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PubMed2002

Active Alu element "A-tails": size does matter.

Long and short interspersed elements (LINEs and SINEs) are retroelements that make up almost half of the human genome. L1 and Alu represent the most prolific human LINE and SINE families, respectively. Only a few Alu elements are able to retropose, and the factors determining their retroposition capacity are poorly understood. The data presented in this paper indicate that the length of Alu "A-tails" is one of the principal factors in determining the retropositional capability of an Alu element. The A stretches of the Alu subfamilies analyzed, both old (Alu S and J) and young (Ya5), had a Poisson distribution of A-tail lengths with a mean size of 21 and 26, respectively. In contrast, the A-tails of very recent Alu insertions (disease causing) were all between 40 and 97 bp in length. The L1 elements analyzed displayed a similar tendency, in which the "disease"-associated elements have much longer A-tails (mean of 77) than do the elements even from the young Ta subfamily (mean of 41). Analysis of the draft sequence of the human genome showed that only about 1000 of the over one million Alu elements have tails of 40 or more adenosine residues in length. The presence of these long A stretches shows a strong bias toward the actively amplifying subfamilies, consistent with their playing a major role in the amplification process. Evaluation of the 19 Alu elements retrieved from the draft sequence of the human genome that are identical to the Alu Ya5a2 insert in the NF1 gene showed that only five have tails with 40 or more adenosine residues. Sequence analysis of the loci with the Alu elements containing the longest A-tails (7 of the 19) from the genomes of the NF1 patient and the father revealed that there are at least two loci with A-tails long enough to serve as source elements within our model. Analysis of the A-tail lengths of 12 Ya5a2 elements in diverse human population groups showed substantial variability in both the Alu A-tail length and sequence homogeneity. On the basis of these observations, a model is presented for the role of A-tail length in determining which Alu elements are active.

3' Flanking Region↗

PubMed2005

Analysis of the human Alu Ye lineage.

BACKGROUND: Alu elements are short (approximately 300 bp) interspersed elements that amplify in primate genomes through a process termed retroposition. The expansion of these elements has had a significant impact on the structure and function of primate genomes. Approximately 10 % of the mass of the human genome is comprised of Alu elements, making them the most abundant short interspersed element (SINE) in our genome. The majority of Alu amplification occurred early in primate evolution, and the current rate of Alu retroposition is at least 100 fold slower than the peak of amplification that occurred 30-50 million years ago. Alu elements are therefore a rich source of inter- and intra-species primate genomic variation. RESULTS: A total of 153 Alu elements from the Ye subfamily were extracted from the draft sequence of the human genome. Analysis of these elements resulted in the discovery of two new Alu subfamilies, Ye4 and Ye6, complementing the previously described Ye5 subfamily. DNA sequence analysis of each of the Alu Ye subfamilies yielded average age estimates of approximately 14, approximately 13 and approximately 9.5 million years old for the Alu Ye4, Ye5 and Ye6 subfamilies, respectively. In addition, 120 Alu Ye4, Ye5 and Ye6 loci were screened using polymerase chain reaction (PCR) assays to determine their phylogenetic origin and levels of human genomic diversity. CONCLUSION: The Alu Ye lineage appears to have started amplifying relatively early in primate evolution and continued propagating at a low level as many of its members are found in a variety of hominoid (humans, greater and lesser ape) genomes. Detailed sequence analysis of several Alu pre-integration sites indicated that multiple types of events had occurred, including gene conversions, near-parallel independent insertions of different Alu elements and Alu-mediated genomic deletions. A potential hotspot for Alu insertion in the Fer1L3 gene on chromosome 10 was also identified.

Alu Elements↗

PubMed2001

[Genetics of autoimmune diseases].

The publication of the human genome sequence this year was an important milestone in Biology. Autoimmune diseases arise through a complex interaction of genetics and environmental factors. They are influenced by more than one gene and do not exhibit a simple mode of inheritance. Some of the involved genes are thought to play a role in several autoimmune diseases whereas others seem to be specific for one of them. We have studied mainly genes located on the Major Histocompatibility Complex situated on the short arm of the 6th chromosome. This region is the most important genetic determinant for autoimmune diseases. It carries many genes playing a role in immune response and several have been observed to be associated with autoimmune diseases susceptibility. Although what has been published is just a draft of the human genome sequence, and a lot of work is needed to make sense of all these data and move into the study of gene function, the important technology breakthroughs of the last few years in genomics, proteomics and bioinformatics will speedup the study and results may come much earlier than could be imagined some years ago.

Autoimmune Diseases↗

PubMed2026

Comparative genomic analysis of Streptococcus parasuis and Streptococcus suis reveals mobile element-associated enrichment of antimicrobial resistance and lack of detectable same-MGE colocalization with virulence-associated genes within stable species boundaries.

Streptococcus suis is a major porcine pathogen and a zoonotic agent that causes meningitis and septicemia in humans. Streptococcus parasuis, a recently recognized close relative, remains poorly characterized with regard to its clinical significance and genomic features. In this study, we generated a single-contig closed genome assembly with genome-wide DNA methylation profiles for S. parasuis strain A1, isolated from a diseased pig in Xinjiang, China, and complemented in silico genomic predictions with isolate-level experimental validation of antimicrobial resistance (AMR) genotypes, virulence genotypes, and phenotypic susceptibility for this reference strain. Using this high-quality genome as a reference anchor, we performed comparative genomic analyses across 195 streptococcal genomes, comprising 15 S. parasuis and 180 S. suis strains, to distinguish genome-level co-occurrence of resistance and virulence determinants from their physical colocalization on the same mobile genetic element (MGE).Species boundaries remained clearly delineated at the genomic level, with a median interspecies average nucleotide identity (ANI) of approximately 86.0%, compared with intraspecies ANI medians of 97.5% for S. parasuis and 96.2% for S. suis. Pangenome analysis identified 12,693 gene clusters, of which 1086 were core clusters, and functional annotation revealed significant differences in accessory gene repertoires between the two species. Within this stable genomic framework, S. parasuis genomes carried a higher AMR gene burden; strain A1 harbored 10 AMR genes, multiple virulence-associated genes, three genomic islands, and eight prophage regions. For strain A1, PCR validation confirmed six AMR genes and six virulence genes, and disk diffusion testing demonstrated a multidrug-resistant phenotype consistent with the genotypic profile.Among 235 predicted mobile elements, 19 harbored AMR genes and seven carried Virulence Factor Database (VFDB) homologs, but none carried both categories simultaneously. This finding reflects a lack of detectable same-MGE colocalization under the applied annotation and assembly framework; it should not be interpreted as evidence of biological physical decoupling. Under a random-placement model, the expected number of co-carrying regions was only 0.57, and the probability of observing zero co-carrying regions was P = 0.55. This negative result should be interpreted with caution, given the limited number of cargo-bearing regions and the predominantly draft status of most genomes. Furthermore, the A1 genome contained multiple restriction-modification systems, showed depletion of several methylation motif families in mobile regions, and had limited CRISPR spacer matching evidence, suggesting prior exposure to the relevant sequence space. None of the genomes met our predefined criteria for whole-genome convergence.Collectively, our results support a model in which S. parasuis accumulates AMR-related genes in a modular fashion via mobile elements within stable species boundaries, with no detectable same-MGE colocalization of AMR and virulence determinants under our analytical pipeline. These findings imply that AMR surveillance strategies for this species should prioritize tracking mobile genetic elements rather than inferring wholesale genomic convergence toward S. suis.

Streptococcus suis↗

PubMed2001

The human repertoire of odorant receptor genes and pseudogenes.

The nose of Homo sapiens is a sophisticated chemical sensor. It is able to smell almost any type of volatile molecule, often at extraordinarily low concentrations, and can make fine perceptual discriminations between structurally related molecules. The diversity of odor recognition is mediated by odorant receptor (OR) genes, discovered in 1991 by Buck & Axel. OR genes form the largest gene families in mammalian genomes. A decade after their discovery, advances in the sequencing of the human genome have provided a first draft of the human OR repertoire: It consists of approximately 1000 sequences, residing in multiple clusters spread throughout the genome, with more than half being pseudogenes. Allelic variants are beginning to be recognized and may provide an opportunity for genotype-phenotype correlations. Here, I review the current knowledge of the human OR repertoire and summarize the limited information available regarding putative pheromone and taste receptors in humans.

Animals↗

PubMed2004

PCR-based genotyping of the rat Atrn(mv) mutation.

Rat myelin vacuolation mutation at the Attractin locus (Atrn(mv)) is a genomic deletion including the whole exon 1 of the Atrn gene. The precise size and location of the deleted region has not yet been identified because of poor information on genomic organization of the rat Atrn gene. Here, we identified the breakpoints of the Atrn(mv) mutation, using a draft sequence of the rat genome. In the Atrn(mv/mv) rat, a 6,914-bp genomic region was deleted. Primers flanked 5'- and 3'- breakpoints amplified the Atrn(mv) allele but not the wild-type allele. This primer set enables us to distinguish Atrn(mv/+) heterozygous rats from Atrn(+/+) rats, and will contribute to the efficient production of Atrn(mv/mv) rats.

Animals↗

PubMed2000

Functional genomics.

We are in the midst of a genomics revolution. The first chapter of this revolution will end later this year with the completion of the first draft of the entire human genome; estimates for the exact number of genes in the human genome vary from 50,000 to 140,000. This endeavor has been a major catalyst for the genomics revolution and has moved science into uncharted territories, which has led to the need to establish both new disciplines and a new vocabulary. Thus we now have pharmacogenomics, genotyping, pharmacogenetics, microarrays, biochips, differential display, bioinformatics and cheminformatic. The meeting provided a taste of the wealth of information that is now being accumulated under the name of both genomics and proteomics. The challenge ahead will be turning this information into knowledge and then translating this knowledge into new therapies.

Journal Article↗

PubMed2001

The role of genetic testing and effect on patient care.

The heralded report of the first draft of the Human Genome Project highlights the role genetics plays in nearly all medical disciplines, including dermatology. Many inherited disorders have dermatological features, and dermatological pathologic conditions frequently can be traced to a genetic cause. Suspicion of a genetic disorder is often suggested first by a practitioner such as a dermatologist, who is likely to be the first to identify characteristic features of the disease. This review highlights the relationship between the clinician and genetics professional in genetic testing using a case example of a familial cancer syndrome, Cowden syndrome, as a model.

Female↗

PubMed2002

rSNP_Guide: an integrated database-tools system for studying SNPs and site-directed mutations in transcription factor binding sites.

Since the human genome was sequenced in draft, single nucleotide polymorphism (SNP) analysis has become one of the keynote fields of bioinformatics. We have developed an integrated database-tools system, rSNP_Guide (http://wwwmgs.bionet.nsc.ru/mgs/systems/rsnp/), devoted to prediction of transcription factor (TF) binding sites, alterations of which could be associated with disease phenotype. By inputting data on alterations in DNA sequence and in DNA binding pattern of an unknown TF, rSNP_Guide searches for a known TF with alterations in the recognition score calculated on the basis of TF site's sequence and consistent with the input alterations in DNA binding to the unknown TF. Our system has been tested on many relationships between known TF sites and diseases, as well as on site-directed mutagenesis data. Experimental verification of rSNP_Guide system was made on functionally important SNPs in human TDO2and mouse K-ras genes. Additional examples of analysis are reported involving variants in the human gammaA-globin (HBG1), hsp70(HSPA1A), and Factor IX (F9) gene promoters.

Animals↗

PubMed2001

The myosin light chain kinase gene is not duplicated in mouse: partial structure and chromosomal localization of Mylk.

The gene encoding myosin light chain kinase (MYLK) is duplicated on human chromosome 3 (HSA3; 3p13;3q21) and on a chromosome with conserved synteny to HSA3 in most non-human primate species. In human, the functional copy resides on 3q21, whereas the 3p13 site contains a pseudogene. To trace the origin of the duplication, we characterized the mouse gene Mylk. A single sequence corresponding to the functional Mylk was detected. We sequenced a 180-kb bacterial artificial chromosome clone containing the 24 first exons of Mylk; the complete mouse gene is expected to span >200 kb. Comparisons with the draft of the human genome revealed that the sequence and structure of MYLK are conserved in mammals. Fluorescence in situ hybridization (FISH) analysis indicated that the mouse gene localizes to a single site on chromosome 16B4-B5, a region with conserved synteny with HSA3q. Our study provides information on both the structure and the evolution of MYLK in mammals and suggests that it was duplicated after the divergence of rodents and primates.

Amino Acid Sequence↗

PubMed2002

Genetics and cardiac anomalies: the heart of the matter.

The recent exponential increase in knowledge in genetics has revolutionized all aspects of medicine. The completion of the first draft of the human genome project has provided for clinicians a range and depth of information never before imagined. Over the last 25 years understanding the anatomical and physiological basis of a number of congenital cardiac anomalies has led to better care and outcome for the patients born with congenital cardiac defects. In the last decade the role of genes, their critical timing of expression, and understanding of important downstream pathways for optimizing normal development and control of the left right asymmetry have emerged. The progress in cardiac genetics has been supplemented by advances in cardiac imaging modalities leading to improvements in diagnosis of the cardiac anomalies. About 30% of all congenital heart diseases are associated with extra- cardiac malformations. Chromosomal anomalies are more common in patients with cardiac anomalies than the general population. Presence of facial dysmorphic features and associated extra-cardiac anomalies should alert the pediatricians to an underlying syndrome diagnosis. Newer molecular cytogenetics techniques such as fluorescence in situ hybridization (FISH) and molecular tests are now routinely utilized for confirming clinical diagnoses. In this review we have summarized clinical features and discussed the genetic basis of several syndromes (for example, 22q11 deletion syndrome, Williams syndrome, Down Syndrome, Kabuki syndrome etc.) where specific cardiac anomalies are frequently encountered. The importance of establishing an accurate clinical diagnosis cannot be over emphasized. The families need genetic counselling with accurate information on the recurrence risks. With the advent of the Internet and rapid access to information, the clinicians and the patient families can access valuable information regarding the prognosis, natural history, and clinical interventions for the affected child, and useful support groups for the family. Detection of cardiac anomalies during antenatal period warrants a genetics assessment.

Chromosome Deletion↗

PubMed2000

Challenges in human genetics in India in the new millennium.

This editorial provides information on the first draft of the human genome, and examines the impact this will have on the practice of medicine, with special reference to India. It examines what is currently possible in India, what we should do in the immediate future, and what is in store in the long run. The future is indeed bright and India needs to expand the genetic services and research facilities.

Forecasting↗

PubMed2005

Adaptive diversification of vomeronasal receptor 1 genes in rodents.

The vomeronasal receptor 1 (V1R) are believed to be pheromone receptors in rodents. Here we used computational methods to identify 95 and 62 new putative V1R genes from the draft rat and mouse genome sequence, respectively. The rat V1R repertoire consists of 11 subfamilies, 10 of which are shared with the mouse, while rat appears to lack the H and I subfamilies found in mouse and possesses one unique subfamily (M). The estimations of the relative divergence times suggest that many subfamilies originated after the split of rodents and primates. The analysis also reveals that these clusters underwent an expansion very close to the split of mouse and rat. In addition, maximum likelihood analysis showed that the nonsynonymous and synonymous rate ratio for most of these clusters was much higher than one, suggesting the role of positive selection in the diversification of these duplicated V1R genes. Because V1R are thought to mediate the process of signal transduction in response to pheromone detection, we speculate that the V1R genes have evolved under positive Darwinian selection to maintain the ability to discriminate between large and complex pheromonal mixtures.

Adaptation, Physiological↗

PubMed2003

A comprehensive radiation hybrid map of bovine Chromosome 26 (BTA26): comparative chromosomal organization between HSA10q and BTA26 and BTA28.

In this study, we present a comprehensive 3000-rad radiation hybrid (RH) map of bovine Chromosome (Chr) 26 (BTA26) with 80 markers including 50 genes or ESTs: 44 have an ortholog mapping to human Chr 10 (HSA10) and 29 to mouse Chr (MMU) 7, 10, and 19. Moreover, 12 other HSA10 genes were integrated in a newly developed RH map of BTA28 (seven represent new assignments). The available draft of the mouse genome allowed us to present a detailed picture of the distribution of conserved synteny segments among the three species (human, cattle, and mouse) and to propose a simple model of the comparative chromosomal organization between the long arm of HSA10 and BTA26 and 28. Finally, the INRA bovine BAC library was screened for most of the BTA26 markers considered in this study to provide anchors for the bovine physical map.

Animals↗

PubMed2004

Towards a mutant map of the mouse--new models of neurological, behavioural, deafness, bone, renal and blood disorders.

With the completion of the first draft of the human genome sequence, the next major challenge is assigning function to genes. One approach is genome-wide random chemical mutagenesis, followed by screening for mutant phenotypes of interest and subsequent mapping and identification of the mutated genes in question. We (a consortium made up of GlaxoSmithKline, the MRC Mammalian Genetics Unit and Mouse Genome Centre, Harwell, Imperial College, London, and the Royal London Hospital) have used ENU mutagenesis in the mouse for the rapid generation of novel mutant phenotypes for use as animal models of human disease and for gene function assignment (Nolan et al., 2000). As of 2003, 35,000 mice have been produced to date in a genome-wide screen for dominant mutations and screened using a variety of screening protocols. Nearly 200 mutants have been confirmed as heritable and added to the mouse mutant catalogue and, overall, we can extrapolate that we have recovered over 700 mutants from the screening programme. For further information on the project and details of the data, see http://www.mgu.har.mrc.ac.uk/mutabase.

Animals↗

PubMed2004

The future of genetic research on appetitive behavior.

The risk for developing obesity has a significant genetic component. Several quantitative trait loci and candidate genes have been identified using current methodological approaches however the information gained thus far is insufficient to adequately explain the genetics underlying human obesity. The completion of a draft of the human genome sequence, the potential benefit of single nucleotide polymorphisms association studies for identifying risk conferring alleles, and developing functional genomics technologies promise to accelerate obesity gene discovery. These advances, used with current evaluative tools (murine molecular genetic techniques), may increase our understanding of human obesity, and ultimately provide better approaches to diagnosis and treatment.

Appetite↗

PubMed2005

Characterization of the AMP-activated protein kinase pathway in chickens.

In mammals, AMP-activated protein kinase (AMPK) is involved in the regulation of cellular energy homeostasis and, on the whole animal level, in regulating energy balance and food intake. Because the chicken is a valuable experimental animal model and considering that a first draft of the chicken genome sequence has recently been completed, we were interested in verifying the genetic basis for the LKB1/AMPK pathway in chickens. We identified distinct gene homologues for AMPK alpha, beta and gamma subunits and for LKB1, MO25 and STRAD. Analysis of gene expression by RT-PCR showed that liver, brain, kidney, spleen, pancreas, duodenum, abdominal fat and hypothalamus from 3 wk-old broiler chickens preferentially expressed AMPK alpha-1, beta-2 and gamma-1 subunit isoforms. Heart predominantly expressed alpha-2, beta-2 and gamma-1, whereas skeletal muscle expressed alpha-2, beta-2 and gamma-3 preferentially. Moreover, the AMPK gamma-3 gene was only expressed in heart and skeletal muscle. Genes encoding LKB1, MO25 alpha, MO25 beta, and STRAD beta were expressed in all examined tissues, whereas STRAD alpha was expressed exclusively in brain, hypothalamus, heart and skeletal muscle. Alterations in energy status (fasting and refeeding) produced little significant change in AMPK subunit gene transcription. We also determined the level of phosphorylated (active) AMPK in different tissues and in different states of energy balance. Immunocytochemical analysis of the chicken hypothalamus showed that activated AMPK was present in hypothalamic nuclei involved in regulation of food intake and energy balance. Together, these findings suggest a functional LKB1/AMPK pathway exists in chickens similar to that observed in mammals.

AMP-Activated Protein Kinases↗

PubMed2003

Comparative promoter analysis and its application in analysis of PTH-regulated gene expression.

Taking advantage of the "working draft" of the human genome and the MIT shotgun assembly of the mouse genome, we performed a comparative promoter analysis of human RefSeq mRNA (sequences from GenBank's RefSeq database). By combining this analysis with a transcription factor (TF) binding site analysis using a TRANSFAC position weight matrix (PWM) search, 86% of non-specific TF sites were removed. Using a set of genes that are regulated by parathyroid hormone (PTH), a statistical analysis was performed on the conserved TF binding sites among a set of eight human and mouse genes. From among the eight genes tested, we obtained a set of 31 TFs, suggesting possible roles for associated genes in PTH-mediated pathways. All three known PTH-responsive TFs (AP1, RUNX2, CREB) were correctly predicted by this analysis as well as two other potential TFs (VDR and CEBP Delta). Additionally, a model was made to describe the TF site characteristic module of PTH-regulated genes. This model was then used to search all human RefSeq gene promoters with established human-mouse ortholog relationships to identify other PTH-regulated genes. This comparative approach combined with statistical analysis proved to be sufficiently specific to decipher critical TFs involved in PTH-regulated pathways.

Algorithms↗