Contamination in the draft of the human genome masquerades as lateral gene transfer.
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Animals↗
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Results for “draft genome sequence”
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Towards the human cancer epigenome: a first draft of histone modifications.
The disruption of genomic DNA methylation patterns was the first epigenetic abnormality to be described in human cancer. This imbalance involves the promoter CpG island hypermethylation of tumor-suppressor genes, causing transcriptional repression, and global genomic hypomethylation, leading to chromosomal instability and reactivation of endoparasitic sequences. The relationship between DNA methylation and histone modifications was initially described in the context of the inactivation of female X chromosomes and of the demonstration of strong interactions between the DNA methylation machinery and chromatin modifiers. The repression of tumor-suppressor genes by promoter hypermethylation was also found to be associated with a specific histone modification index. However, this jigsaw was missing a piece: a global view of how the histone modification landscape was distorted in cancer cells. We have recently discovered this piece of the puzzle, demonstrating that the association between DNA methylation and histone modification aberrations in cancer also occurs at the global level. In human and mouse tumors, histone H4 undergoes a loss of monoacetylated and trimethylated lysines 16 and 20, respectively. Most importantly, these alterations occur within the context of the repetitive DNA sequences that also become hypomethylated in transformed cells. The global alterations of histone acetylation status suggest novel pathways by which histone acetyltransferases (HATs), histone methyltransferases (HMTs), and histone deacetylases (HDACs) may play roles as tumor-suppressor genes or oncogenes. In this regard, we have shown how the generation of particular fusion proteins involving HATs in leukemias is associated with an erasure of the monoacetylated lysine 16-H4 marker, whilst the loss of trimethylation at lysine 20-H4 disrupts heterochromatic domains and may reduce the response to DNA damage of cancer cells.
Acetylation↗
Identification of candidate genes at quantitative trait loci on chicken chromosome Z using orthologous comparison of chicken, mouse, and human genomes.
This study was undertaken to identify novel candidate genes at quantitative trait loci (QTL) on chicken chromosome Z (GGAZ) by comparing orthologous regions of chicken, human and mouse genomes. Primer sequences from marker flanking QTL positions (https://acedb.asg.wur.nl/) were obtained from www.iastate.edu/chickmap and blasted against the chicken genome (www.ensembl.org) using BLASTN. The best matches were those with the highest score, lowest E-values and highest percent identity. Orthologous regions in mice and humans, together with genes located on or around those loci were identified using the Ensembl website. Forty-six chicken genes, 91 mouse genes and 60 human genes associated with QTL on GGAZ were identified in the current study. Among the most promising candidate genes for egg production and egg shell quality are annexin A1 (ANXA1), osteoclast stimulating factor (OSF), thrombospondin-4 (THBS4), programmed cell death proteins (PDCD), follistatin (FST), growth hormone receptor (GHR), interferon (IFN) alpha and beta. The chicken IFN alpha and beta were located on GGAZ around position 13,000,000 bp on the draft chicken sequence map. The neuronal nicotinic acetylcholine receptor (nAChR) is located at a QTL region for abdominal fat (GGAZ 25483091 bp). Nicotine is an agonist at the nAChRs and has been shown to decrease lipolysis and triglyceride uptake, thereby reducing net storage in adipose tissue. Therefore, the nAchRs could be used as therapeutic targets for regulating feed intake and obesity. This study has identified 197 putative candidate genes in probable QTL regions of chicken chromosome Z.
Animals↗
An evaluation of the assembly of an approximately 15-Mb region on human chromosome 13q32-q33 linked to bipolar disorder and schizophrenia.
The human 13q32-q33 region has been linked to both bipolar disorder and schizophrenia. Before completion of the draft sequences, we developed an approximately 15-Mb comprehensive map for the region extending from D13S1300 to ATA35H12. This map was assembled using publicly available mapping data and sequence-tagged site (STS)-based PCR confirmation. We then compared this map with the NCBI, Celera Genomics, and UCSC Golden Path data in February, June, and September 2001. All data sets showed gaps, misassignment of STSs, and errors in orientation and marker order. Surprisingly, the completed sequences of many bacterial artificial chromosomes (BACs) had been truncated. Of 21 gaps that were detected, 4 were present in both the NCBI and Celera databases. All gaps could be filled using 1-2 BAC clones. A total of 39 loci mapped to additional sites within the human genome, providing evidence of segmental duplications. Additionally, 61 unique cDNA clones were sequenced to increase available transcribed sequence, and 11,353 reference single-nucleotide polymorphisms (SNPs) with an average density of 1 SNP/3720 bases were identified. Overall, integration of the data from multiple sources is still needed for complete assembly of the 13q32-q33 region. (c)
Bipolar Disorder↗
Multiple new and isolated families within the mouse superfamily of V1r vomeronasal receptors.
Seven-transmembrane-domain proteins encoded by the vomeronasal receptor V1r and V2r gene superfamilies, and expressed by vomeronasal sensory neurons, are believed to be pheromone receptors in rodents. Four V1r gene families have been described in the mouse (V1ra, V1rb, V1rc and V3r). Here we have screened near-complete mouse genomic databases to obtain a first global draft of the mouse V1r repertoire, including 104 new V1r genes. It comprises eight new and extremely isolated families in addition to the four families previously identified. Members of these new families were expressed in vomeronasal sensory neurons. The genome-wide view revealed great sequence diversity within the V1r superfamily. Phylogenetic analyses suggested an ancient original radiation, followed by the isolation, divergence and expansion of families by extensive gene duplications and frequent gene loss. The isolated nature of these gene families probably reflects a specialization of different receptor classes in the detection of specific types of chemicals.
Animals↗
T-box genes in the ascidian Ciona intestinalis: characterization of cDNAs and spatial expression.
Members of the T-box family of transcription factors share an evolutionarily conserved DNA-binding domain and play significant roles in various processes of embryonic development. Vertebrate T-box genes are categorized into the following five major subfamilies (eight groups), depending on sequence similarities: Brachyury, Tbx1 (Tbx1/10, Tbx15/18/22, Tbx20), Tbx2/3/4/5 (Tbx2/3 and Tbx4/5), Tbx6, and Tbr/Eomes/TBX21. Ascidians are primitive chordates, and their tadpole larva are considered to represent the simplified and basic body plan of vertebrates. In addition, it has been revealed that the ascidian genome contains the basic ancestral complement of genes involved in development. The present characterization of cDNAs and survey of the Ciona intestinalis draft genome demonstrated that the Ciona genome contains a single copy gene for each of the Brachyury, Tbx1/10, Tbx15/18/22, Tbx20, Tbx2/3, and Tbr/Eomes/TBX21 groups, and at least three copies of the Tbx6 subfamily. Each of the Ciona T-box genes shows a characteristic expression pattern, although that of Tbx20 was not determined in the present study. These results provide basic information that will be useful for future studies of the function of each gene, genetic cascades of different T-box genes, and genome-wide surveys of evolutionary changes in the T-box gene structure and organization in this primitive chordate.
Animals↗
AGMIAL: implementing an annotation strategy for prokaryote genomes as a distributed system.
We have implemented a genome annotation system for prokaryotes called AGMIAL. Our approach embodies a number of key principles. First, expert manual annotators are seen as a critical component of the overall system; user interfaces were cyclically refined to satisfy their needs. Second, the overall process should be orchestrated in terms of a global annotation strategy; this facilitates coordination between a team of annotators and automatic data analysis. Third, the annotation strategy should allow progressive and incremental annotation from a time when only a few draft contigs are available, to when a final finished assembly is produced. The overall architecture employed is modular and extensible, being based on the W3 standard Web services framework. Specialized modules interact with two independent core modules that are used to annotate, respectively, genomic and protein sequences. AGMIAL is currently being used by several INRA laboratories to analyze genomes of bacteria relevant to the food-processing industry, and is distributed under an open source license.
Bacterial Proteins↗
Chicken genome: new tools and concepts.
Last spring, the Second International Chicken Genome Workshop was held at the Stowers Institute for Medical Research, less than 2 months after the first draft of the chicken genome was publicly released in March, 2004. This major event was highly anticipated by the chicken community, because of the invaluable resources that would be newly provided. In addition, from an evolutionary standpoint, birds are the species most closely related to mammals, whose genome has been sequenced. The meeting gathered both agricultural and academic chicken communities and provided the opportunity to discuss the status of the chicken genome sequencing, the preliminary analysis of the chicken genome sequences freshly available, and the impact on avian genetic tools.
Animals↗
The Clinician-reported Genetic Testing Utility InDEx for Neonatal Intensive Care (C-GUIDE NICU): Quantifying genome-wide sequencing utility in the NICU.
PURPOSE: Use of genomic sequencing (GS) in neonatal intensive care units (NICUs) has increased with improved diagnostic yield. However, uncertainty persists regarding when and for whom GS is most useful. Because a standardized approach to assessing utility is lacking, we developed a novel version of the Clinician-reported Genetic testing Utility InDEx (C-GUIDE) to quantify the utility of GS in NICUs. METHODS: Informed by a scoping review, we developed a draft C-GUIDE NICU tool to quantify utility, which underwent iterative revisions through feedback from clinician interviews and questionnaires on item relevance, comprehensibility, and comprehensiveness. We finalized the expert-informed C-GUIDE NICU using an international Delphi consensus process. RESULTS: Scoping review (n = 25 articles) and interviews (n = 21) revealed key themes of utility. Guided by qualitative feedback and item scoring, C-GUIDE was iteratively reduced to include 21, 18, and 14 items. The Delphi consensus process with 22 experts achieved item consensus and stability, yielding a final 10-item tool. CONCLUSION: Using a rigorous process, we developed a consensus-based standardized method for capturing the clinical utility of GS in NICUs. C-GUIDE NICU can be used by clinicians, researchers, and payers to assess GS value to patient care and will be available for licensed use following reliability and validity testing.
Humans↗
Leprosy research--setting priorities and facilitating collaborations: a personal perspective.
In recent years, as the prevalence of leprosy has declined and the tuberculosis epidemic has gained increasing attention, leprosy research has generally taken a 'back seat' to research in tuberculosis and other emerging and re-emerging infections. This has resulted as much from perceived differences of scientific opportunities in these fields as from differences of the disease burden. At the United States National Institutes of Health (NIH), research priority setting is typically based on a number of factors. In the case of leprosy research, the technical difficulties associated with this scientific area have clearly lessened enthusiasm for and progress in this field. Today, however, we are confronted by the reality of not having sufficient scientific understanding to explain a stable or increasing number of leprosy cases detected annually in the face of a dramatically decreasing total number of identified cases. We also lack adequate tools for diagnosis and prevention. At the same time, new molecular and cellular approaches and knowledge of the complete sequence of the genome of Mycobacterium leprae render leprosy research significantly more tractable than ever before. The combination of these factors has led a number of groups, including the National Institute of Allergy and Infectious Diseases of the NIH, to review the current state of knowledge in leprosy research and draft recommendations for future leprosy research priorities. It is clear that many of the necessary and exciting research activities can best be addressed through collaborations among investigators, with control programmes, and among countries of high and low endemicity.
Developing Countries↗
Bioinformatics, target discovery and the pharmaceutical/biotechnology industry.
With the first draft of the human genome now available a directed genome-wide mining strategy is being implemented by many pharmaceutical and biotechnology companies in order to identify novel members of the most therapeutically relevant target families. At the same time there is an increasing amount of annotation relevant to the human genome sequence entering into the public domain. The ability to identify protein families on a genome-wide scale can only be done at speed by using high-throughput computational approaches. This review describes many of the latest algorithmic developments in this field and shows how they can be best put to use for target identification and prioritization.
Algorithms↗
Coronavirus Cryptic Landscape and Draft Genome of a Novel CoV Clade Related to MERS From Bats Circulating in Northeastern Brazil.
We identified seven distinct coronaviruses (CoVs) in bats from Brazil, classified into 229E-related (Alpha-CoV), Nobecovirus, Sarbecovirus, and Merbecovirus (Beta-CoV), including one closely related to MERS-like CoV with 82.8% genome coverage. To accomplish this, we screened 423 oral and rectal swabs from 16 different bat species using molecular assays, RNA sequencing, and evolutionary analysis. Notably, gaps in the spike-encoding gene led us to design new primers and perform Sanger sequencing, which revealed high similarities to MERS-related (MERSr) CoV strains found in humans and camels. Additionally, we identified key residues in the receptor-binding domain (RBD) of the spike protein, suggesting potential interactions with DPP4, the receptor for MERSr-CoV. Our analyses also revealed evidence of recombination involving our laboratory-produced sequences. These findings highlight the extensive genetic diversity of CoVs, the presence of novel viral lineages, and the occurrence of recombination events among bat CoVs circulating in Brazil, underscoring the critical role bats play as reservoirs for emerging viruses and emphasizing the necessity of ongoing surveillance to monitor the public health risks associated with CoV spillover events.
Chiroptera↗
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↗
The first-generation whole-genome radiation hybrid map in the horse identifies conserved segments in human and mouse genomes.
A first-generation radiation hybrid (RH) map of the equine (Equus caballus) genome was assembled using 92 horse x hamster hybrid cell lines and 730 equine markers. The map is the first comprehensive framework map of the horse that (1) incorporates type I as well as type II markers, (2) integrates synteny, cytogenetic, and meiotic maps into a consensus map, and (3) provides the most detailed genome-wide information to date on the organization and comparative status of the equine genome. The 730 loci (258 type I and 472 type II) included in the final map are clustered in 101 RH groups distributed over all equine autosomes and the X chromosome. The overall marker retention frequency in the panel is approximately 21%, and the possibility of adding any new marker to the map is approximately 90%. On average, the mapped markers are distributed every 19 cR (4 Mb) of the equine genome--a significant improvement in resolution over previous maps. With 69 new FISH assignments, a total of 253 cytogenetically mapped loci physically anchor the RH map to various chromosomal segments. Synteny assignments of 39 gene loci complemented the RH mapping of 27 genes. The results added 12 new loci to the horse gene map. Lastly, comparison of the assembly of 447 equine genes (256 linearly ordered RH-mapped and additional 191 FISH-mapped) with the location of draft sequences of their human and mouse orthologs provides the most extensive horse-human and horse-mouse comparative map to date. We expect that the foundation established through this map will significantly facilitate rapid targeted expansion of the horse gene map and consequently, mapping and positional cloning of genes governing traits significant to the equine industry.
Animals↗
In silico exploration of the fructose-6-phosphate phosphorylation step in glycolysis: genomic evidence of the coexistence of an atypical ATP-dependent along with a PPi-dependent phosphofructokinase in Propionibacterium freudenreichii subsp. shermanii.
We performed a detailed bioinformatic study of the catalytic step of fructose-6-phosphate phosphorylation in glycolysis based on the raw genomic draft of Propionibacterium freudenreichii subsp. shermanii (P. shermanii) ATCC9614 [Meurice et al., 2004]. Our results provide the first in silico evidence of the coexistence of genes coding for an ATP-dependent phosphofructokinase (ATP-PFK) and a PPi-dependent phosphofructokinase (PPi-PFK), whereas the fructose-1,6-bisphosphatase (FBP) and ADP-dependent phosphofructokinase (ADP-PFK) are absent. The deduced amino acid sequence corresponding to the PPi-PFK (AJ508922) shares 100% similarity with the already characterised propionibacterial protein (P29495; Ladror et al., 1991]. The unexpected ATP-PFK gene (AJ509827) encodes a protein of 373 aa which is highly similar (50% positive residues) along at least 95% of its sequence length to different well-characterised ATP-PFKs. The characteristic PROSITE pattern important for the enzyme function of ATP-PFKs (PS00433) was conserved in the putative ATP-PFK sequence: 8 out of 9 amino acid residues. According to the recent evolutionary study of PFK proteins with different phosphate donors [Bapteste et al., 2003], the propionibacterial ATP-PFK harbours a G104-K124 residue combination, which strongly suggested that this enzyme belongs to the group of atypical ATP-PFKs. According to our phylogenetic analyses the amino acid sequence of the ATP-PFK is clustered with the atypical ATP-PFKs from group III of the Siebers classification [Siebers et al., 1998], whereas the expected PPi-PFK protein is closer to the PPi-PFKs from clade P [Müller et al., 2001]. The possible significance of the co-existence of these two PFKs and their importance for the regulation of glycolytic pathway flux in P. shermanii is discussed.
Adenosine Triphosphate↗
Anchoring of a large set of markers onto a BAC library for the development of a draft physical map of the grapevine genome.
Five hundred and six EST-derived markers, 313 SSR markers and 26 BAC end-derived or SCAR markers were anchored by PCR on a subset of a Cabernet Sauvignon BAC library representing six genome equivalents pooled in three dimensions. In parallel, the 12,351 EST clusters of the grapevine UniGene set (build #11) from NCBI were used to design 12,125 primers pairs and perform electronic PCR on 67,543 nonredundant BAC-end sequences. This in silico experiment yielded 1,140 positive results concerning 638 different markers, among which 602 had not been already anchored by PCR. The data obtained will provide an easier access to the regulatory sequences surrounding important genes (represented by ESTs). In total, 1,731 islands of BAC clones (set of overlapping BAC clones containing at least one common marker) were obtained and 226 of them contained at least one genetically mapped anchor. These assigned islands are very useful because they will link the genetic map and the future fingerprint-based physical map and because they allowed us to indirectly place 93 ESTs on the genetic map. The islands containing two or more mapped SSR markers were also used to assess the quality of the integrated genetic map of the grapevine genome.
Chromosomes, Artificial, Bacterial↗
Human genomic variation.
: The recent completion and assembly of the first draft of the human genome, which combines samples from several ethnically diverse males and females, provides preliminary data on the extent of human genetic variation.
DNA, Mitochondrial↗
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↗