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PubMed2000

The DNA Rx. Advances in genetics give physicians ability to tailor drugs to patients' unique makeup.

Thanks to the recently completed first draft of the human genome map, the potential for advances in medical science seems endless. That's especially true in pharmacogenomics, with futuristic-sounding drugs and screening tests already available. William Evans (left), chairman of pharmaceutical science at St. Jude Children's Research Hospital, Memphis, Tenn., developed one of only a few pharmacogenomic applications available so far.

Cost Savings↗
PubMed2005

Gene finding in the chicken genome.

BACKGROUND: Despite the continuous production of genome sequence for a number of organisms, reliable, comprehensive, and cost effective gene prediction remains problematic. This is particularly true for genomes for which there is not a large collection of known gene sequences, such as the recently published chicken genome. We used the chicken sequence to test comparative and homology-based gene-finding methods followed by experimental validation as an effective genome annotation method. RESULTS: We performed experimental evaluation by RT-PCR of three different computational gene finders, Ensembl, SGP2 and TWINSCAN, applied to the chicken genome. A Venn diagram was computed and each component of it was evaluated. The results showed that de novo comparative methods can identify up to about 700 chicken genes with no previous evidence of expression, and can correctly extend about 40% of homology-based predictions at the 5' end. CONCLUSIONS: De novo comparative gene prediction followed by experimental verification is effective at enhancing the annotation of the newly sequenced genomes provided by standard homology-based methods.

Animals↗
PubMed2002

Biomarkers in cancer screening: a public health perspective.

The last three decades have witnessed a rapid advancement and diffusion of technology in health services. Technological innovations have given health service providers the means to diagnose and treat an increasing number of illnesses, including cancer. In this effort, research on biomarkers for cancer detection and risk assessment has taken a center stage in our effort to reduce cancer deaths. For the first time, scientists have the technologies to decipher and understand these biomarkers and to apply them to earlier cancer detection. By identifying people at high risk of developing cancer, it would be possible to develop intervention efforts on prevention rather than treatment. Once fully developed and validated, then the regular clinical use of biomarkers in early detection and risk assessment will meet nationally recognized health care needs: detection of cancer at its earliest stage. The dramatic rise in health care costs in the past three decades is partly related to the proliferation of new technologies. More recent analysis indicates that technological change, such as new procedures, products and capabilities, is the primary explanation of the historical increase in expenditure. Biomarkers are the new entrants in this competing environment. Biomarkers are considered as a competing, halfway or add-on technology. Technology such as laboratory tests of biomarkers will cost less compared with computed tomography (CT) scans and other radiographs. However, biomarkers for earlier detection and risk assessment have not achieved the level of confidence required for clinical applications. This paper discusses some issues related to biomarker development, validation and quality assurance. Some data on the trends of diagnostic technologies, proteomics and genomics are presented and discussed in terms of the market share. Eventually, the use of biomarkers in health care could reduce cost by providing noninvasive, sensitive and reliable assays at a fraction of the cost of definitive technology, such as CT scan. The National Cancer Institute's Early Detection Research Network (EDRN) has begun an innovative, investigator-initiated project to improve methods for detecting the biomarkers of cancer cells. The EDRN is a consortium of more than 32 institutions to link discovery of biomarkers to the next steps in the process of developing early detection tests. These discoveries will lead to early clinical validation of tests with improved accuracy and reliability.

Biomarkers↗
PubMed2004

The family medical history.

In this era of genomic medicine it is easy to be dazzled by an array of diagnostic tools to aid in clinical diagnosis and presymptomatic risk assessment, yet a simple family medical history remains the single most cost-effective "genetic test." A family medical history can be compared with a genetic "biopsy." Learning the skills of obtaining and interpreting a family history is just as central for primary care clinicians as a basic proficiency in interpreting pathology or radiograph reports. In this article the essentials of recording a medical family history and basic inheritance patterns are reviewed. Suggestions for dealing with sensitive family information are also discussed.

Genetic Testing↗
PubMed2001

Applications of gene arrays in environmental toxicology: fingerprints of gene regulation associated with cadmium chloride, benzo(a)pyrene, and trichloroethylene.

Toxicity testing of unknown chemicals currently uses a number of short-term bioassays. These tests are costly and time consuming, require large numbers of animals, and generally focus on a single end point. The recent development of DNA arrays provides a potential mechanism for increasing the efficiency of standard toxicity testing through genome-wide assessments of gene regulation. In this study, we used DNA arrays containing 148 genes for xenobiotic metabolizing enzymes, DNA repair enzymes, heat shock proteins, cytokines, and housekeeping genes to examine gene expression patterns in the liver in response to cadmium chloride, benzo(a)pyrene (BaP), and trichloroethylene (TCE). Dose-response studies were carried out in mice for each chemical; each produced a unique pattern of gene induction. As expected, CdCl2 markedly up-regulated metallothionine I and II (5- to 10,000-fold at the highest doses) and several of the heat shock/stress response proteins and early response genes. In contrast, administration of BaP up-regulated only Cyp1a1 and Cyp1a2 genes and produced no significant increases in any of the stress response genes or any of the DNA repair genes present on the array. Likewise, TCE-induced gene induction was highly selective; only Hsp 25 and 86 and Cyp2a were up-regulated at the highest dose tested. Microarray analysis with a highly focused set of genes is capable of discriminating between different classes of toxicants and has potential for differentiating highly noxious versus more subtle toxic agents. These data suggest that use of microarrays to evaluate the potential hazards of unknown chemicals or chemical mixtures must include multiple doses and time points to provide effective assessments of potential toxicity of these substances.

Animals↗
PubMed1998

Genetic toxicology.

Systems for testing genetic toxicology are components of carcinogenic and genetic risk assessment. Present routine genotoxicity-testing is based on at least 20 years of development during which many different test systems have been introduced and used. Today, it is clear that no single test is capable of detecting all genotoxic agents. Therefore, the usual approach is to perform a standard battery of in-vitro and in-vivo tests for genotoxicity. Work-groups of the European Union (EU), the Organization for Economic Co-operation and Development (OECD), and, very recently, the work-group of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) have defined such standard battery tests. These and some currently used supplementary or confirmatory tests are briefly discussed here. Additional test systems for the assessment of genotoxic and carcinogenic hazard and risk are seriously needed. These tests must be more relevant to man than are current assays and less demanding in respect of cost, time and number of animals. Another aspect for reassessment derives from the actual situation in the pharmaceutical industry. Companies have to prepare for the world economy of the 21st century. Therefore, pharmaceutical research is speeding up tremendously by use of tools such as genomics, combinatorial chemistry, high throughput screening and proteomics. Toxicology and genotoxicology need to re-evaluate their changing environment and must find ways to respond to these needs. In conclusion, genetic toxicology needs to answer questions coming from two major directions: hazard and risk identification and high throughput testing.

Humans↗
PubMed2006

Validation of an automated real-time PCR protocol for detection and quantitation of HIV and HCV genomes in semen.

The ability to detect and quantify HIV and HCV genomes is important for checking spermatozoid preparation protocols also known as "sperm washing". But no commercial assay is available. A method was developed for detecting HIV and HCV in semen fractions using the COBAS Ampliprep and COBAS Taqman instruments. It will detect fewer than 200 copies of HIV RNA per ml of semen plasma and fewer than 200 copies/3 x 10(6) semen cells. The sensitivity for HCV is similar at more than 200 IU/ml and below 200 IU/3 x 10(6) semen cells. No inhibitor of PCR amplification was detected. This automated protocol permits a convenient, standardized testing for HIV and HCV in semen. The performance is the same as that of the previous generation of automated assays but the cost and operating time are both reduced.

Genome, Viral↗
PubMed2005

Complete gene scanning by temperature gradient capillary electrophoresis using the cystic fibrosis transmembrane conductance regulator gene as a model.

Many inherited diseases involve large genes with many different mutations. Identifying a wide spectrum of mutations requires an efficient gene-scanning method. By differentiating thermodynamic stability and mobility of heteroduplexes from heterozygous samples, temperature gradient capillary electrophoresis (TGCE) was used to scan the entire coding region of the cystic fibrosis transmembrane conductance regulator gene. An initial panel (29 different mutations) showed 100% agreement between TGCE scanning and previously genotyped results for heterozygous samples. Different peak patterns were observed for single base substitutions and base insertions/deletions. Subsequently, 12 deidentified clinical samples genotyped as wild type for 32 mutations were scanned for the entire 27 exons. Results were 100% concordance with the bidirectional sequence analysis. Ten samples had nucleotide variations including a reported base insertion in intron 14b (2789 + 2insA) resulting in a possible mRNA splicing defect, and an unreported missense mutation in exon 20 (3991 G/A) with unknown clinical significance. This methodology does not require labeled primers or probes for detection and separation through a temperature gradient eliminates laborious temperature optimization required for other technologies. TGCE automation and high-throughput capability can be implemented in a clinical environment for mutation scanning with high sensitivity, thus reducing sequencing cost and effort.

Cystic Fibrosis Transmembrane Conductance Regulato↗
PubMed2002

Genetic redundancy in evolving populations of simulated robots.

A number of authors have argued that redundancy in biological organisms contributes to their evolvability. We investigate this hypothesis via the experimental manipulation of genetic redundancy in evolving populations of simulated robots controlled by artificial neural networks. A genetic algorithm is used to simulate the evolution of robots with the ability to perform a previously studied task. Redundancy is measured using systematic lesioning. In our experiments, populations of robots with larger genotypes achieve systematically higher fitness than populations whose genotypes are smaller. It is shown that, in principle, robots with smaller genotypes have enough computational power to achieve optimal fitness. Populations with larger (redundant) genotypes appear, however, to be more evolvable and display significantly higher diversity. It is argued that this enhanced evolvability is a direct effect of genetic redundancy, which allows populations of redundant robots to explore neutral networks spanning large areas of genotype space. We conjecture that, where cost considerations allow, redundancy in functional or potentially functional components of the genome may make a valuable contribution to evolution in artificial and perhaps in biological systems. The methods described in the article provide a practical way of testing this hypothesis for the artificial case.

Models, Genetic↗
PubMed1992

A non-organic and non-enzymatic extraction method gives higher yields of genomic DNA from whole-blood samples than do nine other methods tested.

We compared ten methods for extraction of DNA from whole blood. Nine methods require incubation with either enzymes or treatment of organic solvents or both. The 'Rapid Method' (RM) (Method 10) avoids the use of organic solvents (phenol/chloroform) and eliminates completely the use of proteinase K. Thus, the time and cost of DNA extraction are reduced significantly. This is accomplished by salting out and precipitation of the cellular proteins in saturated sodium chloride. This method takes less than an hour to completion, without compromising the yield or the quality of DNA. Using RM, we can make DNA from 0.1 ml of whole blood and as little as 0.5 ml of blood yields DNA sufficient to run a few Southern blots. The RM can also be applied to packed cells. The DNA is free of RNA, protein and degrading enzymes. The uncut DNA runs as a typical slow-migrating, high-molecular-weight and undegraded species in an agarose gel. The DNA is suitable for digestion by various restriction endonucleases. This procedure works equally well with fresh blood samples and with those that are stored at 4 degrees C and -70 degrees C. To our knowledge the RM reported here is the safest, fastest and most quantitative and economical method for preparation of DNA from whole blood and cells.

Chemistry Techniques, Analytical↗
PubMed2026

Weak but repeated patterns of co-introgression of nuclear OXPHOS genes and mitochondrial DNA in Iberian wall lizards.

In this study, we took advantage of the previously reported instances of mitochondrial DNA capture in the Podarcis Iberian group, a speciose group of Iberian wall lizards, to test the hypothesis that nuclear genes from the OXPHOS (Oxidative phosphorylation) chain can co-introgress with the mitochondria as an evolutionary response to mitigate the costs of mitonuclear incompatibilities. Using dense population sampling and transcriptome data, we generated capture-sequence datasets for nuclear OXPHOS chain genes (nucOXPHOS), random nuclear loci (nucControl) and the complete mitochondrial genome. Phylogenetic analyses of nuclear and mitochondrial genes confirmed two previously identified events of mitochondrial introgression in the Podarcis Iberian group and revealed two new cases. Three of these cases have led to complete local mitochondrial DNA replacements, where the introgressed mitotypes have replaced the native ones in several populations, and involve a currently unknown and presumably extinct donor species, so-called "ghost lineage". Detecting introgression from ghost lineages, whose genomes are not accessible, remains challenging. To overcome this issue, we designed or adapted several tests aimed at detecting differential signals of introgression between our nucOXPHOS and nucControl gene sets. One of these tests, based on the effects of introgression on branch lengths in phylogenetic trees, uncovered a weak but consistently significant signal of partial co-introgression of nucOXPHOS genes compared to the genomic background (represented by the nucControl gene set) in three out of four cases of mtDNA introgression.

mitochondrial introgression↗
PubMed2005

Specificity and overlap in gene segment-defined antibody repertoires.

BACKGROUND: To date several studies have sought to catalog the full suite of antibodies that humans naturally produce against single antigens or other specificities (repertoire). Here we analyze the properties of all sequenced repertoires in order to better understand the specificity of antibody responses. Specifically, we ask whether the large-scale sequencing of antibody repertoires might provide a diagnostic tool for detecting antigen exposure. We do this by examining the overlap in VH-, D-, and JH- segment usage among sequenced repertoires. RESULTS: We find that repertoire overlap in VH-, D-, and JH-segment use is least for VH segments and greatest for JH segments, consistent with there being more VH than JH segments in the human genome. We find that for any two antigens chosen at random, chances are 90 percent that their repertoires' VH segments will overlap by less than half, and 98 percent that their VDJH combinations will overlap by < or =10 percent. We ran computer simulations to test whether enrichment for specific VDJH combinations could be detected in "antigen-exposed" populations, and found that enrichment is detectable with moderate-to-high sensitivity and high specificity, even when some VDJH combinations are not represented at all in some test sets. CONCLUSION: Thus, as large-scale sequencing becomes cost-effective for clinical testing, we suggest that sequencing an individual's expressed antibody repertoire has the potential to become a useful diagnostic modality.

Algorithms↗
PubMed2006

Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis.

A pragmatic approach that balances the benefit of a whole-genome association (WGA) experiment against the cost of individual genotyping is to use pooled genomic DNA samples. We aimed to determine the feasibility of this approach in a WGA scan in rheumatoid arthritis (RA) using the validated human leucocyte antigen (HLA) and PTPN22 associations as test loci. A total of 203 269 single-nucleotide polymorphisms (SNPs) on the Affymetrix 100K GeneChip and Illumina Infinium microarrays were examined. A new approach to the estimation of allele frequencies from Affymetrix hybridization intensities was developed involving weighting for quality signals from the probe quartets. SNPs were ranked by z-scores, combined from United Kingdom and New Zealand case-control cohorts. Within a 1.7 Mb HLA region, 33 of the 257 SNPs and at PTPN22, 21 of the 45 SNPs, were ranked within the top 100 associated SNPs genome wide. Within PTPN22, individual genotyping of SNP rs1343125 within MAGI3 confirmed association and provided some evidence for association independent of the PTPN22 620W variant (P=0.03). Our results emphasize the feasibility of using genomic DNA pooling for the detection of association with complex disease susceptibility alleles. The results also underscore the importance of the HLA and PTPN22 loci in RA aetiology.

Arthritis, Rheumatoid↗
PubMed1996

Control of hereditary diseases. Report of a WHO Scientific Group.

Possibilities for treating--or, ideally, avoiding--hereditary diseases have increased enormously with the rapid and radical developments in the field of molecular biology. This report of a WHO Scientific Group deals first with the human genome and the genetic basis of disease, then continues with a review of the epidemiology of genetic disorders and the role of genetic predisposition in various common conditions, including coronary heart disease, cancer, asthma, diabetes and mental disorders. In discussing prevention, the report considers both genetic family studies and population screening. It is pointed out that the cost-benefit ratio of providing genetic services is extremely favourable, and prevention is often far cheaper than treatment. An entire section of the report is devoted to genetic counseling, which is particularly important because of the psychological impact of knowledge of genetic risk and the difficult decisions that often face individuals identified as being at risk. Obstetric aspects of prenatal diagnosis are considered; techniques discussed include ultrasound scanning, chorionic villus and fetal blood sampling, and amniocentesis. Organization of genetic services is reviewed, and the ethical, social and legal aspects of genetic technology in medicine are examined. The report concludes with a summary of the Scientific Group's recommendations.

Chromosome Aberrations↗
PubMed2005

DArT for high-throughput genotyping of Cassava (Manihot esculenta) and its wild relatives.

Understanding the distribution of genetic diversity within and among individuals, populations, species and gene pools is crucial for the efficient management of germplasm collections. Molecular markers are playing an increasing role in germplasm characterization, yet their broad application is limited by the availability of markers, the costs and the low throughput of existing technologies. This is particularly true for crops of resource-poor farmers such as cassava, Manihot esculenta. Here we report on the development of Diversity Arrays Technology (DArT) for cassava. DArT uses microarrays to detect DNA polymorphism at several hundred genomic loci in a single assay without relying on DNA sequence information. We tested three complexity reduction methods and selected the two that generated genomic representations with the largest frequency of polymorphic clones (PstI/TaqI: 14.6%, PstI/BstNI: 17.2%) to produce large genotyping arrays. Nearly 1,000 candidate polymorphic clones were detected on the two arrays. The performance of the PstI/TaqI array was validated by typing a group of 38 accessions, 24 of them in duplicate. The average call rate was 98.1%, and the scoring reproducibility was 99.8%. DArT markers displayed fairly high polymorphism information content (PIC) values and revealed genetic relationships among the samples consistent with the information available on these samples. Our study suggests that DArT offers advantages over current technologies in terms of cost and speed of marker discovery and analysis. It can therefore be used to genotype large germplasm collections.

Cluster Analysis↗
PubMed2003

STRP screening sets for the human genome at 5 cM density.

BACKGROUND: Short tandem repeat polymorphisms (STRPs) are powerful tools for gene mapping and other applications. A STRP genome scan of 10 cM is usually adequate for mapping single gene disorders. However mapping studies involving genetically complex disorders and especially association (linkage disequilibrium) often require higher STRP density. RESULTS: We report the development of two separate 10 cM human STRP Screening Sets (Sets 12 and 52) which span all chromosomes. When combined, the two Sets contain a total of 782 STRPs, with average STRP spacing of 4.8 cM, average heterozygosity of 0.72, and total sex-average coverage of 3535 cM. The current Sets are comprised almost entirely of STRPs based on tri- and tetranucleotide repeats. We also report correction of primer sequences for many STRPs used in previous Screening Sets. Detailed information for the new Screening Sets is available from our web site: http://research.marshfieldclinic.org/genetics. CONCLUSION: Our new human STRP Screening Sets will improve the quality and cost effectiveness of genotyping for gene mapping and other applications.

Base Sequence↗