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PubMed2001

Guide to the draft human genome.

There are a number of ways to investigate the structure, function and evolution of the human genome. These include examining the morphology of normal and abnormal chromosomes, constructing maps of genomic landmarks, following the genetic transmission of phenotypes and DNA sequence variations, and characterizing thousands of individual genes. To this list we can now add the elucidation of the genomic DNA sequence, albeit at 'working draft' accuracy. The current challenge is to weave together these disparate types of data to produce the information infrastructure needed to support the next generation of biomedical research. Here we provide an overview of the different sources of information about the human genome and how modern information technology, in particular the internet, allows us to link them together.

Amino Acid Sequence↗
PubMed2004

Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks.

Hindlimb loss has evolved repeatedly in many different animals by means of molecular mechanisms that are still unknown. To determine the number and type of genetic changes underlying pelvic reduction in natural populations, we carried out genetic crosses between threespine stickleback fish with complete or missing pelvic structures. Genome-wide linkage mapping shows that pelvic reduction is controlled by one major and four minor chromosome regions. Pitx1 maps to the major chromosome region controlling most of the variation in pelvic size. Pelvic-reduced fish show the same left-right asymmetry seen in Pitx1 knockout mice, but do not show changes in Pitx1 protein sequence. Instead, pelvic-reduced sticklebacks show site-specific regulatory changes in Pitx1 expression, with reduced or absent expression in pelvic and caudal fin precursors. Regulatory mutations in major developmental control genes may provide a mechanism for generating rapid skeletal changes in natural populations, while preserving the essential roles of these genes in other processes.

Amino Acid Sequence↗
PubMed1999

Complete sequence of the 23-kilobase human COL9A3 gene. Detection of Gly-X-Y triplet deletions that represent neutral variants.

We report the complete sequence of the human COL9A3 gene that encodes the alpha3 chain of heterotrimeric type IX collagen, a member of the fibril-associated collagens with interrupted triple helices family of collagenous proteins. Nucleotide sequencing defined over 23,000 base pairs (bp) of the gene and about 3000 bp of the 5'-flanking sequences. The gene contains 32 exons. The domain and exon organization of the gene is almost identical to a related gene, the human COL9A2 gene. However, exon 2 of the COL9A3 gene codes for one -Gly-X-Y- triplet less than exon 2 of the COL9A2 gene. The difference is compensated by an insertion of 9 bp coding for an additional triplet in exon 4 of the COL9A3 gene. As a result, the number of -Gly-X-Y- repeats in the third collagenous domain remains the same in both genes and ensures the formation of an in-register triple helix. In the course of screening this gene for mutations, heterozygosity for separate 9-bp deletions within the COL1 domain were identified in two kindreds. In both instances, the deletions did not co-segregate with any disease phenotype, suggesting that they were neutral variants. In contrast, similar deletions in triple helical domain of type I collagen are lethal. To study whether alpha3(IX) chains with the deletion will participate in the formation of correctly folded heterotrimeric type IX collagen, we expressed mutant alpha3 chains together with normal alpha1 and alpha2 chains in insect cells. We show here that despite the deletion, mutant alpha3 chains were secreted as heterotrimeric, triple helical molecules consisting of three alpha chains in a 1:1:1 ratio. The results suggest that the next noncollagenous domain (NC2) is capable of correcting the alignment of the alpha chains, and this ensures the formation of an in-register triple helix.

Amino Acid Sequence↗
PubMed1992

Sequence of genome segment 9 of bluetongue virus (serotype 1, South Africa) and expression analysis demonstrating that different forms of VP6 are derived from initiation of protein synthesis at two distinct sites.

Bluetongue virus (BTV) VP6 is often resolved into two closely migrating bands by SDS-PAGE (VP6 and VP6a). RNA segment 9 of BTV-serotype 1 South Africa (encoding VP6) has been cloned as cDNA, and the complete sequence has been determined. Expression of this clone both in vitro and in tissue culture produced the same polypeptide doublet as seen previously in extracts from BTV-infected cells. Modification of the cDNA, including the removal of the first initiation codon, demonstrated that the two forms of VP6 are derived from initiation of protein synthesis at two distinct sites and not by post-translational modification.

Amino Acid Sequence↗
PubMed1995

I-CeuI recognition sites in the rrn operons of the Bacillus subtilis 168 chromosome: inherent landmarks for genome analysis.

The Bacillus subtilis 168 circular chromosome yielded ten fragments on I-CeuI endonuclease digestion. I-CeuI recognizes a 26 bp sequence that is located within the gene encoding the 23S subunit of the rRNA in Chlamydomonas eugametos, Escherichia coli and Salmonella typhimurium. The precise locations of the I-CeuI sites of the B. subtilis chromosome were determined on a NotI-SfiI physical map by (i) double digestion analyses with I-CeuI and SfiI, (ii) comparison of mutant strains lacking a specific rrn operon, (iii) using an I-CeuI linking clone and (iv) analysis of nucleotide sequence data of some rrn operons. In conclusion, all the I-CeuI sites were located within the B. subtilis rrn operons and the I-CeuI sites were conserved in all the B. subtilis 168 derivatives tested. Thus, variations in size of the I-CeuI fragments must be due to genome alterations. A B. subtilis 168 strain was investigated with I-CeuI. We demonstrated that the aberrant structure was the outcome of the inversion of an approximately 1700 kb DNA segment.

Bacillus subtilis↗
PubMed2005

Chromosome triplication found across the tribe Brassiceae.

We have used an approximately 8.7-Mb BAC contig of Arabidopsis thaliana Chromosome 4 to trace homeologous chromosome regions in 21 species of the family Brassicaceae. Homeologs of this segment could be identified in all tested species. Painting of pachytene chromosomes of Calepina, Conringia, and Sisymbrium species (2n = 14, 16), traditionally placed in tribe Brassiceae, showed one homeologous copy of the Arabidopsis contig, while the remaining taxa of the tribe (2n = 14-30) revealed three, and three Brassica species (2n = 34, 36, and 38) and Erucastrum gallicum (2n = 30) had six copies corresponding to the 8.7-Mb segment. The multiple homeologous copies corresponded structurally to the Arabidopsis segment or were rearranged by inversions and translocations within the diploidized genomes. These chromosome rearrangements accompanied by chromosome fusions/fissions led to the present-day chromosome number variation within the Brassiceae. Phylogenetic relationships based on the chloroplast 5'-trnL (UAA)-trnF(GAA) region and estimated divergence times based on sequence data of the chalcone synthase gene are congruent with comparative painting data and place Calepina, Conringia, and Sisymbrium outside the clade of Brassiceae species with triplicated genomes. Most likely, species containing three or six copy pairs descended from a common hexaploid ancestor with basic genomes similar to that of Arabidopsis. The presumed hexaploidization event occurred after the Arabidopsis-Brassiceae split, between 7.9 and 14.6 Mya.

Arabidopsis↗
PubMed2002

Human immunodeficiency viruses and drug therapy: resistance and implications for antiretroviral therapy.

Through a concerted effort to combat the human immunodeficiency virus (HIV) epidemic, researchers have made significant strides in molecular biology, virology, and immunology, which have resulted in an increased understanding of the complexities of this infection. The biggest obstacle to the success of current HIV therapy, however, is the emergence of viral resistance. Viral resistance is caused by mutations in the HIV-1 genome coding for structural changes in the target enzymes that can affect the binding or activity of the inhibitors. More information on the genetic basis of HIV resistance, mechanisms of viral variation, and therapeutic strategies for overcoming HIV resistance are needed. Sixty million people have been infected with HIV, 24 million have died, and it is projected that 200 million individuals will be infected by 2020.

Anti-HIV Agents↗
PubMed1999

Evolutionary relationships among seventeen human papillomavirus genotypes.

The DNA and the protein sequences of the six major open reading frames (ORFs) of 17 human papillomavirus (HPV) genotypes have been carefully aligned. Conserved primary and probable secondary structural features of the proteins have been identified. From the analysis of variations in the aligned positions, the most consistent evolutionary relationships have been reconstructed for each gene and for the genomes as a whole. The L1 gene encoding the major capsid protein and the E1 gene encoding a replication protein are the most conserved. The hinge region in E2 is the most divergent. With varying degrees of sequence relatedness, the major groups and subgroups of HPV genotypes can be recognized, these clusters: the mucosotrophic virus types (33, 58), (16, (31, 35)), (18, 39), (51), (6b, 11); mucosal/cutaneous transitional virus types (2a, 57); and the cutaneous virus types (47, (5, 8)), (1a), (41), closely reflect epithelial tissue-type predilections and clinical pathogenicities.

Amino Acid Sequence↗
PubMed2000

Complete genome sequence of Neisseria meningitidis serogroup B strain MC58.

The 2,272,351-base pair genome of Neisseria meningitidis strain MC58 (serogroup B), a causative agent of meningitis and septicemia, contains 2158 predicted coding regions, 1158 (53.7%) of which were assigned a biological role. Three major islands of horizontal DNA transfer were identified; two of these contain genes encoding proteins involved in pathogenicity, and the third island contains coding sequences only for hypothetical proteins. Insights into the commensal and virulence behavior of N. meningitidis can be gleaned from the genome, in which sequences for structural proteins of the pilus are clustered and several coding regions unique to serogroup B capsular polysaccharide synthesis can be identified. Finally, N. meningitidis contains more genes that undergo phase variation than any pathogen studied to date, a mechanism that controls their expression and contributes to the evasion of the host immune system.

Antigenic Variation↗
PubMed1990

Cis elements and trans-acting factors involved in the RNA dimerization of the human immunodeficiency virus HIV-1.

The retroviral genome consists of two identical RNA molecules joined at their 5' ends by the Dimer Linkage Structure (DLS). To study the mechanism of dimerization and the DLS of HIV-1 RNA, large amounts of bona fide HIV-1 RNA and of mutants have been synthesized in vitro. We report that HIV-1 RNA forms dimeric molecules and that viral nucleocapsid (NC) protein NCp15 greatly activates dimerization. Deletion mutagenesis in the RNA 5' 1333 nucleotides indicated that a small domain of 100 nucleotides, located between positions 311 to 415 from the 5' end, is necessary and sufficient to promote HIV-1 RNA dimerization. This dimerization domain encompasses an encapsidation element located between the 5' splice donor site and initiator AUG of gag and shows little sequence variations in different strains of HIV-1. Furthermore, cross-linking analysis of the interactions between NC and HIV-1 RNA (311 to 415) locates a major contact site in the encapsidation element of HIV-1 RNA. The genomic RNA dimer is tightly associated with nucleocapsid protein molecules in avian and murine retroviruses, and this ribonucleoprotein structure is believed to be the template for reverse transcription. Genomic RNA-protein interactions have been analyzed in human immunodeficiency virus (HIV) virions and results showed that NC protein molecules are tightly bound to the genomic RNA dimer. Since retroviral RNA dimerization and packaging appear to be under the control of the same cis element, the encapsidation sequences, and trans-acting factor, the NC protein, they are probably related events in the course of virion assembly.

Base Sequence↗
PubMed1987

Characterization of genotypic and phenotypic variation in plaque-purified strains of HzSNPV Elkar isolate.

Twenty plaque-purified strains of Heliothis zea S-type nuclear polyhedrosis virus (HzSNPV) were characterized based upon restriction endonuclease digests of viral DNAs, structural protein profiles, and larval melanization response. Each of the 20 strains had a unique genotype. Genomic heterogeneity between strains was localized to 4 regions of the HzSNPV genome. Differences in protein profiles of occluded virus were noted for each strain relative to the wild-type isolate. The strains were separated into 3 groups based upon differences in relative virulence and rate of larval melanization upon death. There was no correlation between differences in pathology and specific alterations in either genotype or structural proteins. The genotype of strain HzS-15 was extensively characterized. Physical maps were constructed for the HzS-15 strain and all of the plaque-purified strains.

Animals↗
PubMed2025

Genomic exploration of the journey of Plasmodium vivax in Latin America.

Plasmodium vivax is the predominant malaria parasite in Latin America. Its colonization history in the region is rich and complex, and is still highly debated, especially about its origin(s). Our study employed cutting-edge population genomic techniques to analyze whole genome variation from 620 P. vivax isolates, including 107 newly sequenced samples from West Africa, Middle East, and Latin America. This sampling represents nearly all potential source populations worldwide currently available. Analyses of the genetic structure, diversity, ancestry, coalescent-based inferences, including demographic scenario testing using Approximate Bayesian Computation, have revealed a more complex evolutionary history than previously envisioned. Indeed, our analyses suggest that the current American P. vivax populations predominantly stemmed from a now-extinct European lineage, with the potential contribution also from unsampled populations, most likely of West African origin. We also found evidence that P. vivax arrived in Latin America in multiple waves, initially during early European contact and later through post-colonial human migration waves in the late 19th-century. This study provides a fresh perspective on P. vivax's intricate evolutionary journey and brings insights into the possible contribution of West African P. vivax populations to the colonization history of Latin America.

Plasmodium vivax↗
PubMed2026

Strong phylogenetic signal from chloroplast genomes of three Barringtonia species provides the first genomic resources for their conservation.

BACKGROUND: The genus Barringtonia (Lecythidaceae) is a vital component of tropical coastal forests and mangrove ecosystems. Among its members, B. racemosa and B. fusicarpa are classified as Endangered and Vulnerable, respectively, due to habitat degradation and anthropogenic pressures, underscoring the urgent need for genetic studies to guide conservation. Chloroplast (cp.) genomes serve as essential resources for phylogenetic reconstruction and conservation genetics. However, the scarcity of cp. genome data for Barringtonia has limited comprehensive evolutionary and conservation-oriented investigations. RESULTS: We assembled and annotated the first complete cp. genomes of B. racemosa, B. fusicarpa, and B. acutangula. All three genomes exhibit the typical quadripartite structure, ranging from 158,959 bp (B. racemosa) to 159,837 bp (B. acutangula), and contain 132 genes (87 protein-coding, 37 tRNA, 8 rRNA) with a GC content of 36.68%-36.86%. Collinearity and IR boundary analyses revealed high structural conservation without large-scale rearrangements. Interspecific sequence-level variations were detected in simple sequence repeats (SSRs) and long repeats. Nucleotide diversity (π) analysis identified highly polymorphic regions, including rpl20 (π = 0.080), rpoA (π = 0.064), rps3 (π = 0.063), and ndhF (π = 0.060), which represent promising molecular markers for population genetics within the genus. Codon-based selection analyses (Ka/Ks) showed that all protein-coding genes are under strong purifying selection (mean Ka/Ks 0.32-0.37), with no evidence of positive selection. Pairwise genetic distances (p-distances) among Barringtonia species are extremely low (mean 0.0046), while distances to the related genus Bertholletia are ~ 6-fold higher, supporting their generic distinction. CONCLUSIONS: Phylogenetic analysis robustly supports Barringtonia as a monophyletic clade (bootstrap = 100%), with B. racemosa and B. fusicarpa forming a sister lineage to B. acutangula. This study provides the first high-quality cp. genome resources for the two threatened Barringtonia species, revealing strong structural and sequence conservation but no direct chloroplast genomic correlates of endangerment. The identified polymorphic regions and repeat markers lay a foundation for future population genetics, phylogeographic studies, and conservation-oriented genetic management of these ecologically important coastal plants.

Genome, Chloroplast↗
PubMed2006

Meningococcal genome dynamics.

Neisseria meningitidis (the meningococcus) is an important commensal, pathogen and model organism that faces up to the environment in its exclusive human host with a small but hyperdynamic genome. Compared with Escherichia coli, several DNA-repair genes are absent in N. meningitidis, whereas the gene products of others interact differently. Instead of responding to external stimuli, the meningococcus spontaneously produces a plethora of genetic variants. The frequent genomic alterations and polymorphisms have profound consequences for the interaction of this microorganism with its host, impacting structural and antigenic changes in crucial surface components that are relevant for adherence and invasion as well as antibiotic resistance and vaccine development.

Antigenic Variation↗
PubMed2003

Entropy-based SNP selection for genetic association studies.

Because of their abundance, density, and ease of practical use, single-nucleotide polymorphisms (SNPs) have become the major source of information for association gene mapping in humans. Sensible strategies for selecting practically useful SNPs are therefore required. Among the factors influencing the mapping utility of a given set of SNPs are (1). their individual diversity, (2). their haplotype structure in the population of interest, and (3). their physical distribution. We propose a strategy integrating these aspects into a single mapping utility measure, which is based upon Shannon entropy, and which maximizes the amount of information extracted from a genomic region under a Malecot model of linkage disequilibrium (LD) decay. The same utility measure has also been used to define a criterion guiding SNP discovery and rational decision-making about the continuation or termination of a mapping study. The proposed strategy performs consistently well in a data set comprising 549 German control individuals, genotyped for 136 SNPs from four genomic regions of different LD structure. Adoption of the method in practice is estimated to save up to 30% of genotyping load when compared with equidistant SNP localization or pair-wise LD minimization alone.

DNA↗
PubMed2000

A genetic mechanism for deletion of the ser2 gene cluster and formation of rough morphological variants of Mycobacterium avium.

A major phenotypic trait of the Mycobacterium avium complex is the ability to produce rough and smooth colony variants. The chemical basis of this morphological variation is the loss of an antigenic surface structure, termed glycopeptidolipid (GPL), by rough variants. Using M. avium serovar 2 strain 2151 as a model system, this laboratory previously reported that rough variants arise via the deletion of large genomic regions encoding GPL biosynthesis. One such deletion encompasses the gene cluster (ser2) responsible for production of the serovar 2 GPL haptenic oligosaccharide. In this study, nucleotide sequencing revealed that both ends of the ser2 gene cluster are flanked by a novel insertion sequence (IS1601) oriented as direct repeats. Detailed analyses of the site of deletion in the genome of M. avium 2151 Rg-1 demonstrated that a single copy of IS1601 remained and that the ser2 gene cluster was deleted by homologous recombination. This same deletion pattern was observed for 10 out of 15 rough colony variants tested. Additionally, these studies revealed that IS1601 contains portions of three independent insertion sequences. This report is the first to define the precise genetic basis of colony variation in Mycobacterium spp. and provides further evidence that homologous recombination between insertion sequence elements can be a primary determinant of genome plasticity in these bacteria.

DNA Transposable Elements↗
PubMed2000

[Quasispecies and molecular evolution of viruses].

Ribonucleic acid (RNA) viruses evolve as complex distributions of genetically different but closely related variants termed viral quasispecies. The precise genome of a quasispecies cannot be defined, since the consensus genome is an average of many variants. The dynamics of quasispecies has considerable implications for the understanding of the adaptability and pathogenic potential of viruses, and in addition, for the design of preventive and therapeutic measures for the diseases caused by these viruses. The authors summarise current knowledge on the structure of quasispecies, and the biological implications of this structure.

Adaptation, Biological↗
PubMed2006

Unintended consequences of plant transformation: a molecular insight.

Plant genomes are dynamic structures having both the system to maintain and accurately reproduce the information encoded therein and the ability to accept more or less random changes, which is one of the foundations of evolution. Crop improvement and various uncontrolled stress factors can induce unintended genetic and epigenetic variations. In this review it is attempted to summarize factors causing such changes and the molecular nature of these variations in transgenic plants. Unintended effects in transgenic plants can be divided into three main groups: first, pleiotropic effects of integrated DNA on the host plant genome; second, the influence of the integration site and transgene architecture on transgene expression level and stability; and third, the effect of various stresses related to tissue handling, regeneration and clonal propagation. Many of these factors are recently being redefined due to new researches, which apply modern highly sensitive analytical techniques and sequenced model organisms. The ability to inspect large portions of genomes clearly shows that tissue culture contributes to a vast majority of observed genetic and epigenetic changes. Nevertheless, monitoring of thousands transcripts, proteins and metabolites reveals that unintended variation most often falls in the range of natural differences between landraces or varieties. We expect that an increasing amount of evidence on many important crop species will support these observations in the nearest future.

Epigenesis, Genetic↗