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PubMed2005

Genome-wide screening of aluminum tolerance in Saccharomyces cerevisiae.

Genome-wide screening has identified 37 Al-tolerance genes in Saccharomyces cerevisiae. These genes can be roughly categorised into three groups on the basis of function, i.e., genes related to vesicle transport processes, signal transduction pathways, and protein mannosylation. The largest group is composed of genes related to vesicle transport processes; severe Al sensitivity was found in yeast strains lacking these genes. The retrograde transport of endosome-derived vesicles back to the Golgi apparatus is an important factor in determining the Al tolerance of the vesicle transport system. The PKC1-MAPK cascade signalling pathway is important in the Al tolerance of signal transduction. The lack of the gene implicated in this process leads to weakened cell wall architecture, rendering the yeast Al-sensitive. Alternatively, Al might attack the cell wall and/or plasma membrane, and, as signalling is prevented in cells devoid of the genes related to signalling processes, the cells may be unable to alleviate the damage. The genes for protein mannosylation are also associated with Al tolerance, demonstrating the importance of cell wall architecture. These genes are involved in cell integrity processes.

Aluminum↗

PubMed2004

A genome-wide screen for genes influencing conduct disorder.

While behavioral genetic studies have suggested that childhood conduct disorder is under genetic influence, studies aimed at gene identification are lacking. This study represents the first genome-wide linkage analysis directed toward identifying genes contributing to conduct disorder. Genome screens of retrospectively reported childhood conduct disorder and conduct disorder symptomatology were carried out in the genetically informative adult sample collected as part of the Collaborative Study on the Genetics of Alcoholism (COGA). The results suggest that regions on chromosomes 19 and 2 may contain genes conferring risk to conduct disorder. Interestingly, the same region on chromosome 2 has also been linked to alcohol dependence in this sample. Childhood conduct disorder is known to be associated with the susceptibility for future alcohol problems. Taken together, these findings suggest that some of the genes contributing to alcohol dependence in adulthood may also contribute to conduct disorder in childhood.

Adult↗

PubMed2000

Identifying genetic susceptibility factors for tuberculosis in Africans: a combined approach using a candidate gene study and a genome-wide screen.

There is convincing evidence that host genes affect the outcome of infection in human tuberculosis. Two complementary strategies were used to identify the genes involved. A linkage-based genome-wide screen was carried out to locate the positions of genes exerting a major population-wide effect on tuberculosis susceptibility. A candidate-gene-based case-control study was used to examine the effects of genes that may exert a more moderate effect on risk of clinical tuberculosis. The genome screen was conducted in two stages. In the first stage 299 microsatellite markers, spanning all 23 chromosomes, were typed in 92 independent sib-pairs, and seven regions showed some evidence of co-segregation with the disease. These seven regions were examined in a second set of 81 sib-pairs, and markers on chromosomes 15q and Xq showed evidence of linkage to tuberculosis. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in many populations. The candidate gene approach compared the frequency of polymorphisms in several genes in over 400 subjects with smear-positive pulmonary tuberculosis and 400 ethnically matched healthy controls. Polymorphisms in genes encoding natural-resistance-associated macrophage protein, vitamin D receptor and mannose-binding lectin were associated with tuberculosis. These results suggest that many genes may be involved in determining host susceptibility to tuberculosis, and highlight the importance of using several different study methods to locate them.

Adolescent↗

PubMed2005

Endoplasmic reticulum-associated protein quality control and degradation: genome-wide screen for ERAD components.

In this chapter, a genetic approach is presented that leads to the isolation of mutants and to the identification of proteins involved in protein quality control and endoplasmic reticulum-associated degradation (ERAD). The method makes use of a genomic screen of a yeast deletion library (EUROSCARF). Transformation of each of the approx 5000 strains deleted in one nonvital gene each with a CPY* chimera containing CPY* C-terminally fused to a transmembrane domain and the cytosolic Leu2 protein (3-isopropylmalate dehydrogenase) constitutes the basic screening procedure. Because of a Leu2p deficiency in all deletion strains, cells can grow only when the CTL* chimera is present. As the CPY* module of CTL* will be recognized in ERAD-proficient cells, CTL* will be degraded and the strain is unable to grow. Therefore the absence of genes necessary for ER quality control and ERAD will allow cell growth and indicate the necessity of the respective gene for these processes.

3-Isopropylmalate Dehydrogenase↗

PubMed2005

Sex differences in the genetic basis of morning serum cortisol levels: genome-wide screen identifies two novel loci specific to women.

CONTEXT: Relatively little is known about the influence of specific genes on cortisol levels, particularly morning cortisol levels. OBJECTIVE: The objective of this study was to identify quantitative trait loci associated with morning serum cortisol levels. DESIGN: We carried out a genome screen for morning serum cortisol using linkage and association methods tailored for use in large pedigrees. We conducted these analyses both in the whole sample and partitioned by sex. SETTING: This study was conducted on nine communal Hutterite farms in South Dakota. PARTICIPANTS: The Hutterites are a young founder population who practice a communal, farming lifestyle in the western United States and in Canada. Hutterites (n = 504, 53% female) aged 11-89 yr from a single pedigree participated in this study. MAIN OUTCOME MEASURES: The main outcome measures were markers significantly linked or associated with variation in morning serum cortisol levels. RESULTS: One genome-wide significant association was identified in the whole sample on 11p (D11S1981, P = 0.000092). Results of sex-partitioned analyses indicated that this association was restricted to females (females, P = 0.000084; males, P = 0.20). The 146-bp allele at this locus accounted for 7% of the variance in morning cortisol values in females, and females homozygous for the allele had an 89% increase in morning cortisol levels compared with female noncarriers. A second genome-wide significant association in females was identified on 14q (D14S74, P = 0.000091). CONCLUSIONS: Our results suggest that the genetic determinants of morning cortisol levels may be different for men and women and that loci on 11p and 14q influence morning cortisol levels in women.

Adolescent↗

PubMed2003

A genome-wide screen for linkage disequilibrium in Australian HLA-DRB1*1501 positive multiple sclerosis patients.

The association of multiple sclerosis with alleles/haplotypes from the HLA region on chromosome 6p21 is well established although the remainder of the genome remains relatively unexplored. We have completed a genome-wide screen for linkage disequilibrium in a cohort of Australian multiple sclerosis patients positive for HLA-DRB1*1501. A total of 4346 microsatellite markers provided through the "Genetic Analysis of Multiple sclerosis in EuropeanS" (GAMES) collaborative were analysed in DNA separately pooled from cases (n=217) and controls (n=187). Associations were found in four genomic regions (12q15, 16p13, 18p11 and 19q13) previously identified in linkage genome screens. Three additional regions of novel association were also identified (11q12, 11q23 and 14q21). Further analysis of these regions is required to establish whether the associations observed are due to epistatic interaction with the HLA locus.

Adult↗

PubMed2000

A two-stage, genome-wide screen for susceptibility loci in primary Raynaud's phenomenon.

OBJECTIVE: To identify chromosomal regions containing genes involved in the susceptibility to primary Raynaud's phenomenon (RP). METHODS: Six extended families with multiple individuals affected with primary RP (n = 37) were examined for linkage in a 2-stage, whole-genome screen, using a total of 298 microsatellite markers. RESULTS: Multipoint, nonparametric linkage analysis identified 5 areas of possible linkage, with a nominal level of significance of P < or = 0.05. Analysis of a finer map of markers in these regions defined the regions of linkage as 21.4 cM on 6q13-6q23.3 (D6S261; P = 0.0004), 10.2 cM on 7p22-7p15 (D7S664; P = 0.014), 1.6 cM on 9p23-9p22 (D9S156; P = 0.0075), 5.1 cM on 17p13.1-17p12 (D17S1791; P = 0.036), and 11.8 cM on Xp11.4-Xp11.23 (DXS8054; P = 0.006). Three potential candidate genes map to these regions: the beta subunit of the muscle acetylcholine receptor and the serotonin 1B and 1E receptors. CONCLUSION: These results provide evidence of the presence and location of genes that are involved in the genetic susceptibility to primary RP.

Adolescent↗

PubMed2004

Genome-wide high-throughput screens in functional genomics.

The availability of complete genome sequences from many organisms has yielded the ability to perform high-throughput, genome-wide screens of gene function. Within the past year, rapid advances have been made towards this goal in many major model systems, including yeast, worms, flies, and mammals. Yeast genome-wide screens have taken advantage of libraries of deletion strains, but RNA-interference has been used in other organisms to knockdown gene function. Examples of recent large-scale functional genetic screens include drug-target identification in yeast, regulators of fat accumulation in worms, growth and viability in flies, and proteasome-mediated degradation in mammalian cells. Within the next five years, such screens are likely to lead to annotation of function of most genes across multiple organisms. Integration of such data with other genomic approaches will extend our understanding of cellular networks.

Animals↗

PubMed2026

The costs of genomic newborn screening in England: A micro-costing analysis from the Generation Study.

PURPOSE: This study estimates the total cost per newborn of delivering genomic newborn screening (gNBS) within the Genomics England-led Generation Study. METHODS: A time-driven activity-based costing approach was used to estimate gNBS costs from recruitment to confirmatory testing. Resource use data were obtained through document review, semi-structured interviews with study staff, and direct observation across six English National Health Service Trusts. Inputs were categorized as labor, consumables, or equipment, with unit costs sourced from published pay scales, catalogs, or literature. Equipment costs were annualized at a discount rate of 3.5%. All costs were estimated in 2025 Great British Pounds (£) from the healthcare providers perspective, including overheads and data storage. A one-way deterministic sensitivity analysis was conducted, varying key cost parameters (±20%) and testing alternative delivery scenarios. RESULTS: gNBS costs £1208 per newborn, with sequencing comprising 58% of the total costs, mainly consumables. The cost was reduced by 20% to £963 when excluding research-specific recruitment and consent activities to reflect the delivery of gNBS as part of routine clinical care. CONCLUSION: This study provides an estimate of gNBS costs, highlighting sequencing as the main cost driver. Combined with evidence on outcomes and health care utilization, these findings will inform future cost-effectiveness analyses, supporting policy decisions regarding national implementation in England.

Neonatal Screening↗

PubMed2000

GRASP-DNA: a web application to screen prokaryotic genomes for specific DNA-binding sites and repeat motifs.

The ability to control multiple genes at the transcriptional level often relies on the existence of short stretches of well-defined DNA sequences, to which regulatory proteins and transcription factors bind. In this article we present a freely accessible web-based application (GRASP-DNA), that can be used to screen prokaryotic genomes for putative DNA-binding sites of a particular transcription factor or DNA-binding molecule. This application utilizes existing theories, such as information and statistical-mechanical theories, for the calculation of positive weight matrices generated from block aligned binding sites. Using these position weight matrices entire prokaryotic genomes are screened to identify sites that display a high level of sequence similarity to existing binding sites. This application can be used in combination with high-throughput technologies for gene expression analysis and binding site characterization to assist in the elucidation of global regulatory networks.

Base Sequence↗

PubMed1999

Genome-wide screen for atopy susceptibility alleles in the Hutterites.

A genome-wide screen for loci influencing positive skin prick tests (SPT) to airborne allergens was conducted in the Hutterites, a founder population of European ancestry. Positive SPT to 14 standardized allergens was measured in 370 subjects in our primary sample and 324 subjects in a replication sample. Evidence for linkage to positive SPT was assessed using the transmission disequilibrium test (TDT) with 337 autosomal markers (average spacing 9.13 cM, SD = 7.8 cM). Three loci showed the strongest overall evidence of linkage to atopy, with at least one allele-specific and a locus-specific p< 1 x 10(-4). This study provides evidence for at least three atopy-susceptibility loci in the Hutterites on chromosomes 1, 6 and 16.

Adult↗

PubMed2005

Screening for genomic fragments that are methylated specifically in colorectal carcinoma with a methylated MLH1 promoter.

A subset of colorectal carcinomas (CRCs) is associated with microsatellite instability (MSI) of the genome. Although extensive methylation of CpG islands within the promoter regions of DNA mismatch repair genes such as MLH1 is thought to play a central role in tumorigenesis for MSI-positive sporadic CRCs, it has been obscure whether such aberrant epigenetic regulation occurs more widely and affects other cancer-related genes in vivo. Here, by using methylated CpG island amplification coupled with representational difference analysis (MCA-RDA), we screened genomic fragments that are selectively methylated in CRCs positive for MLH1 methylation, resulting in the identification of hundreds of CpG islands containing genomic fragments. Methylation status of such CpG islands was verified for 28 genomic clones in 8 CRC specimens positive for MLH1 methylation and the corresponding paired normal colon tissue as well as in 8 CRC specimens negative for methylation. Many of the CpG islands were preferentially methylated in the MLH1 methylation-positive CRC specimens, although methylation of some of them was more widespread. These data provide insights into the complex regulation of the methylation status of CpG islands in CRCs positive for MSI and MLH1 methylation.

Adaptor Proteins, Signal Transducing↗

PubMed2003

A genome-wide screen for linkage disequilibrium in Sardinian multiple sclerosis.

Using indirect whole genome association screening, we have searched for multiple sclerosis susceptibility genes in the genetically isolated high risk Sardinian population. Two screens were performed; the first was based on 229 cases and 264 unrelated controls, and the second on 235 trio families. Each screen employed a dense set of microsatellite markers and DNA pooling. Data from both screens were available from 2764 markers. Nine markers showed nominally significant results in both screens independently. Five of these markers-D2S408 (2q36), D6S271 (6p21), D6S344 (6p25), D7S1818 (7p12) and D16S420 (16p12)-remained nominally significant in both studies after conservative refining analysis.

Adult↗

PubMed2000

A genome-wide screening in Saccharomyces cerevisiae for genes that confer resistance to the anticancer agent cisplatin.

Cisplatin is a potent DNA-damaging agent that has demonstrated anticancer activities against several tumors. However, manifestation of cellular resistance is a major obstacle in anticancer therapy that severely limits the curative potential of cisplatin. Therefore, understanding the molecular basis of cisplatin resistance could significantly improve the clinical efficacy of this anticancer agent. Here, we employed Saccharomyces cerevisiae as a model organism to study cisplatin resistance mechanisms and describe a one-step cisplatin selection to identify and characterize novel cisplatin resistance genes. Screening a multicopy yeast genomic library enabled us to isolate several yeast clones for which we could confirm that the cisplatin resistance phenotype was linked to the introduced fragment. In a first attempt, a number of open reading frames could be identified. Among these genes, PDE2 and ZDS2 were repeatedly identified as genes whose overexpression confers cellular resistance to cisplatin. PDE2, encoding cAMP-phosphodiesterase 2, is of particular interest because the overexpression of this yeast gene is known to induce cisplatin resistance in mammalian cells as well, providing proof of the principle of our experimental approach. In addition, the identification of PDE2 shows that our yeast screening system can directly be informative for drug resistance in mammalian cells.

Chromosome Mapping↗

PubMed2004

A genome-wide screen identifies Yos9p as essential for ER-associated degradation of glycoproteins.

We undertook a growth-based screen exploiting the degradation of CTL*, a chimeric membrane-bound ERAD substrate derived from soluble lumenal CPY*. We screened the Saccharomyces cerevisiae genomic deletion library containing approximately 5000 viable strains for mutants defective in endoplasmic reticulum (ER) protein quality control and degradation (ERAD). Among the new gene products we identified Yos9p, an ER-localized protein previously involved in the processing of GPI anchored proteins. We show that deficiency in Yos9p affects the degradation only of glycosylated ERAD substrates. Degradation of non-glycosylated substrates is not affected in cells lacking Yos9p. We propose that Yos9p is a lectin or lectin-like protein involved in the quality control of N-glycosylated proteins. It may act sequentially or in concert with the ERAD lectin Htm1p/Mnl1p (EDEM) to prevent secretion of malfolded glycosylated proteins and deliver them to the cytosolic ubiquitin-proteasome machinery for elimination.

Carrier Proteins↗

PubMed2004

Efficient selection of unique and popular oligos for large EST databases.

MOTIVATION: Expressed sequence tag (EST) databases have grown exponentially in recent years and now represent the largest collection of genetic sequences. An important application of these databases is that they contain information useful for the design of gene-specific oligonucleotides (or simply, oligos) that can be used in PCR primer design, microarray experiments and genomic library screening. RESULTS: In this paper, we study two complementary problems concerning the selection of short oligos, e.g. 20-50 bases, from a large database of tens of thousands of ESTs: (i) selection of oligos each of which appears (exactly) in one unigene but does not appear (exactly or approximately) in any other unigene and (ii) selection of oligos that appear (exactly or approximately) in many unigenes. The first problem is called the unique oligo problem and has applications in PCR primer and microarray probe designs, and library screening for gene-rich clones. The second is called the popular oligo problem and is also useful in screening genomic libraries. We present an efficient algorithm to identify all unique oligos in the unigenes and an efficient heuristic algorithm to enumerate the most popular oligos. By taking into account the distribution of the frequencies of the words in the unigene database, the algorithms have been engineered carefully to achieve remarkable running times on regular PCs. Each of the algorithms takes only a couple of hours (on a 1.2 GHz CPU, 1 GB RAM machine) to run on a dataset 28 Mb of barley unigenes from the HarvEST database. We present simulation results on the synthetic data and a preliminary analysis of the barley unigene database. AVAILABILITY: Available on request from the authors.

Algorithms↗

PubMed2005

Expressed sequence tag-linked microsatellites as a source of gene-associated polymorphisms for detecting signatures of divergent selection in atlantic salmon (Salmo salar L.).

The prediction that selection affects the genome in a locus-specific way also affecting flanking neutral variation, known as genetic hitchhiking, enables the use of polymorphic markers in noncoding regions to detect the footprints of selection. However, as the strength of the selective footprint on a locus depends on the distance from the selected site and will decay with time due to recombination, the utilization of polymorphic markers closely linked to coding regions of the genome should increase the probability of detecting the footprints of selection as more gene-containing regions are covered. The occurrence of highly polymorphic microsatellites in the untranslated regions of expressed sequence tags (ESTs) is a potentially useful source of gene-associated polymorphisms which has thus far not been utilized for genome screens in natural populations. In this study, we searched for the genetic signatures of divergent selection by screening 95 genomic and EST-derived mini- and microsatellites in eight natural Atlantic salmon, Salmo salar L., populations from different spatial scales inhabiting contrasting natural environments (salt-, brackish, and freshwater habitat). Altogether, we identified nine EST-associated microsatellites, which exhibited highly significant deviations from the neutral expectations using different statistical methods at various spatial scales and showed similar trends in separate population samples from different environments (salt-, brackish, and freshwater habitats) and sea areas (Barents vs. White Sea). We consider these ESTs as the best candidate loci affected by divergent selection, and hence, they serve as promising genes associated with adaptive divergence in Atlantic salmon. Our results demonstrate that EST-linked microsatellite genome scans provide an efficient strategy for discovering functional polymorphisms, especially in nonmodel organisms.

Animals↗

PubMed2006

Development of a microsatellite marker set applicable to genome-wide screening of cynomolgus monkeys (Macaca fascicularis).

To develop a microsatellite marker set applicable to genome-wide screening of cynomolgus monkeys (Macaca fascicularis), 148 microsatellite markers were selected from the human genome database. The polymorphisms and inheritance of PCR products were determined by screening twenty unrelated monkeys and by analysis of three families, respectively. As a result, 106 primers (72%) gave PCR products of the size expected for humans and rhesus monkeys. Among these products, polymorphism and single-gene inheritance in cynomolgus monkeys was observed for 66 markers (62%). The average number of alleles at the 66 polymorphic loci was 5.86 (range 2-10), and average heterozygosity was 0.63 (range 0.10-0.88). This is the first report of microsatellite markers for cynomolgus monkeys. Chromosomal mapping of these markers is now in progress.

Animals↗