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PubMed2004

Genetic variants for chick biology research: from breeds to mutants.

The availability of the draft sequence of the chicken genome will undoubtedly propel an already important vertebrate research model, the domestic chicken, to a new level. This review describes aspects of chicken natural history and cross-disciplinary biological value. The diversity of extant genetic variants available to researchers is reviewed along with institutional stock locations for North America. An overview of the problem of lack of long-term stability for these resources is presented.

Animals↗

PubMed2003

Additional, physically ordered markers increase linkage signal for bipolar disorder on chromosome 18q22.

BACKGROUND: We recently reported evidence of linkage of bipolar disorder to chromosome 18q, with a paternal logarithm of odds (LOD) score of 4.67 (p =.004) in a clinically defined subset of families. Like other linkage studies, we had to rely on imprecise genetic maps to establish the marker order. Here, we test for linkage in the same sample with a denser set of markers, now physically ordered according to the draft sequence of the human genome. METHODS: Families were ascertained through probands with bipolar I disorder and diagnosed with reliable methods. Genotypes were generated for 12 microsatellite markers within an 11-centimorgan (cM) region of chromosome 18q22. Multipoint affected sib-pair linkage analysis was performed in a set of 16 nuclear families. RESULTS: The additional markers significantly increased the total genetic information extracted from our sample. We also observed an increase in the LOD score (to 5.42, p =.0066) and linkage resolution. The approximate 1-LOD support interval is now 9 male cM. CONCLUSIONS: The results strengthen our previous findings and further define a region suitable for genetic fine-mapping analysis on chromosome 18q. Our data suggest that a dense set of markers, when physically ordered, can increase the informational value of genetic linkage signals.

Adult↗

PubMed2003

Genetic variation and hematology: single-nucleotide polymorphisms, haplotypes, and complex disease.

In the course of generating a draft sequence of the human genome, we now recognize the enormous scope of genetic variation among humans, which can be used to probe the genetics of complex diseases such as leukemia or thrombosis. There is already mounting evidence of new susceptibility genes and genes that interact with environmental factors. Genetic variants, especially single-nucleotide polymorphisms (SNPs), also can be utilized to investigate potential modifiers of disease. Genetic variation can be applied to study pharmacogenomics, which could eventually drive the choice of therapeutic and interventional strategies. The genomic revolution ultimately should give insights into key mechanisms in hematological disorders that can be translated into targeted therapies.

Genetic Predisposition to Disease↗

PubMed2003

cDNA microarray analysis reveals an overexpression of the dual-specificity MAPK phosphatase PYST2 in acute leukemia.

The information contained in the draft sequence of the human genome offers a solid basis to study gene function. The DNA microarray technology is one of the most important tools enabling the performance of such studies. The global expression analysis using microarrays enables the construction of a simultaneous expression pattern of thousands of genes and thus an unprecedented opportunity to obtain molecular signatures of the state of activity of diseased cells. Microarray analysis may thus provide invaluable information on disease pathology, progression, resistance to treatment, and response to cellular microenvironments. Ultimately such analyses may lead to improved early diagnosis and innovative therapeutic approaches. Yet, by employing this advanced technology in order to identify new target molecules for diagnosis or therapy, one is faced with the necessity to focUs on one or several genes and to investigate them further. A huge number of differentially expressed genes are usually identified when 2 cell samples are comparatively analyzed in an individual assay. Several factors, mainly a possible genetic diversity between the samples, minimize the capability of reaching an educated conclusion as to which gene or genes to select for further studies. Gene expression arrays were employed to identify genes whose expression characterizes leukemic leukocytes. Many different genes were differentially expressed by "leukemic-phase leukocytes," derived from three untreated acute myelogenous leukemia (AML) patients and by "remission-phase leukocytes," obtained from the same patients following induction of remission. However, only two of these genes, the dual-specificity MAPK phosphatase PYST2 and the tryptophan 5-hydroxylase, were found to be more highly expressed by the leukemic-phase than by remission-phase leukocytes of all three patients. The microarray results of only the PYST2 gene could be verified by RT-PCR. By focusing on genes that had a similar expression pattern in cells from multiple donors we overcame the problem of genetic diversity and identified, out of 60 differentially expressed genes, a single candidate target gene in AML. Pooling specimens in order to overcome the problem of genetic diversity (e.g., clinical material obtained from treated patients and from untreated ones), is not recommended because it may dilute the treatment effects. Therefore, it is essential to perform each experiment using individual preparations.

Adult↗

PubMed2003

How incorrect annotations evolve--the case of short ORFs.

The draft of the human genome sequence is still incomplete. The outstanding tasks include filling in some gaps, finalizing the assembly of short sequences, improving sequence accuracy and correctly identifying coding regions. However, a closely related problem that receives little attention is the substantial number of incorrect annotations that have penetrated some of the widely used databases. This article illustrates this problem using the example of ubiquitin genes, and draws some conclusions that apply to false annotations in other short open reading frames (ORFs). Although the focus is on the human genome, other genomes are equally prone to similar propagation of false annotations.

Databases, Nucleic Acid↗

PubMed2001

Analysis of human Per4.

The molecular mechanism of the circadian pacemaker depends on the oscillatory expression of clock gene constituents. The Drosophila period gene is central to the clock mechanism in these animals. Three homologs of this gene identified in mice (mPer1-3) and humans (hPer1-3) display rhythmic expression and are important for normal clock function. Recently, analysis of the draft sequence of the human genome has revealed the presence of a fourth Per gene family member. Surprisingly, the deduced hPer4 cDNA has no open reading frame encoding a full-length PER-like protein. This sequence is characterized by numerous deletions, insertions, frame shifts and base pair changes, and its genomic structure is devoid of introns. The presence of an MER-2 mobile element fossil within the Per4 locus predicted that this gene would also be present in non-human primates. Rhesus monkey Per4 displays similar sequence anomalies and is 92.8% identical to hPer4. Sequence comparisons indicate that Per4 originated from a Per3 predecessor and that it is relatively new to the Period gene family. We conclude that hPer4 and RmPer4 are pseudogenes and descended from the retrotransposition of an ancestral Per3 gene.

Amino Acid Sequence↗

PubMed2003

Using yeast to place human genes in functional categories.

The availability of the draft sequence of the human genome has created a pressing need to assign functions to each of the 35,000 or so genes that it defines. One useful approach for this purpose is to use model organisms for both bioinformatic and functional comparisons. We have developed a complementation system, based on the model eukaryote Saccharomyces cerevisiae, to clone human cDNAs that can functionally complement yeast essential genes. The system employs two regulatable promoters. One promoter, tetO (determining doxycycline-repressible expression), is used to control essential S. cerevisiae genes. The other, pMET3 (which is switched off in the presence of methionine), is employed to regulate the expression of mammalian cDNAs in yeast. We have demonstrated that this system is effective for both individual cDNA clones and for cDNA libraries, permitting the direct selection of functionally complementing clones. Three human cDNA libraries have been constructed and screened for clones that can complement specific essential yeast genes whose expression is switched off by the addition of doxycycline to the culture medium. The validity of each complementation was checked by showing that the yeast cells stop their growth in the presence of doxycycline and methionine, which represses the expression of the yeast and mammalian coding sequence, respectively. Using this system, we have screened 25 tetO replacement strains and succeeded in isolating human cDNAs complementing six essential yeast genes. In this way, we have uncovered a novel human ubiquitin-conjugating enzyme, have isolated a human cDNA clone that may function as a signal peptidase and have demonstrated that the functional segment of the human Psmd12 proteosome sub-unit contains a PINT domain.

Cerebellum↗

PubMed2002

Unravelling novel intracellular pathways in cell-based assays.

The pharmaceutical industry is currently facing several challenges to identify and develop novel drug targets. Traditional drug discovery focussed on a small number of well-characterized gene products. Recently, this picture has changed with the completion of the draft sequence of the human genome, which has led to the identification of thousands of novel genes with unknown or poorly understood function. To cope with this overwhelming number of potential drug target candidates, new strategies for the elucidation of gene function, as well as their involvement in intracellular pathways, are required.

Biological Assay↗

PubMed2003

Starch synthesis in the cereal endosperm.

The pathway of starch synthesis in the cereal endosperm is unique, and requires enzyme isoforms that are not present in other cereal tissues or non-cereal plants. Recent information on the functions of individual enzyme isoforms has provided insight into how the linear chains and branch linkages in cereal starch are synthesized and distributed. Genetic analyses have led to the formulation of models for the roles of de-branching enzymes in cereal starch production, and reveal pleiotropic effects that suggest that certain enzymes may be physically associated. For the first time, tools for global analyses of starch biosynthesis are available for cereal crops, and are heralded by the draft sequence of the rice genome.

1,4-alpha-Glucan Branching Enzyme↗

PubMed2002

Using genetic variation to study immunomodulation.

The generation of a draft sequence of a human genome has led to the identification of millions of common variants, known as single nucleotide polymorphisms, which constitute a resource for studying complex diseases. Currently, high-density maps of variants in candidate genes, chromosomal regions or the entire genome should encourage investigation of determinants of human immune response, using quantitative analysis. Ultimately, this approach should identify novel targets for therapeutic intervention.

Adjuvants, Immunologic↗

PubMed2001

Using genetic variation to study human disease.

The generation of a draft sequence of the human genome has spawned a unique opportunity to investigate the role of genetic variation in human diseases. The difference between any two human genomes has been estimated to be less than 0.1% overall, but still, this means that there are at least several million nucleotide differences per individual. The study of single nucleotide polymorphisms (SNPs), the most common type of variant, is likely to contribute substantially to deciphering genetic determinants of common and rare diseases. The effort to identify SNPs has been accelerated by three developments: the availability of sequence data from the genome project, improved informatic tools for searching the former and high-throughput genotype platforms. With these new tools in hand, dissecting the genetics of disease will rapidly move forward, although a number of formidable challenges will have to be met to see its promise realized in clinical medicine.

Genetic Predisposition to Disease↗

PubMed2003

Genetic variation and hematopoietic stem cell transplantation: expansion of the paradigm.

Genetic variation has been the mainstay of hematopoietic stem cell transplantation since the first transplants were attempted. A significant expansion of genetic knowledge is under way, as the draft sequence of the human genome is annotated. Hematopoietic stem cell transplantation is a field that will greatly benefit from this new knowledge, but the manner in which it is applied is daunting. Variation within key molecules related to hematopoietic stem cell transplant in combination with the current knowledge of human leukocyte antigen variation will serve to improve donor-recipient matches and clinical outcome.

Databases, Nucleic Acid↗

PubMed2003

The genetics of autoimmune endocrine disease.

The common autoimmune endocrinopathies result from an interaction between environmental factors and genetic predisposition. Several chromosomal gene regions have been shown to contribute to more than one disease, supporting the clinical observation that the autoimmune endocrine diseases cluster within individuals and families. Genetic studies have implicated the major histocompatability complex (MHC)-human leucocyte antigen (HLA) genes on chromosome 6p21, although this chromosomal region does not explain all of the genetic contribution to the various disorders. Non-MHC-HLA genes, including disease-specific loci, are beginning to be identified and the publication of the draft sequence of the human genome will undoubtedly expediate future discoveries. Combined with the establishment of large cohorts of subjects with disease and the development of technology capable of performing high-throughput genotyping, genetic studies are likely to impact on the future treatment and prevention of the common autoimmune endocrine diseases.

Antigens, CD↗

PubMed2005

Speciation in birds: genes, geography, and sexual selection.

Molecular studies of speciation in birds over the last three decades have been dominated by a focus on the geography, ecology, and timing of speciation, a tradition traceable to Mayr's Systematics and the Origin of Species. However, in the recent years, interest in the behavioral and molecular mechanisms of speciation in birds has increased, building in part on the older traditions and observations from domesticated species. The result is that many of the same mechanisms proffered for model lineages such as Drosophila--mechanisms such as genetic incompatibilities, reinforcement, and sexual selection--are now being seriously entertained for birds, albeit with much lower resolution. The recent completion of a draft sequence of the chicken genome, and an abundance of single-nucleotide polymorphisms on the autosomes and sex chromosomes, will dramatically accelerate research on the molecular mechanisms of avian speciation over the next few years. The challenge for ornithologists is now to inform well studied examples of speciation in nature with increased molecular resolution-to clone speciation genes if they exist--and thereby evaluate the relative roles of extrinsic, intrinsic, deterministic, and stochastic causes for avian diversification.

Animals↗

PubMed2003

Clinical relevance of pharmacogenetics.

Pharmacogenetics fields of research was initially restricted to drug metabolism enzymes. It has recently progressed to drug transporters, receptors, and any kind of targets that can modulate drug response. This rapid extension of pharmacogenetics to all the different medical specialties is in close relation with the recent completion of the draft sequence of the human genome and the discovery that about 0.1% of its sequence is polymorphic. The goal of pharmacogenetics for the next years is clearly to determine the clinical consequences of these 2-3 million single nucleotide polymorphisms (SNPs). Things can be schematically divided in two situations. (1) Frequent SNPs (allele frequency > 10%) which have a low impact on drug response (odds ratios < 2), even combined with other SNPs in haplotype combinations. Such situations, which are by far the most frequent, have no clinical relevance for a single patient to predict its response to a particular drug. CYP3A and MDR1 allelic variants are good examples of such frequent situations. (2) Rare SNPs, which dramatically alter the expression or the activity of a target protein, can sometimes have a real clinical relevance (odds ratios > 5), usually to predict drug side effects. Only few examples, such as TPMT and CYP2C9 genetic polymorphisms, can illustrate this rare situation. Unfortunately, less than 1% of the population is concerned by these rare SNPs, and genotyping can only explain a small part of the variability of the response to a single drug. Beside the impressive mass of data available for pharmacogenetics, it is surprising to observe its poor development in routine medical practice. This discrepancy relies mainly on educational and methodological problems, which might be solved in the decade. To promote pharmacogenetics in routine medical practice, large prospective randomized trials are needed to demonstrate that pharmacogenetic orientated prescription can sometimes predict drug response without dramatic increase in costs.

Animals↗

PubMed2002

A perspective on epistasis: limits of models displaying no main effect.

The completion of a draft sequence of the human genome and the promise of rapid single-nucleotide-polymorphism-genotyping technologies have resulted in a call for the abandonment of linkage studies in favor of genome scans for association. However, there exists a large class of genetic models for which this approach will fail: purely epistatic models with no additive or dominance variation at any of the susceptibility loci. As a result, traditional association methods (such as case/control, measured genotype, and transmission/disequilibrium test [TDT]) will have no power if the loci are examined individually. In this article, we examine this class of models, delimiting the range of genetic determination and recurrence risks for two-, three-, and four-locus purely epistatic models. Our study reveals that these models, although giving rise to no additive or dominance variation, do give rise to increased allele sharing between affected sibs. Thus, a genome scan for linkage could detect genomic subregions harboring susceptibility loci. We also discuss some simple multilocus extensions of single-locus analysis methods, including a conditional form of the TDT.

Alleles↗

PubMed2002

Common deletion of SMAD4 in juvenile polyposis is a mutational hotspot.

Juvenile polyposis (JP) is an autosomal dominant syndrome in which affected patients develop upper- and/or lower-gastrointestinal (GI) polyps. A subset of families with JP have germline mutations in the SMAD4 (MADH4) gene and are at increased risk of GI cancers. To date, six families with JP have been described as having the same SMAD4 deletion (1244-1247delAGAC). The objective of the present study is to determine whether this deletion is a common ancestral mutation or a mutational hotspot. DNA from members of four families with JP, from Iowa, Mississippi, Texas, and Finland, that had this 4-bp deletion was used to genotype 15 simple tandem repeat polymorphism (STRP) markers flanking the SMAD4 gene, including 2 new STRPs within 6.3 and 70.9 kb of the deletion. Haplotypes cosegregating with JP in each family were constructed, and the distances of the closest markers were determined from the draft sequence of the human genome. No common haplotype was observed in these four families with JP. A 14-bp region containing the deletion had four direct repeats and one inverted repeat. Because no common ancestor was suggested by haplotype analysis and the sequence flanking the deletion contains repeats frequently associated with microdeletions, this common SMAD4 deletion in JP most likely represents a mutational hotspot.

Adenomatous Polyposis Coli↗

PubMed2003

Imaging genomics.

The recent completion of a working draft of the human genome sequence promises to provide unprecedented opportunities to explore the genetic basis of individual differences in complex behaviours and vulnerability to neuropsychiatric illness. Functional neuroimaging, because of its unique ability to assay information processing at the level of brain within individuals, provides a powerful approach to such functional genomics. Recent fMRI studies have established important physiological links between functional genetic polymorphisms and robust differences in information processing within distinct brain regions and circuits that have been linked to the manifestation of various disease states such as Alzheimer's disease, schizophrenia and anxiety disorders. Importantly, all of these biological relationships have been revealed in relatively small samples of healthy volunteers and in the absence of observable differences at the level of behaviour, underscoring the power of a direct assay of brain physiology like fMRI in exploring the functional impact of genetic variation.

Apolipoproteins E↗