We propose three key surveillance needs that could improve the current understanding of the WNV disease burden in Africa, to strengthen the global public health response to this vector-borne disease.
A 277-bp long DNA fragment, Ba813, was isolated from an avirulent Bacillus anthracis strain 7700 genomic library. Two oligonucleotides derived from the Ba813 sequence were used as primers in polymerase chain reaction tests on genomic DNA from 28 Bacillus anthracis and from 33 heterologous bacteria strains. A specific, 152-bp long DNA fragment was amplified only when Bacillus anthracis DNA was used as the target. The amplified product was analysed by non-radioactive sandwich hybridisation in microtiter plates using two oligonucleotides. The capture oligonucleotide C1 was covalently linked onto aminated wells of microtiter plates. The detection oligonucleotide D3 was labelled with biotine. The hybrid molecules were detected by avidine conjugated with alkaline phosphatase and chromogenic substrate. Amplification of Ba813 sequence may provide the basis for rapid and reliable assay for the detection and identification of Bacillus anthracis.
Genomes reveal vast functional potential, but harbor genomic noise that obscures prediction of metabolic and environmental preferences. Genomic databases are skewed towards clinically relevant and easily cultivated bacteria, limiting predictions for diverse and underrepresented environmental taxa. Psychrotrophic bacteria, which can survive and grow in cold, nutrient-limited, dry, and saline environments, are especially underrepresented despite their relevance for understanding microbial responses to changing cold environments and potential biotechnological value given growth at low temperatures. Assembling complete genomes of 48 isolates from Alaskan permafrost, seasonally frozen active layer soils, and terrestrial ice, we used Kyoto Encyclopedia of Genes and Genomes (KEGG) ortholog annotations to evaluate the predictability of metabolic resource-use traits observed using phenotypic tests. Genome-predicted values for glycolytic versus gluconeogenic catabolic preference index, or sugar-acid preference (SAP), explained over 50% of the variance in empirically observed SAP. SAP was inversely correlated to genomic GC content, which follows phylum-level trends, indicating that coarse metabolic preference covaries with phylogeny. Regularized elastic net models offered a more granular view, linking KEGG genes to specific substrate utilization and sensitivity phenotypes and yielding moderate but reproducible accuracy (AUC 0.70-0.79) for 11 substrates, demonstrating that specific substrate responses may be predictable from relatively small subsets of KO genes. These results extend recent advances, such as the SAP metric, and highlight associations among genomic GC content, phylum, and broad metabolic strategy. Linking genomic content to phenotype using isolates is a necessary step toward predictive models of microbial function in environmental communities, and this work can be used for hypothesis generation, with applications towards more expansive data sets.IMPORTANCECold region soils and ice host psychrotrophic bacteria with metabolic traits and adaptations that enable persistence in harsh, resource-limited environments. However, these taxa are underrepresented in genomic reference databases dominated by well-studied, mesophilic organisms. This gap limits inference of ecological strategies and our ability to predict how these microbes may influence the large, thaw-vulnerable carbon reservoirs in permafrost. Here, we show that genomic GC content is associated with the sugar-versus-acid catabolic preference (SAP) of isolates across major phyla, suggesting that broad genomic features may provide a coarse signal of metabolic strategy. We demonstrate that a modified SAP metric, using binary (positive/negative) substrate utilization rather than detailed growth rate measurements, is moderately predictive, thus extending its application to slow-growing or difficult-to-culture taxa. Together, these advances broaden the toolkit for linking genome content to resource-use traits (phenotype) in poorly characterized, cold-adapted bacteria and offer a tractable entry point to broad prediction and hypothesis generation.
Covarion models of molecular evolution allow the rate of evolution of a site to vary through time. There are few simple and effective tests for covarion evolution, and consequently, little is known about the presence of covarion processes in molecular evolution. We describe two new tests for covarion evolution and demonstrate with simulations that they perform well under a wide range of conditions. A survey of covarion evolution in sequenced plastid genomes found evidence of covarion drift in at least 26 out of 57 genes. Covarion evolution is most evident in first and second codon positions of the plastid genes, and there is no evidence of covarion evolution in third codon positions. Therefore, the significant covarion tests are likely due to changes in the selective constraints of amino acids. The frequency of covarion evolution within the plastid genome suggests that covarion processes of evolution were important in generating the observed patterns of sequence variation among plastid genomes.
The phenotypically similar hamster mutants irs1 and irs1SF exhibit high spontaneous chromosome instability and broad-spectrum mutagen sensitivity, including extreme sensitivity to DNA cross-linking agents. The human XRCC2 and XRCC3 genes, which functionally complement irs1 and irs1SF, respectively, were previously mapped in somatic cell hybrids. Characterization of these genes and sequence alignments reveal that XRCC2 and XRCC3 are members of an emerging family of Rad51-related proteins that likely participate in homologous recombination to maintain chromosome stability and repair DNA damage. XRCC3 is shown to interact directly with HsRad51, and like Rad55 and Rad57 in yeast, may cooperate with HsRad51 during recombinational repair. Analysis of the XRCC2 mutation in irs1 implies that XRCC2's function is not essential for viability in cultured hamster cells.
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The tobacco etch potyvirus (TEV) polyprotein is proteolytically processed by three viral proteinases (NIa, HC-Pro, and P1). While the NIa and HC-Pro proteinases each provide multiple functions essential for viral infectivity, the role of the P1 proteinase beyond its autoproteolytic activity is understood poorly. To determine if P1 is necessary for genome amplification and/or virus movement from cell to cell, a mutant lacking the entire P1 coding region (delta P1 mutant) was produced with a modified TEV strain (TEV-GUS) expressing beta-glucuronidase (GUS) as a reporter, and its replication and movement phenotypes were assayed in tobacco protoplasts and plants. The delta P1 mutant accumulated in protoplasts to approximately 2 to 3% the level of parental TEV-GUS, indicating that the P1 protein may contribute to but is not strictly required for viral RNA amplification. The delta P1 mutant was capable of cell-to-cell and systemic (leaf-to-leaf) movement in plants but at reduced rates compared with parental virus. This is in contrast to the S256A mutant, which encodes a processing-defective P1 proteinase and which was nonviable in plants. Both delta P1 and S256A mutants were complemented by P1 proteinase expressed in a transgenic host. In transgenic protoplasts, genome amplification of the delta P1 mutant relative to parental virus was stimulated five- to sixfold. In transgenic plants, the level of accumulation of the delta P1 mutant was stimulated, although the rate of cell-to-cell movement was the same as in nontransgenic plants. Also, the S256A mutant was capable of replication and systemic infection in P1-expressing transgenic plants. These data suggest that, in addition to providing essential processing activity, the P1 proteinase functions in trans to stimulate genome amplification.
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Algorithms inspired by comparative genomics calculate an edit distance between two linear orders based on elementary edit operations such as inversion, transposition and reciprocal translocation. All operations are generally assigned the same weight, simply by default, because no systematic empirical studies exist verifying whether algorithmic outputs involve realistic proportion of each. Nor do we have data on how weights should vary with the length of the inverted or transposed segment of the chromosome. In this paper, we present a rapid algorithm that allows each operation to take on a range of weights, producing an relatively tight upper bound on the distance between single-chromosome genomes, by means of a greedy search with look-ahead. The efficiency of this algorithm allows us to test random genomes for each parameter setting, to detect gene order similarity and to infer the parameter values most appropriate to the phylogenetic domain under study. We apply this method to genome segments in which the same gene order is conserved in Escherichia coli and Bacillus subtilis, as well as to the gene order in human versus Drosophila mitochondrial genomes. In both cases, we conclude that it is most appropriate to assign somewhat more than twice the weight to transpositions and inverted transpositions than to inversions. We also explore segment-length weighting for fungal mitochondrial gene orders.