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PubMed2005

Pharmacogenomics and therapeutic prospects in Alzheimer's disease.

Approximately 10-20% of the direct costs of Alzheimer's disease are attributed to pharmacological treatment. Less than 20% of Alzheimer's disease patients are moderate responders to conventional drugs (e.g., donepezil, rivastigmine, galantamine, memantine) with doubtful cost-effectiveness. In total, 15% of the Caucasian population with Alzheimer's disease are carriers of defective CYP2D6 polymorphic variants that are potentially responsible for therapeutic failures when receiving cholinesterase inhibitors and psychotropic drugs. In addition, structural genomics studies demonstrate that > 100 genes might be involved in Alzheimer's disease pathogenesis, regulating dysfunctional genetic networks leading to premature neuronal death. The Alzheimer's disease population exhibits a higher genetic variation rate than the control population, with absolute and relative genetic variations of 40-60% and 0.85-1.89%, respectively. Alzheimer's disease patients also differ from patients with other forms of dementia in their genomic architecture, possibly with different genes acting synergistically to influence the phenotypic expression of biological traits. Functional genomics studies in Alzheimer's disease reveal that age of onset, brain atrophy, cerebrovascular haemodynamics, brain bioelectrical activity, cognitive decline, apoptosis, immune function and amyloid deposition are associated with Alzheimer's disease-related genes. Pioneering pharmacogenomics studies also demonstrate that the therapeutic response in Alzheimer's disease is genotype-specific, with APOE-4/4 carriers as the worst responders to conventional treatments. It is likely that pharmacogenetic and pharmacogenomic factors account for 60-90% of drug variability in drug disposition and pharmacodynamics. The incorporation of pharmacogenomic/pharmacogenetic protocols in Alzheimer's disease may foster therapeutic optimisation by helping to develop cost-effective drugs, improving efficacy and safety, and reducing adverse events and cutting-down unnecessary cost for the industry and the community.

Alzheimer Disease↗
PubMed2005

Cyclic GMP-dependent protein kinases in protozoa.

PKG (cGMP-dependent protein kinase) is a major intracellular receptor for cGMP and mediates a range of downstream physiological functions. Although most studies have concentrated on mammalian isoforms, the advent of whole genome sequencing has lead to identification of orthologues from other diverse species. Many biochemical and regulatory properties and structural features of PKG have been conserved throughout evolution. However, in protozoa there can be variation in the number of cGMP-binding sites and a tendency toward degeneracy of these additional sites. Recent work on the protozoan PKGs is the major focus of this review. Important functional data are emerging for these and other non-mammalian isoforms. Intriguingly, a role for PKG in locomotion is becoming a common functional theme across diverse phyla.

Animals↗
PubMedDate not supplied

Genomics and phenotypic profiles in dementia: implications for pharmacological treatment.

Constitutive genomics are probably determinant for the onset of dementia in conjunction with cerebrovascular and environmental factors. Furthermore, pharmacogenomic studies predict that the therapeutic response in Alzheimer's disease (AD) is genotype-specific, and that the expression of genes involved in the regulation of drug metabolism can influence efficacy and safety issues in pharmacotherapy. AD and dementia with a vascular component (DVC = VD + MXD) are the most prevalent forms of dementia. These clinical entities share many similarities, but they differ in major phenotypic and genotypic profiles, as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometry, cardiovascular function, aortic atherosclerosis, brain atrophy, blood pressure, blood biochemistry, hematology, thyroid function, folic acid and vitamin B(12) levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: (a) anthropometric values, (b) cardiovascular function, (c) blood pressure, (d) lipid metabolism, (e) uric acid levels, (f) peripheral calcium levels, (g) liver function (GOT, GPT, GGT), (h) alkaline phosphatase, (i) lactate dehydrogenase, (j) red and white blood cells, (k) regional brain atrophy (left temporal region, inter-hippocampal distance) and (l) brain blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. Structural genomics studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS and PRNP genes, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate ranging from 30 to 80%, depending upon genes and genetic clusters. Single gene analysis identifies relative genetic variations ranging from 0 to 5%. The relative polymorphic variation in genetic clusters integrated by 2, 3 or 4 genes associated with AD ranges from 1 to 3%. The main phenotypic differences between AD and DVC are genotype-dependent, especially in AD, probably indicating that different genomic factors are essential for the expression of dementia symptoms that might be accelerated or induced by environmental and/or cerebrovascular factors.

Age Distribution↗
PubMed1995

Structural comparison of the plant satellite viruses.

Detailed structures are now available for three plant satellite viruses, satellite tobacco necrosis virus (STNV), satellite tobacco mosaic virus (STMV), and satellite panicum mosaic virus (SPMV). It is, therefore, possible to compare the tertiary structure of viral protein subunits, their quaternary interactions, and the interactions of protein subunits with the RNA genome. This analysis indicates that, in spite of common function and preservation of a "jelly-roll" motif in the protein monomer, the three viruses are remarkably different. The differences include the arrangement of secondary structural elements, interactions of adjacent subunits, and the disposition of subunits relative to icosahedral symmetry axes. In each of the three viruses, however, the narrow end of the jelly roll forms fivefold contacts. The fivefold protein interactions are organized about a Ca2+ ion for STNV, an anion for STMV, and, apparently, neither of these for SPMV. Low-resolution neutron diffraction studies using H2O/D2O solvent contrast variation revealed the general location of the RNA genome within the STNV. In the case of SPMV, regions of electron density on the interior of the capsid could be assigned to RNA, although it was not possible to model the nucleic acid. Only for STMV was nucleic acid visible in election density maps, and this was manifested as double-helical RNA segments associated with each coat protein dimer. The observations presented here provide no support for any common evolutionary relationship.

Amino Acid Sequence↗
PubMedDate not supplied

[The genomic variability of adenovirus serotype 7].

Genetic heterogeneity and evolutionary relationships among selected strains of adenovirus type 7 (Ad7) isolated in the former USSR were examined using the restriction endonuclease Cfr131 with a 4-base recognition cleavage site. The population of adenovirus type 7 showed less expressed genome polymorphism and significant structural distinctions as compared with that of adenovirus type 3. The Ad7 evolution in the USSR (1976-1988) independent on that demonstrated in other countries is discussed.

Adenoviruses, Human↗
PubMed2026

Long-read low-pass sequencing enhances variant detection in a peanut MAGIC population.

Accurate genotyping accelerates crop improvement, yet long-read sequencing remains underused in breeding due to cost. We present a scalable long-read low-pass (LRLP) sequencing framework for high-throughput variant discovery and trait mapping. Using PacBio HiFi reads in an allotetraploid peanut (Arachis hypogaea; AABB, 2n = 4x = 40) MAGIC population, we generated both LRLP and short-read low-pass (SRLP) data. At comparable depths, LRLP achieved substantially greater whole-genome and gene-space coverage than SRLP. Data were analyzed using both a single-reference genome and an 18-parent pangenome graph constructed with KhufuPan, a new tool for graph-based genotyping. Across analytical approaches, LRLP consistently identified more SNPs, indels (2-1,000 bp), and structural variants (>1 kb) than SRLP, improving genotype resolution and selection accuracy, particularly for large structural variants. By reducing cost barriers and increasing variant discovery in complex genomes, LRLP provides a practical path for deploying advanced genomics in under-resourced and orphan crops critical to global food security.

Arachis↗
PubMed2001

Genetic differences between humans and great apes.

The remarkable similarity among the genomes of humans and the African great apes could warrant their classification together as a single genus. However, whereas there are many similarities in the biology, life history, and behavior of humans and great apes, there are also many striking differences that need to be explained. The complete sequencing of the human genome creates an opportunity to ask which genes are involved in those differences. A logical approach would be to use the chimpanzee genome for comparison and the other great ape genomes for confirmation. Until such a great ape genome project can become reality, the next best approach must be educated guesses of where the genetic differences may lie and a careful analysis of differences that we do know about. Our group recently discovered a human-specific inactivating mutation in the CMP-sialic acid hydroxylase gene, which results in the loss of expression of a common mammalian cell-surface sugar throughout all cells in the human body. We are currently investigating the implications of this difference for a variety of issues relevant to humans, ranging from pathogen susceptibility to brain development. Evaluating the uniqueness of this finding has also led us to explore the existing literature on the broader issue of genetic differences between humans and great apes. The aim of this brief review is to consider a listing of currently known genetic differences between humans and great apes and to suggest avenues for future research. The differences reported between human and great ape genomes include cytogenetic differences, differences in the type and number of repetitive genomic DNA and transposable elements, abundance and distribution of endogenous retroviruses, the presence and extent of allelic polymorphisms, specific gene inactivation events, gene sequence differences, gene duplications, single nucleotide polymorphisms, gene expression differences, and messenger RNA splicing variations. Evaluation of the reported findings in all these categories indicates that the CMP-sialic hydroxylase mutation is the only one that has so far been shown to result in a global biochemical and structural difference between humans and great apes. Several of the other known genetic dissimilarities deserve more exploration at the functional level. Among the areas of focus for the future should be genes affecting development, mental maturation, reproductive biology, and other aspects of life history. The approaches taken should include both going from the genome up to the adaptive potential of the organisms and going from novel adaptive regimes down to the relevant repercussions in the genome. Also, as much as we desire a simple genetic explanation for the human phenomenon, it is much more probable that our evolution occurred in multiple genetic steps, many of which must have left detectable footprints in our genomes. Ultimately, we need to know the exact number of genetic steps, the order in which they occurred, and the temporal, spatial, environmental, and cultural contexts that determined their impact on human evolution.

Animals↗
PubMed2003

[Sequence aanlysis of intergenic region of rice stripe virus RNA4: evidence for mixed infection and genomic variation].

The intergenic region (IR) of the RNA4 of 22 isolates of Rice stripe virus (RSV) in China was cloned and sequenced. The IR sequences were compared with one another and with that from Japan. Sequence comparisons showed that these isolates could be divided into three different types, with the IR length of 634 bp, 654 bp and 732 bp, respectively. It is interesting to note three different types all occurred in Yunnan RSV natural population, whereas other province only existed 654 bp type length isolates. Mixed infections with different types of IR length coexisting in some isolates in Yunnan was observed. IR sequences were not more conserved (83% - 100%) among the populations of RSV from China than with those of RSV isolates from Japan (83% - 94%). There were two important structure characteristics in IRs sequences. Firstly, there was a-19 nt insertion in 654 bp type isolates and a-103 nt in 732 bp type isolates in comparison to 634 bp type isolates. This inserted sequences were rather highly conserved. Blast analysis indicates the 16 nt (AGAAACATGAGAGTA) in 19 nt insertation was very similar in sequence to wheat cDNA library; and the 20 nt (AGAATTGCCTTGGTGTTAT) in 103 nt insertion was identical to a stretch sequences of barley cDNA library. Recombination hot-spot sequences existed in RNA4 IR. Secondly, IRs sequence was rich in U and A residues where two distant hairpin structures could be formed with computer-assisted folding analysis. One was highly conserved and stable, but the other was rather unstable because of bases variation. It is believed that this stabilised hairpin structure, rather than a sequence motif, might serve as a transcription terminator during the synthesis of mRNAs from the ambisense segments. Negative selection constraints imposed by secondary structure might have maintained the conserved sequences. In this paper, the relationship between the lowest free energy of the unstable hairpin structures and the different pathogenesis among some isolates was also discussed in this paper.

Amino Acid Sequence↗
PubMed1986

Identification and characterization of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS.

To determine the extent and nature of genetic variation present in independent isolates of HTLV-III/LAV, the nucleotide sequences of the entire envelope gene and parts of gag and pol were determined for two AIDS viruses. The results indicated that variation throughout the viral genome is extensive and that the envelope gene in particular is most highly variable. Within the envelope, changes were most prevalent within the extracellular region where clustered nucleotide substitutions and deletions/insertions were evident. Based on predicted secondary protein structure and hydrophilicity, these hypervariable regions represent potential antigenic sites. In contrast to the hypervariable regions, other sequences in the extracellular envelope and the overall envelope structure (including 18 of 18 cysteine residues), as well as most of the transmembrane region, were highly conserved.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

[Genome of influenza virus: organization, function, evolution].

Basic features of influenza virus genome structure, replication and evolution are reviewed with a special emphasis upon the segmentary structure of the genome and the use of cell mRNA as primer in virus-specific transcription. The structural and functional autonomy of virus genomic segments and the selection of the segments in the process of viral genome assembly is considered to be the basis for the gene reassortment and the appearance of recombinants. The reassortment of genes is discussed in relation to the nature of "new" antigenic subtypes of human influenza A virus, that is, to the orivin of antigenic shifts and pandemic strains. Another kind of antigenic variation (antigenic drift) is produced by the accumulation of mutations under the conditions of selection pressure in an immune population. Together with the conservation of earlier antigenic subtypes in animal populations these two types of evolutionary changes produce a complex pattern of influenza virus evolution. The prospects of influenza control are briefly discussed in connection with the characteristics of influenza virus genome structure and evolution.

Antigens, Viral↗
PubMedDate not supplied

Early detection of G + C differences in bacterial species inferred from the comparative analysis of the two completely sequenced Helicobacter pylori strains.

Identifying the G + C difference between closely related bacterial species or between different strains of the same species is one of the first steps in understanding the evolutionary mechanisms accounting for the differences observed among bacterial species. The G + C content can be one of the most important factors in the evolution of genomic structures. In this paper, we describe a new method for detecting an initial stage of differentiation of the G + C content at the third codon base position between two strains of the same bacterial species. We apply this method to the two strains of Helicobacter pylori. A group of genes is detected with large variations of G + C in the third positions-apparently genes of early response to pressures of changing G + C. We discuss our findings from the viewpoint of genomic evolution.

Bacteria↗
PubMed2006

Population genetics of the bovine/cattle lungworm (Dictyocaulus viviparus) based on mtDNA and AFLP marker techniques.

Mitochondrial DNA (mtDNA) sequence data and amplified fragment length polymorphism (AFLP) patterns were compared for the lungworm Dictyocaulus viviparus, a nematode parasite of cattle. Eight individual D. viviparus samples from each of 8 herds in Sweden and 1 laboratory isolate were analysed, with the aim of describing the diversity and genetic structure in populations using different genetic markers on exactly the same DNA samples. There was qualitative agreement between the whole-genome AFLP data and the mtDNA sequence data, both indicating relatively strong genetic differentiation among the Swedish farms. However, the AFLP data detected much more genetic variation than did the mtDNA data, even after allowing for the different inheritance patterns of the markers, and indicated that there was much less differentiation among the populations. The mtDNA data therefore seemed to be more informative about the most recent history of the parasite populations, as the general patterns were less obscured by detailed inter-relationships among individual worms. The 4 mtDNA genes sequenced (1542 bp) showed consistent patterns, although there was more genetic variation in the protein-coding genes than in the structural RNA genes. Furthermore, there appeared to be at least 3 distinct genetic groups of D. viviparus infecting Swedish cattle, 1 of which was predominant and showed considerable differentiation between farms, but not necessarily within farms. Second, the 2 smaller genetic groups occurred on farms where the predominant group also occurred, suggesting that these farms have had multiple introductions of D. viviparus.

Animals↗
PubMed2003

Analysis of the role of predicted RNA secondary structures in Ebola virus replication.

Thermodynamic modeling of Ebola viral RNA predicts the formation of RNA stem-loop structures at the 3' and 5' termini and panhandle structures between the termini of the genomic (or antigenomic) RNAs. Sequence analysis showed a high degree of identity among Ebola Zaire, Sudan, Reston, and Cote d'Ivoire subtype viruses in their 3' and 5' termini (18 nucleotides in length) and within a second region (internal by approximately 20 nucleotides). While base pairing of the two conserved regions could lead to the formation of the base of the putative stem-loop or panhandle structures, the intervening sequence variation altered the predictions for the rest of the structures. Using an in vivo minigenome replication system, we engineered mutations designed to disrupt potential base pairing in the viral RNA termini. Analysis of these variants by screening for enhanced green fluorescent protein reporter expression and by quantitation of minigenomic RNA levels demonstrated that the upper portions of the putative panhandle and 3' genomic structures can be destabilized without affecting virus replication.

Base Sequence↗
PubMed2004

Genomic characterization of two Chinese isolates of porcine respiratory and reproductive syndrome virus.

The genomes of two isolates of porcine respiratory and reproductive syndrome virus (PRRSV) from China, designated HB-1(sh)/2002 and HB-2(sh)/2002, were sequenced and analyzed. The size of the genomes of HB-1(sh)/2002 and HB-2(sh)/2002 were 15,411 and 15,373 nucleotides respectively, excluding the poly(A) tails. Comparative analysis with the genomic sequences of another Chinese isolate (BJ-4) and North American (VR2332) and European (Lelystad virus, LV) viruses revealed that HB-1(sh)/2002 shared 89.8% identity with BJ-4 and VR2332, but only 54.7% with LV; while HB-2(sh)/2002 shared 89.4% and 89.5% identity with BJ-4 and VR2332 respectively and 54.3% with LV, indicating that the two new Chinese isolates were related to the North American PRRSV genotype. Phylogenetic analysis based on the nucleotide sequence of the structural protein ORF's showed that the two new Chinese isolates belong to same genetic subgroup. HB-2(sh)/2002 additionally exhibited variations in the NSP2 nonstructural protein encoded by ORF1 and the structural protein GP3 encoded by ORF3 in comparison with other North American PRRSV isolates, namely a 12 amino acids deletion in Nsp2 and one amino acid deletion in GP3 were found in HB-2(sh)/2002. Therefore, HB-2(sh)/2002 was a novel strain with unique deletions.

5' Untranslated Regions↗
PubMed2006

Genomic structure, promoter analysis, and expression of the porcine (Sus scrofa) Mx1 gene.

Allelic polymorphisms at the mouse Mx1 locus affect the probability of survival after experimental influenzal disease, raising the possibility that marker-assisted selection using the homologous locus could improve the innate resistance of pigs to natural influenza infections. Several issues need to be resolved before efficient large scale screening of the allelic polymorphism at the porcine (Sus scrofa) Mx1 locus can be implemented. First, the Mx1 genomic structure has to be established and sufficient flanking intronic sequences have to be gathered to enable simple PCR amplification of the coding portions of the gene. Then, a basic knowledge of the promoter region needs to be obtained as an allelic variation there can significantly alter absolute levels and/or tissue-specificity of MX protein expression. The results gathered here show that the porcine Mx1 gene and promoter share the major structural and functional characteristics displayed by their homologs described in cattle, mouse, chicken, and man. The crucial function of the proximal interferon-sensitive response elements motif for gene expression is also demonstrated. The sequence data compiled here will allow an extensive analysis of the polymorphisms present among the widest spectrum possible of porcine breeds with the aim to identify an Mx1 allele providing antiviral resistance.

Amino Acid Sequence↗
PubMed1997

High-level genetic diversity in the vapD chromosomal region of Helicobacter pylori.

Helicobacter pylori isolates from different patients are characterized by diversity in the nucleotide sequences of individual genes, variation in genome size, and variation in gene order. Genetic diversity is particularly striking in vacuolating cytotoxin (vacA) alleles. In this study, five open reading frames (ORFs) were identified within a 4.2-kb region downstream from vacA in H. pylori 60190. One of these ORFs was closely related to the virulence-associated protein D (vapD) gene of Dichelobacter nodosus (64.9% nucleotide identity). A probe derived from vapD of H. pylori 60190 hybridized with only 19 (61.3%) of 31 H. pylori strains tested. Sequence analysis of the vapD region in vapD-negative H. pylori strains revealed that there were two different families of approximately 0.5-kb DNA segments, which were both unrelated to vapD. The presence of vapD was not associated with any specific family of vacA alleles. These findings are consistent with a recombinational population structure for H. pylori.

Alleles↗
PubMed1995

Intraspecific phylogeography of the gopher tortoise, Gopherus polyphemus: RFLP analysis of amplified mtDNA segments.

The slow rate of mtDNA evolution in turtles poses a limitation on the levels of intraspecific variation detectable by conventional restriction fragment surveys. We examined mtDNA variation in the gopher tortoise (Gopherus polyphemus) using an alternative restriction assay, one in which PCR-amplified segments of the mitochondrial genome were digested with tetranucleotide-site endonucleases. Restriction fragment polymorphisms representing four amplified regions were analysed to evaluate population genetic structure among 112 tortoises throughout the species' range. Thirty-six haplotypes were identified, and three major geographical assemblages (Eastern, Western, and Mid-Florida) were resolved by UPGMA and parsimony analyses. Eastern and Western assemblages abut near the Apalachicola drainage, whereas the Mid-Florida assemblage appears restricted to the Brooksville Ridge. The Eastern/Western assemblage boundary is remarkably congruent with phylogeographic profiles for eight additional species from the south-eastern U.S., representing both freshwater and terrestrial realms.

Animals↗
PubMed2002

Comparison of two aquatic alphaviruses, salmon pancreas disease virus and sleeping disease virus, by using genome sequence analysis, monoclonal reactivity, and cross-infection.

Cell culture isolates of salmon pancreas disease virus (SPDV) of farmed Atlantic salmon and sleeping disease virus (SDV) of rainbow trout were compared. Excluding the poly(A) tracts, the genomic nucleotide sequences of SPDV and SDV RNAs include 11,919 and 11,900 nucleotides, respectively. Phylogenetic analysis places SPDV and SDV between the New World viruses of Venezuelan equine encephalitis virus and Eastern equine encephalitis virus and the Old World viruses of Aura virus and Sindbis virus. When compared to each other, SPDV and SDV show 91.1% nucleotide sequence identity over their complete genomes, with 95 and 93.6% amino acid identities over their nonstructural and structural proteins, respectively. Notable differences between the two viruses include a 24-nucleotide insertion in the C terminus of nsP3 protein of SPDV and amino acid sequence variation at the C termini of the capsid and E1 proteins. Experimental infections of Atlantic salmon and rainbow trout with SPDV and SDV confirmed that the disease lesions induced by SPDV and SDV were similar in nature. Although infections with SPDV and SDV produced similar levels of histopathology in rainbow trout, SDV induced significantly less severe lesions in salmon than did SPDV. Virus neutralization tests performed with sera from experimentally infected salmon indicated that SPDV and SDV belonged to the same serotype; however, antigenic variation was detected among SDV and geographically different SPDV isolates by using monoclonal antibodies. Although SPDV and SDV exhibit minor biological differences, we conclude on the basis of the close genetic similarity that SPDV and SDV are closely related isolates of the same virus species for which the name Salmonid alphavirus is proposed.

Alphavirus↗