Biomedical subjects

Genomics

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PubMed2005

Wide-cross whole-genome radiation hybrid mapping of the cotton (Gossypium barbadense L.) genome.

Whole-genome radiation hybrid mapping has been applied extensively to human and certain animal species, but little to plants. We recently demonstrated an alternative mapping approach in cotton (Gossypium hirsutum L.), based on segmentation by 5-krad gamma-irradiation and derivation of wide-cross whole-genome radiation hybrids (WWRHs). However, limitations observed at the 5-krad level suggested that higher doses might be advantageous. Here, we describe the development of an improved second-generation WWRH panel after higher dose irradiation and compare the resulting map to the 5-krad map. The genome of G. hirsutum (n = 26) was used to rescue the radiation-segmented genome of G. barbadense (n = 26) introduced via 8- and 12-krad gamma-irradiated pollen. Viable seedlings were not recovered after 12-krad irradiation, but 8-krad irradiation permitted plant recovery and construction of a 92-member WWRH mapping panel. Assessment of 31 SSR marker loci from four chromosomes revealed that the 8-krad panel has a marker retention frequency of ca. 76%, which is approximately equivalent to the rate of loss in a low-dose animal radiation hybrid panel. Retention frequencies of loci did not depart significantly from independence when compared between the A and D subgenomes, or according to positions along individual chromosomes. WWRH maps of chromosomes 10 and 17 were generated by the maximum likelihood RHMAP program and the general retention model. The resulting maps bolster evidence that WWRH mapping complements traditional linkage mapping and works in cotton, and that the 8-krad panel complements the 5-krad panel by offering higher rates of chromosome breakages, lower marker retention frequency, and more retention patterns.

Chromosome Mapping↗

PubMed2005

Macro- and microcolinearity between the genomic region of wheat chromosome 5B containing the Tsn1 gene and the rice genome.

The Tsn1 gene in wheat confers sensitivity to a proteinaceous host-selective toxin (Ptr ToxA) produced by the tan spot fungus (Pyrenophora tritici-repentis) and lies within a gene-rich region of chromosome 5B. To use the rice genome sequence information for the map-based cloning of Tsn1, colinearity between the wheat genomic region containing Tsn1 and the rice genome was determined at the macro- and microlevels. Macrocolinearity was determined by testing 28 expressed sequence markers (ESMs) spanning a 25.5-cM segment and encompassing Tsn1 for similarity to rice sequences. Twelve ESMs had no similarity to rice sequences, and 16 had similarity to sequences on seven different rice chromosomes. Segments of colinearity with rice chromosomes 3 and 9 were identified, but frequent rearrangements and disruptions occurred. Microcolinearity was determined by testing the sequences of 26 putative genes identified from BAC contigs of 205 and 548 kb in length and flanking Tsn1 for similarity to rice genomic sequences. Fourteen of the predicted genes detected orthologous sequences on six different rice chromosomes, whereas the remaining 12 had no similarity with rice sequences. Four genes were colinear on rice chromosome 9, but multiple disruptions, rearrangements, and duplications were observed in wheat relative to rice. The data reported provide a detailed analysis of a region of wheat chromosome 5B that is highly rearranged relative to rice.

Ascomycota↗

PubMed1992

The Taiwanese hepatitis C virus genome: sequence determination and mapping the 5' termini of viral genomic and antigenomic RNA.

The complete nucleotide sequence of hepatitis C virus (HCV) cloned from the liver tissue of a Taiwanese patient with post-transfusion type C hepatitis was determined. The 5' end of HCV genomic RNA was located 341 nucleotides upstream from the initiation codon for the viral polyprotein open reading frame. The 5' end of the viral antigenomic RNA was shown to have 13 consecutive As. Thus the 3' terminus of the viral genome is a stretch of U which ends about 50 nucleotides downstream from the stop codon of the large open reading frame. The nucleotide sequence homology between this HCV strain and two Japanese isolates was 90.5 and 90.7%, respectively. Homology with the United States strain, however, was only 77.8%. Accordingly, the indigenous Taiwanese HCV strain is of the same subtype as the Japanese isolates. Novel features of the viral genome termini are possibly relevant to HCV genome replication.

Amino Acid Sequence↗

PubMed1992

Nucleotide sequence of the genome of the bacteriophage alpha 3: interrelationship of the genome structure and the gene products with those of the phages, phi X174, G4 and phi K.

The complete nucleotide sequence of the genome of the circular single-stranded DNA (isometric) phage alpha 3 has been determined and compared with that of the related phages phi X174 and G4. The alpha 3 genome consists of 6087 nucleotides, which is 701 nucleotides longer than the nucleotide sequence of the phi X174 genome and 510 nucleotides more than that of the G4 genome. The results demonstrated that the three phage species have 11 homologous genes (A, A*, B, C, K, D, E, J, F, G and H), the order of which is fundamentally identical, suggesting that they have evolved from a common ancestor. The sequence of some genes and untranslated intergenic regions, however, differs significantly from phage to phage: for example, the degree of amino acid sequence homology of the gene product is averaged at 47.7% between alpha 3 and phi X174 and 46.9% between alpha 3 and G4, and alpha 3 has a remarkable longer intergenic region composed of 758 nucleotides between the genes H and A compared with the counterparts of phi X174 and G4. Meanwhile, in vivo experiments of genetic complementation showed that alpha 3 can use none of the gene products of phi X174 and G4, whereas the related phage phi K can rescue alpha 3 nonsense mutants of the genes B, C, D and J. These sequencing and in vivo rescue results indicated that alpha 3 is closely related to phi K, but distantly remote from phi X174 or G4, and supported an evolutional hypothesis which has been so far proposed that the isometric phages are classified into three main groups: the generic representatives are phi X174, G4 and alpha 3.

Amino Acid Sequence↗

PubMed1993

Possible relation between the U54 segment of the CTHV genome and the conserved gene block C rearranged in alpha and gamma herpesvirus genomes.

The genome of CTHV is an atypical member of the gamma-2 subgroup of herpesvirus genomes that contains two segments (instead of one) of DNA with low G+C content flanked by highly repetitious DNA with high G+C content. The segments freely undergo polarity inversion with respect to one another. We have found nucleotide sequences in one of these segments, the U54 segment, whose putative translational products show clear similarity to two ubiquitous herpesvirus gene products, a single-stranded DNA binding protein and a protein of the helicase superfamily. These sequences are located within 5 kilobase pairs of the ends of the segment, suggesting that U54 may be related to a genetically defined entity (gene block C; Davison and Taylor (1987) J. Gen Virol. 68, 36-48) issuing from a previous sequence comparison of the gamma-1 genome of Epstein-Barr virus and the alpha genome of varicella-zoster virus.

Alphaherpesvirinae↗

PubMed2005

Genomic changes identified by comparative genomic hybridisation in docetaxel-resistant breast cancer cell lines.

Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. In this study high-level, docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) were created, and comparative genomic hybridisation was used to identify genomic regions associated with resistance to docetaxel. MCF-7 resistant cells showed an amplification of chromosomes 7q21.11-q22.1, 17q23-q24.3, 18, and deletion of chromosomes 6p, 10q11.2-qter and 12p. MDA-MB-231 resistant cells showed a gain of chromosomes 5p, 7q11.1-q35, 9, and loss of chromosomes 4, 8q24.1-qter, 10, 11q23.1-qter, 12q15-q24.31, 14q and 18. Whole chromosome paints confirmed these findings. Amplification of 7q21 and loss of 10q may represent a common mechanism of acquired docetaxel resistance in breast cancer cells. This study is the first description of a genomic approach specifically to identify genomic regions involved in resistance to docetaxel.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Lessons from a small, dispensable genome: the mitochondrial genome of yeast.

This article reviews the investigations on the mitochondrial genomes of yeast carried out in the author's laboratory during a quarter of a century (to be precise between 1966 and 1992). Our studies dealt with the structural basis for the cytoplasmic petite mutation, the replication, the transcription and the recombination of the mitochondrial genome, a genome which is dispensable and which comprises abundant non-coding sequences. This work led to some general conclusions on the nuclear genome of eukaryotes. Some recent results in apparent contradiction with our conclusions on ori sequences will also be briefly discussed.

Base Sequence↗

PubMed2006

Mapping Drosophila genomic aberration breakpoints with comparative genome hybridization on microarrays.

Chromosomal aberrations are genetic "reagents" that are commonly used in Drosophila research. Stocks containing chromosomes carrying large deletions of DNA (deficiency stocks, designated Df) as well as stocks carrying an extra copy of a chromosomal region (duplication stocks, designated Dp) are essential for a variety of genetic analyses. The extent of what is deleted or duplicated has typically been determined cytologically by salivary gland polytene chromosome squashes, which identify the edges of the aberration (so-called breakpoints) of each Df or Dp at low resolution. The margin of error for this technique can be quite high, however, because it is dependent on the quality of the squash and the experience of the scientist interpreting the data. Comparative genome hybridization on microarrays provides a precise molecular method to identify which regions of the genome are deleted or duplicated in these stocks by examining a change in chromosomal ploidy across the whole genome. Furthermore, this technique allows genetic data obtained with these strains to be placed in a molecular genomic context.

Animals↗

PubMed2001

Characterization of a minimal screening set of 172 microsatellite markers for genome-wide screens of the canine genome.

We have characterized a subset of 172 microsatellite markers from the canine map, termed 'Minimal Screening Set 1' (Canine MSS-1), which we propose be used for initial genome-wide genetic linkage studies. Three hierarchical criteria were used to select markers from the current meiotic linkage and radiation hybrid maps for MSS-1. Markers were selected that (1) provided as complete coverage as possible of the canine genome, (2) were highly informative, and (3) have been ordered in linkage groups with a high degree of statistical support. This resulting screening set spans all reported meiotic linkage and RH groups, leaving only 10 known gaps > or = 20 cM. The average polymorphic information content (PIC) value of markers tested is 0.74. Coverage estimates suggest 42% of the genome is within 5 cM of at least one marker in the minimal screening set, 77% of the genome is within 10 cM. This minimal mapping set therefore provides an efficient and cost effective way to begin screening pedigrees of interest for genetic linkage.

Animals↗

PubMed2000

Progress in Arabidopsis genome sequencing and functional genomics.

Arabidopsis thaliana has a relatively small genome of approximately 130 Mb containing about 10% repetitive DNA. Genome sequencing studies reveal a gene-rich genome, predicted to contain approximately 25000 genes spaced on average every 4.5 kb. Between 10 to 20% of the predicted genes occur as clusters of related genes, indicating that local sequence duplication and subsequent divergence generates a significant proportion of gene families. In addition to gene families, repetitive sequences comprise individual and small clusters of two to three retroelements and other classes of smaller repeats. The clustering of highly repetitive elements is a striking feature of the A. thaliana genome emerging from sequence and other analyses.

Agriculture↗

PubMed2004

Genomic and non-genomic effects of glucocorticoids on aggressive behavior in male rats.

An increasing body of evidence suggests that glucocorticoids--besides their well-known genomic effects--can affect neuronal function via mechanisms that do not involve the genome. Data obtained mainly in amphibians and birds suggest that such mechanisms play a role in the control of behavior. Acute glucocorticoid treatments increase aggressive behavior in rats, but the mechanism of action has not been investigated to date. To clarify the issue, we have assessed the aggressiveness of male rats after treating them with the corticosterone synthesis inhibitor metyrapone, corticosterone, and the protein synthesis inhibitor cycloheximide. Metyrapone applied intraperitoneally (i.p.) decreased the aggressiveness of residents faced with smaller opponents. Corticosterone administered i.p. 20 or 2 min before a 5-min encounter abolished these changes irrespective of the delay of behavioral testing. Thus, the effects of glucocorticoids on aggressive behavior occurred in less than 7 min (the delay and duration of testing taken together), and lasted more than 25 min. Corticosterone applied centrally (infused into the right lateral ventricle) also stimulated aggressive behavior rapidly, which shows that the effect was centrally mediated. The protein synthesis inhibitor cycloheximide did not affect the aggression-promoting effects of corticosterone when the hormone was injected 2 min before the aggressive encounter. Surprisingly, however, the effects were completely abolished when the hormone was injected 20 min before the encounter. These data suggest that glucocorticoids rapidly increase aggressive behavior via non-genomic mechanisms. In later phases of the aggressive encounter, aggressive behavior appears to be stimulated by genomic mechanisms.

Aggression↗

PubMed2000

Densities, length proportions, and other distributional features of repetitive sequences in the human genome estimated from 430 megabases of genomic sequence.

The densities of repetitive elements in the human genome were calculated in each GC content class using non-overlapping windows of 50kb. The density of Alu is two to three times higher in GC-rich regions than in AT-rich regions, while the opposite is true for LINE1. In contrast, LINE2 and other elements, such as DNA transposons, are more uniformly distributed in the genome. The number of Alus in the human genome was estimated to be 1.4 million, higher than previous estimates. About 40% of the autosomes and approximately 51% of the X and Y chromosomes are occupied by repetitive elements. In total, the human genome is estimated to contain more than 4 million repetitive elements. The GC contents (%) of repetitive elements and their flanking regions were also calculated. The GC contents of almost all kinds of repeats are positively correlated with the window GC contents, suggesting that a repetitive sequence is subject to the same mutation pressure as its surrounding regions, so it tends to have the same GC content as its surrounding regions. This observation supports the regional mutation hypothesis. The only two exceptions are AluYa and AluYb8, the two youngest Alu subfamilies. The GC content of AluYb8 is negatively correlated with that of its surrounding regions, while AluYa shows no correlation, suggesting different insertion patterns for these two young Alu subfamilies. This suggestion was supported by the fact that the average genetic distance between members of AluYb8 in each GC window class is positively correlated with the GC content of the window, but no correlation was found for AluYa. AluYa is more frequent in Y chromosome than in other chromosomes; the same is true for LTR retroviruses. This pattern might be correlated with the evolutionary history of Y chromosome.

Alu Elements↗

PubMed2002

Two-dimensional display and whole genome comparison of bacterial pathogen genomes of high G+C DNA content.

High-resolution comparison of bacterial genomes facilitates the identification of the genetic changes responsible for clinically relevant phenotypes. For this purpose we have established a method for the display and comparison of high G+C bacterial genomes in two dimensions. Here we describe the application of two-dimensional bacterial genomic display to resolve the genomes of Bordetella pertussis, Mycobacterium avium and Mycobacterium tuberculosis, and its utility in strain comparison and detection of insertion and substitution mutations.

Bacteria↗

PubMed2002

The Brucella genome at the beginning of the post-genomic era.

The year 2002 began with the publication of the first complete genome sequence for a Brucella species, that of the two replicons of B. melitensis 16M. Hopefully in 2002, the complete genome of B. suis 1330, and, perhaps, a B. abortus strain will be published. This is the culmination of over 30 years investigation of the composition, structure, organisation and evolution of the Brucella genome. Brucella research must now adapt to the new challenges of the post-genomic era.

Brucella↗

PubMed2003

Multiple mechanisms control brain aromatase activity at the genomic and non-genomic level.

Evidence has recently accumulated indicating that aromatase activity in the preoptic area is modulated in parallel by both slow (hours to days) genomic and rapid (minutes to hours) non-genomic mechanisms. We review here these two types of control mechanisms and their potential contribution to various aspects of brain physiology in quail. High levels of aromatase mRNA, protein and activity (AA) are present in the preoptic area of this species where the transcription of aromatase is controlled mainly by steroids. Estrogens acting in synergy with androgens play a key role in this control and both androgen and estrogen receptors (ER; alpha and beta subtypes) are present in the preoptic area even if they are not necessarily co-localized in the same cells as aromatase. Steroids have more pronounced effects on aromatase transcription in males than in females and this sex difference could be caused, in part, by a sexually differentiated expression of the steroid receptor coactivator 1 in this area. The changes in aromatase concentration presumably control seasonal variations as well as sex differences in brain estrogen production. Aromatase activity in hypothalamic homogenates is also rapidly (within minutes) down-regulated by exposure to conditions that enhance protein phosphorylation such as the presence of high concentrations of calcium, magnesium and ATP. Similarly, pharmacological manipulations such as treatment with thapsigargin or stimulation of various neurotransmitter receptors (alpha-amino-3-hydroxy-methyl-4-isoxazole propionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA)) leading to enhanced intracellular calcium concentrations depress within minutes the aromatase activity measured in quail preoptic explants. The effects of receptor stimulation are presumably direct: electrophysiological data confirm the presence of these receptors in the membrane of aromatase-expressing cells. Inhibitors of protein kinases interfere with these processes and Western blotting experiments on brain aromatase purified by immunoprecipitation confirm that the phosphorylations regulating aromatase activity directly affect the enzyme rather than another regulatory protein. Accordingly, several phosphorylation consensus sites are present on the deduced amino acid sequence of the recently cloned quail aromatase. Fast changes in the local availability of estrogens in the brain can thus be caused by aromatase phosphorylation so that estrogen could rapidly regulate neuronal physiology and behavior. The rapid as well as slower processes of local estrogen production in the brain thus match well with the genomic and non-genomic actions of steroids in the brain. These two processes potentially provide sufficient temporal variation in the bio-availability of estrogens to support the entire range of established effects for this steroid.

Amino Acid Sequence↗

PubMed2000

International Rice Genome Sequencing Project: the effort to completely sequence the rice genome.

The International Rice Genome Sequencing Project (IRGSP) involves researchers from ten countries who are working to completely and accurately sequence the rice genome within a short period. Sequencing uses a map-based clone-by-clone shotgun strategy; shared bacterial artificial chromosome/P1-derived artificial chromosome libraries have been constructed from Oryza sativa ssp. japonica variety 'Nipponbare'. End-sequencing, fingerprinting and marker-aided PCR screening are being used to make sequence-ready contigs. Annotated sequences are immediately released for public use and are made available with supplemental information at each IRGSP member's website. The IRGSP works to promote the development of rice and cereal genomics in addition to producing genome sequence data.

Chromosome Mapping↗

PubMed2001

A powerful and rapid approach to human genome scanning using small quantities of genomic DNA.

Dense maps of short-tandem-repeat polymorphisms (STRPs) have allowed genome-wide searches for genes involved in a great variety of diseases with genetic influences, including common complex diseases. Generally for this purpose, marker sets with a 10 cM spacing are genotyped in hundreds of individuals. We have performed power simulations to estimate the maximum possible intermarker distance that still allows for sufficient power. In this paper we further report on modifications of previously published protocols, resulting in a powerful screening set containing 229 STRPs with an average spacing of 18.3 cM. A complete genome scan using our protocol requires only 80 multiplex PCR reactions which are all carried out using one set of conditions and which do not contain overlapping marker allele sizes. The multiplex PCR reactions are grouped by sets of chromosomes, which enables on-line statistical analysis of a set of chromosomes, as sets of chromosomes are being genotyped. A genome scan following this modified protocol can be performed using a maximum amount of 2.5 micrograms of genomic DNA per individual, isolated from either blood or from mouth swabs.

Alleles↗

PubMed2002

The genome factor in region-specific DNA damage: the DNA-reactive drug U-78779 prefers mixed A/T-G/C sequences at the nucleotide level but is region-specific for long pure AT islands at the genomic level.

Bizelesin is the first anticancer drug capable of damaging specific regions of the genome with clusters of its binding sites T(A/T)(4)A. This study characterized the sequence- and region-specificity of a bizelesin analogue, U-78779, designed to interact with mixed A/T-G/C motifs. At the nucleotide level, U-78779 was found to prefer runs of A/Ts interspersed with 1 or 2 G/C pairs, although 25% of the identified sites corresponded to pure AT motifs similar to bizelesin sites. The in silico computational analysis showed that the preferred mixed A/T-G/C motifs distribute uniformly at the genomic level. In contrast, the secondary, pure AT motifs (A/T)(6)A were found densely clustered in the same long islands of AT-rich DNA that bizelesin targets. Mapping the sites and quantitating the frequencies of U-78779 adducts in model AT island and non-AT island naked DNAs demonstrated that clusters of pure AT motifs outcompete isolated mixed A/T-G/C sites in attracting drug binding. Regional preference of U-78779 for AT island domains was verified also in DNA from drug-treated cells. Thus, while the primary sequence preference gives rise to non-region-specific scattered lesions, the clustering of the minor pure AT binding motifs seems to determine region-specificity of U-78779 in the human genome. The closely correlated cytotoxic activities of U-78779 and bizelesin in several cell lines further imply that both drugs may share common cellular targets. This study underscores the significance of the genome factor in a drug's potential for region-specific DNA damage, by showing that it can take precedence over drug binding preferences at the nucleotide level.

Adenine Nucleotides↗