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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↗

PubMed2000

Conserved noncoding sequences are reliable guides to regulatory elements.

A 'working draft' of the human genome sequence is now available. Comparisons with the sequences of mouse and other species will be a powerful approach to identifying functional segments of the noncoding regions, such as gene regulatory elements. However, the choice of a species for most effective comparison differs among various loci.

Animals↗

PubMed2001

Opportunities and strategies for introducing pharmacogenetics into early drug development.

Following the publication of the first draft of the human genome, this is a good time to re-analyse the potential contribution of genomics to drug development. Pharma, biotech and academia are already queuing up to deliver novel data impinging on every aspect of medicine and we can foresee a five-year scenario in which every new drug with a known mode of action will have a target gene sequence in the public domain. As such, current development strategies must ultimately be capable of anticipating and addressing genetic issues. This article attempts to position recent developments in genomics from an industrial perspective.

Journal Article↗

PubMed2002

Chromosomal localization of the chicken and mammalian orthologues of the orphan phosphatase PHOSPHO1 gene.

PHOSPHO1 is a recently identified phosphatase expressed at high levels in the chicken growth plate and which may be involved in generating inorganic phosphate for skeletal matrix mineralization. Using a degenerate RT-PCR approach a fragment of human PHOSPHO1 was cloned. This enabled the identification of the human orthologue on HSA17q21, and the mouse orthologue on a region of MMU11 that exhibits conservation of synteny with HSA17q21. Chicken PHOSPHO1 was mapped by SSCP analysis to position 44 cM on GGA27, adjacent to the HOXB@ (44 cM) and COL1A1 (36 cM) loci. Comparison of genes on GGA27 with their orthologues on the preliminary draft of the human genome identifies regions of conserved synteny equivalent to 25 Mb on HSA17q21.2-23.3 and approximately 20 Mb on GGA27 in which the gene order appears to be conserved. Mapping of the PHOSPHO1 genes to regions of HSA17q21.3, MMU11 and GGA27 that exhibit conservation of synteny provides strong evidence that they are orthologous.

Amino Acid Sequence↗

PubMed2003

A method for the assessment of disease associations with single-nucleotide polymorphism haplotypes and environmental variables in case-control studies.

The rough draft of the human genome map has been used to identify most of the functional genes in the human genome, as well as to identify nucleotide variations, known as "single-nucleotide polymorphisms" (SNPs), in these genes. By use of advanced biotechnologies, researchers are beginning to genotype thousands of SNPs from biological samples. Among the many possible applications, one of them is the study of SNP associations with complex human diseases, such as cancers or coronary heart diseases, by using a case-control study design. Through the gathering of environmental risk factors and other lifestyle factors, such a study can be effectively used to investigate interactions between genes and environmental factors in their associations with disease phenotype. Earlier, we developed a method to statistically construct individuals' haplotypes and to estimate the distribution of haplotypes of multiple SNPs in a defined population, by use of estimating-equation techniques. Extending this idea, we describe here an analytic method for assessing the association between the constructed haplotypes along with environmental factors and the disease phenotype. This method is also robust to the model assumptions and is scalable to a large number of SNPs. Asymptotic properties of estimations in the method are proved theoretically and are tested for finite sample sizes by use of simulations. To demonstrate the use of the method, we applied it to assess the possible association between apolipoprotein CIII (six coding SNPs) and restenosis by using a case-control data set. Our analysis revealed two haplotypes that may reduce the risk of restenosis.

Apolipoprotein C-III↗

PubMed2003

The state of the art of mammalian promoter recognition.

The draft sequences of whole genomes are being published at an ever-increasing pace, thus providing access to the human genomic sequence and, more recently, the mouse sequence. Genomes of the invertebrates are also becoming available. Now that the genomic DNA of mammalian species is available, an old problem can be tackled with renewed vigour mammalian promoter prediction. Gene promoters have proved elusive for more than a decade, despite their pivotal role in gene regulation. Recently, however, several new developments have made it possible to make meaningful large-scale predictions. This paper reviews the methods used for the prediction of mammalian, mostly human, promoters.

Animals↗

PubMed2003

A review of bioinformatics education in the UK.

If the completion of the first draft of the human genome represents the coming of age of bioinformatics, then the emergence of bioinformatics as a university degree subject represents its establishment. In this paper bioinformatics as a subject for formal study is discussed, rather than as a subject for research, and a selection of the taught, mainly graduate, courses currently available in the UK are reviewed. Throughout, the author tries to draw parallels between the integration of bioinformatics into biomedical research and teaching today, and that of molecular biology, two decades ago. Others have made this analogy between these two relatively young disciplines. Although research sources are referenced, the author makes no pretence of objectivity. This article contains his opinions, and those of a number of current bioinformatics course organisers whose comments on the subject were solicited in advance specifically for this paper. The course organisers kindly advised how they planned their curricula, and described the special strengths of their programmes. Comments from present and former students of several bioinformatics degree programmes were also solicited. Except where individuals are directly quoted, any opinions expressed herein should be considered the author's. Compared with its sister piece [Marion Zatz, in previous issue of Briefings in Bioinformatics pp. 353], this paper is less about funding policy--which, in the UK, has lately (if belatedly) been more generous towards bioinformatics teaching--than it is about practice and content; the requirements of the bioinformatics research communities, the corresponding emphases of bioinformatics courses, and the general market for holders of bioinformatics degrees. Individual courses are cited throughout as examples, but the final section contains a full annotated listing with URL addresses. Based on the author's own experience of practising and teaching bioinformatics, he describes the skills he believes will be most useful to bioinformaticians in the near future and suggests ways to prepare students of bioinformatics for a fall in demand for those abilities.

Computational Biology↗

PubMed2004

TERMINUS--Telomeric End-Read Mining IN Unassembled Sequences.

UNLABELLED: TERMINUS is a set of tools to map telomeres on draft sequences of whole genome shotgun sequencing projects. It mines raw sequence reads (from a trace archive) for telomeric reads, assembles them into contigs representing individual chromosome ends and BLASTs the resulting consensus sequences against the genome assembly to identify telomere-proximal genomic contigs. Finally, it estimates the sizes of telomeric gaps and identifies clones for gap closure. TERMINUS is implemented as a set of Perl scripts that requires two sets of inputs: the NCBI Trace Archive files for a given genome project; and ancillary genome assembly information. Results are output in spreadsheets containing information that facilitates manual validation. AVAILABILITY: The TERMINUS package and supplementary information can be downloaded from http://www.genome.kbrin.uky.edu/fungi_tel/terminus/ CONTACT: farman@uky.edu.

Algorithms↗

PubMed1999

Computational methods for the identification of differential and coordinated gene expression.

With the first complete 'draft' of the human genome sequence expected for Spring 2000, the three basic challenges for today's bioinformatics are more than ever: (i) finding the genes; (ii) locating their coding regions; and (iii) predicting their functions. However, our capacity for interpreting vertebrate genomic and transcript (cDNA) sequences using experimental or computational means very much lags behind our raw sequencing power. If the performances of current programs in identifying internal coding exons are good, the precise 5'-->3' delineation of transcription units (and promoters) still requires additional experiments. Similarly, functional predictions made with reference to previously characterized homologues are leaving >50% of human genes unannotated or classified in uninformative categories ('kinase', 'ATP-binding', etc.). In the context of functional genomics, large-scale gene expression studies using massive cDNA tag sequencing, two-dimensional gel proteome analysis or microarray technologies are the only approaches providing genome-scale experimental information at a pace consistent with the progress of sequencing. Given the difficulty and cost of characterizing genes one by one, academic and industrial researchers are increasingly relying on those methods to prioritize their studies and choose their targets. The study of expression patterns can also provide some insight into the function, reveal regulatory pathways, indicate side effects of drugs or serve as a diagnostic tool. In this article, I review the theoretical and computational approaches used to: (i) identify genes differentially expressed (across cell types, developmental stages, pathological conditions, etc.); (ii) identify genes expressed in a coordinated manner across a set of conditions; and (iii) delineate clusters of genes sharing coherent expression features, eventually defining global biological pathways.

Animals↗

PubMed2003

Adaptive diversification of bitter taste receptor genes in Mammalian evolution.

The diversity and evolution of bitter taste perception in mammals is not well understood. Recent discoveries of bitter taste receptor (T2R) genes provide an opportunity for a genetic approach to this question. We here report the identification of 10 and 30 putative T2R genes from the draft human and mouse genome sequences, respectively, in addition to the 23 and 6 previously known T2R genes from the two species. A phylogenetic analysis of the T2R genes suggests that they can be classified into three main groups, which are designated A, B, and C. Interestingly, while the one-to-one gene orthology between the human and mouse is common to group B and C genes, group A genes show a pattern of species- or lineage-specific duplication. It is possible that group B and C genes are necessary for detecting bitter tastants common to both humans and mice, whereas group A genes are used for species-specific bitter tastants. The analysis also reveals that phylogenetically closely related T2R genes are close in their chromosomal locations, demonstrating tandem gene duplication as the primary source of new T2Rs. For closely related paralogous genes, a rate of nonsynonymous nucleotide substitution significantly higher than the rate of synonymous substitution was observed in the extracellular regions of T2Rs, which are presumably involved in tastant-binding. This suggests the role of positive selection in the diversification of newly duplicated T2R genes. Because many natural poisonous substances are bitter, we conjecture that the mammalian T2R genes are under diversifying selection for the ability to recognize a diverse array of poisons that the organisms may encounter in exploring new habitats and diets.

Amino Acid Sequence↗

PubMed2003

Nonrandom distribution of alu elements in genes of various functional categories: insight from analysis of human chromosomes 21 and 22.

The first draft of the human genome has revealed enormous variability in the global distribution of Alu repeat elements. There are regions such as the four homeobox gene clusters, which are nearly devoid of these repeats that contrast with repeat dense regions in other transcriptionally active regions of the genome. Our analysis of the completely sequenced chromosomes 21 and 22 revealed a striking bias in Alu distribution. These elements are more clustered in genes which are involved in metabolism, transport, and signaling processes. In contrast, they are significantly fewer in genes coding for information pathway components as well as structural proteins. This bias in Alu distribution is independent of the effect of Alu density of the flanking genomic region and is also not affected by the GC content of the gene and its upstream and downstream regions. The relative proportions of Alu subfamilies (Alu J, Alu S, and Alu Y) are not significantly different in genes with high Alu density belonging to the functional categories of transport, metabolism, and signaling. However, in the structural proteins and information genes, these proportions are lower than the other three categories. We suggest that Alu elements might be involved in regulatory mechanisms and are therefore differentially selected in primate genomes.

Alu Elements↗

PubMed2002

Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations.

The recent completion of the first draft of the human genome sequence and advances in technologies for genomic analysis are generating tremendous opportunities for epidemiologic studies to evaluate the role of genetic variants in human disease. Many methodological issues apply to the investigation of variation in the frequency of allelic variants of human genes, of the possibility that these influence disease risk, and of assessment of the magnitude of the associated risk. Based on a Human Genome Epidemiology workshop, a checklist for reporting and appraising studies of genotype prevalence and studies of gene-disease associations was developed. This focuses on selection of study subjects, analytic validity of genotyping, population stratification, and statistical issues. Use of the checklist should facilitate the integration of evidence from these studies. The relation between the checklist and grading schemes that have been proposed for the evaluation of observational studies is discussed. Although the limitations of grading schemes are recognized, a robust approach is proposed. Other issues in the synthesis of evidence that are particularly relevant to studies of genotype prevalence and gene-disease association are discussed, notably identification of studies, publication bias, criteria for causal inference, and the appropriateness of quantitative synthesis.

Case-Control Studies↗

PubMed2002

Use of interphase fluorescence in situ hybridization as a powerful diagnostic tool in cytology.

Interphase fluorescence in situ hybridization (I-FISH) using labeled nucleic acid probes detects chromosomal and genetic aberrations at a cellular level. I-FISH is a relatively fast and sensitive technique for evaluating a large number of cells and revealing more specific information than other techniques. It has been proven to be an invaluable molecular test in cytologic analyses for the detection of subtle genetic alterations that correlate with disease progression. In this postgenomic era, with the draft of the human genome available and expansion of the knowledge of tumor-specific genetic changes, the application of I-FISH probes in cytologic analysis should be of great value in the early detection, risk assessment, and monitoring of therapy efficacy in cancer. Here, we outline the principle of the I-FISH procedure, present suggestions to efficiently analyze cytologic materials, provide examples of practical applications, and discuss new aspects of the technique.

DNA, Neoplasm↗

PubMed2002

Is biology destiny? Is it all in our genes?

The completion of the working draft of the human genome in 2001 is an important milestone in achieving greater understanding of the role of genetics in health and disease. This very important technological achievement holds both promise and peril for the theory and practice of medicine. The author discusses how the information in the genome, coupled with insights into the interactions of gene and environment, may revolutionize clinical practice and eventually make it possible to tailor diagnosis and treatment to the allelic and experiential nature of the individual patient. He also points out the dangers of leaping from gene discovery to premature diagnosis and unproven interventions that may endanger patients and gives several examples of such occurrences. What is known about the relationship between gene and phenotype is reviewed and examples of the different phenotypes that may arise with identical genomes are presented to illustrate how environment influences gene expression, both in humans and other species. Finally, the author considers the challenge in conveying newly gained knowledge of genetic risk in ways that will benefit rather than harm patients.

Journal Article↗

PubMed2002

Long-range heterogeneity at the 3' ends of human mRNAs.

The publication of a draft of the human genome and of large collections of transcribed sequences has made it possible to study the complex relationship between the transcriptome and the genome. In the work presented here, we have focused on mapping mRNA 3' ends onto the genome by use of the raw data generated by the expressed sequence tag (EST) sequencing projects. We find that at least half of the human genes encode multiple transcripts whose polyadenylation is driven by multiple signals. The corresponding transcript 3' ends are spread over distances in the kilobase range. This finding has profound implications for our understanding of gene expression regulation and of the diversity of human transcripts, for the design of cDNA microarray probes, and for the interpretation of gene expression profiling experiments.

3' Flanking Region↗

PubMed2004

Minos transposon causes germline transgenesis of the ascidian Ciona savignyi.

An ascidian, Ciona savignyi, is regarded as a good experimental animal for genetics because of its small and compact genome for which a draft sequence is available, its short generation time and its interesting phylogenic position. ENU-based mutagenesis has been carried out using this animal. However, insertional mutagenesis using transposable elements (transposons) has not yet been introduced. Recently, one of the Tc1/mariner superfamily transposons, Minos, was demonstrated to cause germline transgenesis in the related species Ciona intestinalis. In this report, we show that Minos has the ability to transpose from DNA to DNA in Ciona savignyi in transposition assays. Although the activity was slightly weaker than in Ciona intestinalis, Minos still caused germline transgenesis in Ciona savignyi. In addition, one insertion seemed to have caused an enhancer trapping. These results indicate that Minos provides a potential tool for transgenic techniques such as insertional mutagenesis in Ciona savignyi.

Animals↗

PubMed2006

Epistemological issues in omics and high-dimensional biology: give the people what they want.

Gene expression microarrays have been the vanguard of new analytic approaches in high-dimensional biology. Draft sequences of several genomes coupled with new technologies allow study of the influences and responses of entire genomes rather than isolated genes. This has opened a new realm of highly dimensional biology where questions involve multiplicity at unprecedented scales: thousands of genetic polymorphisms, gene expression levels, protein measurements, genetic sequences, or any combination of these and their interactions. Such situations demand creative approaches to the processes of inference, estimation, prediction, classification, and study design. Although bench scientists intuitively grasp the need for flexibility in the inferential process, the elaboration of formal supporting statistical frameworks is just at the very start. Here, we will discuss some of the unique statistical challenges facing investigators studying high-dimensional biology, describe some approaches being developed by statistical scientists, and offer an epistemological framework for the validation of proffered statistical procedures. A key theme will be the challenge in providing methods that a statistician judges to be sound and a biologist finds informative. The shift from family-wise error rate control to false discovery rate estimation and to assessment of ranking and other forms of stability will be portrayed as illustrative of approaches to this challenge.

Computational Biology↗

PubMed2005

Visualizing chromosomes as transcriptome correlation maps: evidence of chromosomal domains containing co-expressed genes--a study of 130 invasive ductal breast carcinomas.

Completion of the working draft of the human genome has made it possible to analyze the expression of genes according to their position on the chromosomes. Here, we used a transcriptome data analysis approach involving for each gene the calculation of the correlation between its expression profile and those of its neighbors. We used the U133 Affymetrix transcriptome data set for a series of 130 invasive ductal breast carcinomas to construct chromosomal maps of gene expression correlation (transcriptome correlation map). This highlighted nonrandom clusters of genes along the genome with correlated expression in tumors. Some of the gene clusters identified by this method probably arose because of genetic alterations, as most of the chromosomes with the highest percentage of correlated genes (1q, 8p, 8q, 16p, 16q, 17q, and 20q) were also the most frequent sites of genomic alterations in breast cancer. Our analysis showed that several known breast tumor amplicons (at 8p11-p12, 11q13, and 17q12) are located within clusters of genes with correlated expression. Using hierarchical clustering on samples and a Treeview representation of whole chromosome arms, we observed a higher-order organization of correlated genes, sometimes involving very large chromosomal domains that could extend to a whole chromosome arm. Transcription correlation maps are a new way of visualizing transcriptome data. They will help to identify new genes involved in tumor progression and new mechanisms of gene regulation in tumors.

Breast Neoplasms↗