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PubMed2003

Use of genetic distance as a measure of ongoing transmission of Mycobacterium tuberculosis.

The stability of the genotypic marker IS6110, used to define the epidemiology of Mycobacterium tuberculosis, is one of the most important factors influencing the interpretation of DNA fingerprint data. We propose that evolved strains should be considered together with clustered strains to represent chains of ongoing transmission. For the present study we used a large set of fingerprint data for strains collected between 1992 and 1998 from residents of a community with a high incidence of tuberculosis in Cape Town, South Africa. Interstrain genetic distances were calculated by counting the banding pattern mismatches in the IS6110 DNA fingerprints of different isolates. These data demonstrate that the propensity to change by one or two bands is independent of the IS6110 copy number. Hence, the genetic distance between pairs of isolates can be simply expressed as the number of differences in the banding patterns. From this foundation, a data set which identifies newly evolved strains has been generated. Inclusion of these evolved strains into various molecular epidemiological calculations significantly increased the estimate of ongoing transmission in this study setting. The indication is that nearly all cases of tuberculosis in this community are due to ongoing transmission. This has important implications for tuberculosis control, as it indicates that the control measures used at present are unable to reduce the level of transmission. This technique may also be applicable to the study of low-incidence tuberculosis outbreaks as well as the analysis of epidemiological data from other disease epidemics.

DNA Fingerprinting↗

PubMed2005

Cloning and molecular characterization of B-hordeins from Hordeum chilense (Roem. et Schult.).

One of the main limitations of cereal breeding is the lack of genetic variability within cultivated crops. Hordeum chilense is a wild relative of Hordeum vulgare, which has been successfully used in the synthesis of amphiploids by crossing with Triticum spp. Among the agronomic traits of these new amphiploids, the allelic variation in the endosperm storage proteins and their influence on breadmaking and malting quality are of special interest. B-hordeins are sulfur rich prolamins, which account for 70-80% of the total hordein fraction in barley. In this work, rapid amplification of cDNA ends by PCR (RACE-PCR) has been used for the cloning of the full-length open reading frame (ORF) of six sequences of B3-hordeins from two lines of H. chilense. Two consensus sequences of 813 and 822 bp for the H1 and H7 lines, respectively, were determined by alignment of all the sequences generated. Between both lines, differences involving single base changes, which could correspond to single nucleotide polymorphisms (SNP), insertions and deletions were observed. Of these differences, only six out of the 13 within the ORF caused a change of amino acid. Two insertions/deletions of 9 and 12 bp were also observed between both lines. The derived amino acid sequences showed a similar structure to the B-hordeins from cultivated barley and other prolamins. The repetitive region is based on the repetition of the motif PQQPFPQQ. The copy number of the B3-hordeins was estimated as a minimum of nine and five copies for the H1 and H7 lines, respectively. The expression profile of the B-hordeins through the developing endosperm is also described in this work. This study of the storage proteins of H. chilense is a useful contribution to the knowledge of the genetic diversity available in wild relatives of cultivated barley. In addition, the origin of the different prolamins can be better understood with an in-depth knowledge of its wild equivalent.

Amino Acid Motifs↗

PubMed1990

The subtelomeric Y' repeat family in Saccharomyces cerevisiae: an experimental system for repeated sequence evolution.

The subtelomeric Y' repeated sequence families in two divergent strains of the yeast Saccharomyces cerevisiae have been characterized in terms of copy number, location and restriction site differences. The strain YP1 has 26 to 30 Y's that fall into two previously described, long (6.7 kb) and short (5.2 kb), size classes. These Y's reside at 19 of the 32 chromosome ends and are concentrated in the higher molecular weight chromosomes. Five ends contain tandem arrays, each of which has only one size class of Y's. There is restriction site homogeneity among the Y's of YP1 even between size classes. The Y's of strain Y55 contrast sharply with the Y's of YP1 in terms of copy number, location and sequence differences. There are 14 to 16 Y's, both long and short, most of which are found at different chromosome ends than those of YP1. None of these are tandemly arrayed. Four to six of the Y's appear degenerate in that they have homology with a telomere distal end Y' probe but no homology with sequences at the telomere proximal end. The majority of the Y55 Y's have the same restriction sites as in YP1. Despite the conservation of restriction sites among Y's, a great deal of restriction fragment length heterogeneity between the strains is observed. The characterized Y' repeated sequence families provide an experimental system in which repeated sequence interactions and subsequent evolution can be studied.

Biological Evolution↗

PubMed1996

Two persistent LINE-1 lineages in Peromyscus have unequal rates of evolution.

LINE-1, the major family of long, interspersed repeats in the mammalian genome, moves via an RNA intermediate and encodes its own reverse transcriptase. Comparative sequence analysis was used to reconstruct the phylogenetic history of LINE-1 dynamics in the deer mouse, Peromyscus. As is the case in Mus and Rattus, a very small number of active templates produce the majority of LINE-1 copies in Peromyscus. However, in contrast to the single LINE-1 lineage seen in the muroid rodents, Peromyscus has at least two LINE-1 lineages whose most recent common ancestor probably existed before the peromyscine radiation. Species-specific variants of Lineage 1, and intact open reading frames in the youngest elements of both Lineages 1 and 2, suggest that both lineages have remained active within the same genome. The higher number of shared-sequence variants in Lineage 1 relative to Lineage 2 suggests that Lineage 1 has replaced its master template much more frequently than Lineage 2 or that the reverse transcriptase Lineage 1 is more error prone. The implications of the method used to acquire LINE-1 sequences for analysis are discussed.

Animals↗

PubMed2004

Microsatellite mapping of Mycobacterium leprae populations in infected humans.

To investigate genetic diversity in a bacterial population, we measured the copy numbers of simple sequence repeats, or microsatellites, in Mycobacterium leprae from patients living in and around Hyderabad, India. Three microsatellite loci containing trinucleotide or dinucleotide repeats were amplified from infected tissues, and the copy numbers were established by sequence analysis. Extensive diversity was observed in a cross-sectional survey of 33 patients, but closely related profiles were found for members of a multicase family likely to share a common transmission source. Sampling of multiple tissues from single individuals demonstrated identical microsatellite profiles in the skin, nasal cavity, and bloodstream but revealed differences at one or more loci for M. leprae present in nerves. Microsatellite mapping of M. leprae represents a useful tool for tracking short transmission chains. Comparison of skin and nerve lesions suggests that the evolution of disease within an individual involves the expansion of multiple distinct subpopulations of M. leprae.

Bacterial Typing Techniques↗

PubMed2005

Background and gender effects on survival in the TgN(SOD1-G93A)1Gur mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder. While most cases of ALS are sporadic, 10-15% are familial, and of these 15-20% possess a mutation in the gene that codes for the enzyme Cu/Zn superoxide dismutase (SOD1). In families of ALS patients with specific SOD1 mutations, affected members demonstrate significant heterogeneity of disease and a large variation in age of onset and severity, suggesting that there are genetic modifiers of disease expression. Transgenic mice expressing mutant forms of SOD1 demonstrate symptoms similar to those seen in patients with ALS. We have observed in our colony of G93A SOD1 transgenic mice a milder phenotype in mice in a C57BL/6J background than the C57BL/6JxSJL/J hybrid background used by Jackson Laboratories to maintain their colony. To investigate the effect of genetic background on phenotype, we have constructed congenic lines on two genetic backgrounds, C57BL/6J (B6) and SJL/J (SJL). We report the influence of background and gender on the survival of these congenic lines compared to the hybrid C57BL/6JxSJL/J background. The mean survival of G93A SOD1 mice in the hybrid B6/SJL background was 130 days, with females surviving significantly longer than males. When compared to the hybrid B6/SJL background, the survival of mice in the SJL background significantly decreased, and the gender difference in survival was maintained. On the other hand, mean survival in the B6 background significantly increased, and in contrast to the B6/SJL and SJL backgrounds, there was no difference in survival between males and females. Transgene copy numbers were verified in all animals to ensure that any phenotypic differences observed were not due to alterations in copy number. This is the first report of a shortened lifespan when the G93A SOD1 transgene is placed on the SJL/J background and an increased survival with the loss of gender influences when the transgene is placed on the C57BL/6J background.

Age Factors↗

PubMed2003

The insulin gene variable number tandem repeat class I/III polymorphism is in linkage disequilibrium with birth weight but not Type 2 diabetes in the Pima population.

The insulin gene variable number tandem repeat (INS-VNTR) is proposed to exert pleiotropic genetic effects on birth weight and diabetes susceptibility. In our study, we examined the influence of a polymorphism in tight linkage disequilibrium with INS-VNTR (-23Hph1) on birth weight and type 2 diabetes in the Pima population. A parent-offspring "trio" design was used to assess parent-of-origin effects and population stratification. The presence of the -23Hph1 T-allele was associated with lower birth weight (n = 192; -140 g per copy of the T-allele; P = 0.04), even after adjustment for effects of population stratification (P = 0.03). The effects of paternally transmitted T-alleles were greater than those of maternally transmitted alleles (paternally transmitted: -250 g, P = 0.05; maternally transmitted: -111 g, P = 0.43), but this difference was not statistically significant (P = 0.50). The -23Hph1 T-allele was associated with an increased prevalence of type 2 diabetes (P = 0.009), which family-based association analysis suggested was attributable to population structure (P = 0.04) without significant evidence of linkage disequilibrium between diabetes prevalence and genotype (P = 0.86). Thus allelic variation of the INS gene is associated with lower birth weight and increased prevalence of type 2 diabetes. Significant linkage disequilibrium was found between -23Hph1 and birth weight but not type 2 diabetes, an observation that supports a potential functional role of INS polymorphisms in the regulation of birth weight.

Adult↗

PubMed2004

Detection and physical mapping of the 18S-5.8S-26S rDNA and the pKFJ660 probe with microsatellite sequences derived from the rice blast fungus (Magnaporthe grisea) in conifer species.

Sequences homologous to the pKFJ660 probe, a fragment of DNA derived from the rice blast fungus (Magnaporthe grisea) carrying TC/AG repeat microsatellite sequences and 30 bp direct repeats were identified in the genome of Picea (spruce) and Pinus (pine) species by fluorescence in situ hybridization (FISH) and slot blot analyses. Slot blot analysis using the pKFJ660 probe revealed hybridization signals with genomic DNAs from various pine and spruce species. Further analyses indicated that the copy number of the (AG)30 motif was higher than 5 x 10(4) per plant genome for all plant samples tested, but the copy number of the sequences homologous to the whole pKFJ660 probe varies considerably among the 25 plant species tested. In situ hybridization of metaphase chromosomes from Pinus resinosa, P. banksiana and P. strobus showed the presence of sequences homologous to this probe on several chromosomes in a dispersed pattern. Major signals were observed on a few chromosomes indicating that some of these sequences are clustered in specific genomic locations. The locations of these repeats were compared to those of 18S-5.8S-26S rDNA in pine species. Chromosomal distribution of 18S-5.8S-26S rDNA varied among the three pine species (P. resinosa, P. banksiana and P. strobus) studied. Ribosomal DNA (rDNA) sites were identified on 14 to 20 chromosomes in these pine species.

Base Sequence↗

PubMed1994

Evidence for Darwinian selection of the 2-micron plasmid STB locus in Saccharomyces cerevisiae.

The 2-microns plasmid of industrial and laboratory strains of Saccharomyces cerevisiae exists as two main polymorphic forms designated type I and type II. Polymorphism is restricted to the 3200-bp right unique region where types I and II show approximately 10% nucleotide divergence in trans-acting REP1 and RAF loci and 30% divergence in the cis-acting STB locus. In addition, the cis-acting STB plasmid partition locus of type II plasmids varies in sequence and copy number of a 125-bp repeat. We devised chimeric and 2-microns plasmid stability experiments to evaluate the effect of STB polymorphism on plasmid fitness in amphiploid industrial and haploid laboratory strains. Reciprocal experiments of type-II STB chimeric plasmids in type-I bakers' yeast or a type-I chimeric plasmid in type-II distillers', wine, or haploid strains showed similar partition efficiencies. However, chimeric and 2-microns plasmids carrying a 250-bp STB from a type-II haploid strain had reduced fitness in a type-II industrial wine strain. These results in conjunction with molecular analyses of 2-microns-like and 2-microns plasmids indicates the coevolution of STB with trans-acting plasmid and host-cell factors.

Biological Evolution↗

PubMed2005

Evolutionary turnover of two pBuM satellite DNA subfamilies in the Drosophila buzzatii species cluster (repleta group): from alpha to alpha/beta arrays.

The pBuM satellite DNA family was studied in seven Drosophila species from the buzzatii cluster (within the large Drosophila repleta group). The pBuM repeats are slightly AT-rich and show high levels of intraspecific sequence homogeneity. The pBuM family can be divided into two subfamilies. The pBuM-1 subfamily consists of tandemly arranged repetition units of approximately 190 bp, termed alpha. Alpha repeats were found in a high copy number in the genome of D. buzzatii, D. serido and D. antonietae. The pBuM-2 subfamily consists of tandemly arranged repetition units of 370 bp. Its origin is explained by an insertion of an approximately 180 bp foreign sequence (termed beta) in an alpha basic repeat unit, with subsequent homogenization/amplification events increasing its frequency. Alpha/beta repeats were found in a high copy number in the genome of D. serido, D. antonietae, D. seriema and D. gouveai. pBuM sequences were not detected in D. koepferae and D. borborema by hybridization experiments. The nucleotide analysis of 74 pBuM repeats revealed that apart from the beta insertion event, the evolution of the pBuM family has proceeded in a gradual fashion, mainly through accumulation and horizontal spread of nucleotide substitutions. Moreover, the data also indicate a faster evolutionary rate for the pBuM-2 subfamily than the pBuM-1 subfamily. Members of both subfamilies display a greater intraspecific than interspecific homogeneity, indicating a concerted mode of pBuM evolution. A scenario to explain the evolution of both satDNA subfamilies in the seven Drosophila species from the buzzatii cluster is proposed.

Animals↗

PubMed1993

Characterization of new variants of a satellite DNA from Oryza officinalis, specific for the CC genome of wild rice.

Two groups of tandemly repeated DNA fragments have been isolated and cloned from the Oryza officinalis genome (W 1278). These fragments have been sequenced and are 374 and 367 bp long. They were compared with an element previously isolated from another O. officinalis accession. They are 76 and 92% homologous to the latter and show 78% homology between themselves. The two types of elements are interspersed within large blocks of tandemly organized units. Their copy number is in the range of 200,000 units. This sequence was present only in wild rice accessions with a CC genome. However, this apparent specificity is even more restricted, since it was absent from some O. officinalis accessions and from the allotetraploid species of the CCDD type. Use of digestions with 4-bp restriction enzyme cutters and analysis on denaturing polyacrylamide gels revealed polymorphism that might be used to map the repeats in the genome as well as to establish the relationship between accessions. Finally, hybridization of the repeated sequence to DNA prepared from the eight available O. sativa-O. officinalis monosomic addition lines revealed that the elements are located on two alien chromosomes. This suggests that these elements have at least some restricted chromosome specificity.

Base Sequence↗

PubMed1999

Assertive community treatment for people with severe mental illness: the effect on hospital use and costs.

OBJECTIVE: To determine the effect of the Program for Assertive Community Treatment (PACT) model on psychiatric inpatient service use in a population of non-emergency psychiatric patients with severe chronic mental illness, and to test for variations in this effect with program staffing levels and patient characteristics such as race and age. DATA SOURCES/STUDY SETTING: Data are taken from a randomized trial of PACT in Charleston, South Carolina for 144 patients recruited from August 1989 through July 1991. STUDY DESIGN: Subjects were randomly assigned either to one of two PACT programs or to usual care at a local mental health center. Effects on hospital use were measured over an 18-month follow-up period via multiple regression analysis. DATA COLLECTION METHODS: Data were obtained from Medicaid claims, chart reviews, subject, case manager, and family interviews; searches of the computerized patient and financial databases of the South Carolina Department of Mental Health and relevant hospitals; and searches of the hard copy and computerized financial databases of the two major local hospitals providing inpatient psychiatric care. PRINCIPAL FINDINGS: PACT participants were about 40 percent less likely to be hospitalized during the follow-up period. The effect was stronger for older patients. Lower PACT client/staff ratios also reduced the risk of hospitalization. No evidence of differential race effects was found. Given some hospital use, PACT did not influence the number of days of use. CONCLUSIONS: Controlling for other covariates, PACT significantly reduces hospitalizations but the size of this effect varies with patient and program characteristics. This study shows that previous results on PACT can be applied to non-emergency patients even when the control condition is an up-to-date CMHC office-based case management program.

Adult↗

PubMedDate not supplied

Mapping variation in chromosome homologues of different Giardia strains.

A landmark physical map of the 2-Mb chromosome of the Giardia duodenalis cloned line WB-1B, constructed using randomly cloned, chromosome specific markers, was used to compare the organisation and map order of the equivalent chromosome in other strains. A representative marker from each of the 13 NotI segments of the 2-Mb chromosome was hybridized to NotI cleavages of whole chromosomes of the other strains. Two strains, one isolated from a human, and one from a cat, had the same chromosome hybridization patterns as WB-1B. A strain isolated from a sheep, had one NotI chromosome 5 segment larger than WB-1B. Two additional strains isolated from a calf and a human had significantly different NotI cleavage patterns from the previous strains and shared no similar-sized chromosome NotI segment from their 2Mb chromosome homologues and only one in common with WB-1B. In one strain, two markers from the same WB-1B NotI segment did not hybridize suggesting deletion events have occurred. The order of some NotI segments within the 2Mb chromosome homologue was maintained, as determined from partial NotI chromosome cleavages, while in the most divergent of strains internal chromosome rearrangements and deletions were evident. All but one of the 2Mb WB-1B chromosome markers examined hybridized to a single chromosome band in all strains. Thus, while Giardia chromosomes vary in size, copy number and organisation, some linkage of markers is apparently maintained in isolates from disparate hosts and localities. We have therefore generated a genetic analysis system for Giardia with landmark maps using representative markers to replace the paucity of classical genetic markers and mutants. This approach is being extended to the complete genome.

Animals↗

PubMed2001

Transcriptional activity of multiple copies of a subtelomerically located olfactory receptor gene that is polymorphic in number and location.

We report here on the transcriptional activity of multiple copies of a subtelomerically located olfactory receptor (OR) gene, OR-A. Due to recent duplication events, both the copy number and chromosomal location of OR-A vary among humans. Sequence analyses of 180 copies of this gene, derived from 12 chromosome ends in 22 individuals, show that the main coding exon of all but one copy is an intact open reading frame with 0-5 predicted amino acid differences. We detected transcription of OR-A in both olfactory epithelium and testis tissue using RT-PCR amplification with primers designed on the basis of a computationally predicted gene structure. Two alternatively spliced forms of transcripts, one encoding an isoform with an extended N-terminus, were found in both tissues. A third transcript, derived from a second promoter, was also observed in testes. The start methionine is predicted in all transcripts to lie in an upstream exon rather than the main coding exon, as is typical for most other OR genes. By examining sequence variants among transcripts, we show that transcription of this gene occurs at multiple chromosomal locations. Our results lend credence to the idea that OR diversity could be generated in rearrangement-prone subtelomeric regions and show that polymorphism in subtelomeric regions could lead to individual-to-individual variation in the expressed repertoire of OR genes.

Alternative Splicing↗

PubMed2005

Natural antisense transcripts with coding capacity in Arabidopsis may have a regulatory role that is not linked to double-stranded RNA degradation.

BACKGROUND: Overlapping transcripts in antisense orientation have the potential to form double-stranded RNA (dsRNA), a substrate for a number of different RNA-modification pathways. One prominent route for dsRNA is its breakdown by Dicer enzyme complexes into small RNAs, a pathway that is widely exploited by RNA interference technology to inactivate defined genes in transgenic lines. The significance of this pathway for endogenous gene regulation remains unclear. RESULTS: We have examined transcription data for overlapping gene pairs in Arabidopsis thaliana. On the basis of an analysis of transcripts with coding regions, we find the majority of overlapping gene pairs to be convergently overlapping pairs (COPs), with the potential for dsRNA formation. In all tissues, COP transcripts are present at a higher frequency compared to the overall gene pool. The probability that both the sense and antisense copy of a COP are co-transcribed matches the theoretical value for coexpression under the assumption that the expression of one partner does not affect the expression of the other. Among COPs, we observe an over-representation of spliced (intron-containing) genes (90%) and of genes with alternatively spliced transcripts. For loci where antisense transcripts overlap with sense transcript introns, we also find a significant bias in favor of alternative splicing and variation of polyadenylation. CONCLUSION: The results argue against a predominant RNA degradation effect induced by dsRNA formation. Instead, our data support alternative roles for dsRNAs. They suggest that at least for a subgroup of COPs, antisense expression may induce alternative splicing or polyadenylation.

Alternative Splicing↗

PubMed1998

Molecular basis for the dominant white phenotype in the domestic pig.

The change of phenotypic traits in domestic animals and crops as a response to selective breeding mimics the much slower evolutionary change in natural populations. Here, we describe that the dominant white phenotype in domestic pigs is caused by two mutations in the KIT gene encoding the mast/stem cell growth factor receptor (MGF), one gene duplication associated with a partially dominant phenotype and a splice mutation in one of the copies leading to the fully dominant allele. The splice mutation is a G to A substitution in the first nucleotide of intron 17 and leads to skipping of exon 17. The duplication is most likely a regulatory mutation affecting KIT expression, whereas the splice mutation is expected to cause a receptor with impaired or absent tyrosine kinase activity. Immunocytochemistry showed that this variant form is expressed in 17- to 19-day-old pig embryos. Hundreds of millions of white pigs around the world are assumed to be heterozygous or homozygous for the two mutations. [The EMBL accession numbers for porcine KIT1*0101, KIT1*0202, KIT2*0202, and KIT2*0101 are AJ223228-AJ223231, respectively.]

Alternative Splicing↗

PubMed2000

Isolation of a new retrotransposon-like DNA sequence and its use in analysis of diversity within the Oryza officinalis complex.

To better understand the genetic diversity of the wild relatives of rice (Oryza sativa L.) in the O. officinalis species complex repetitive DNA markers were obtained from the diploid species of this complex. One cloned sequence from O. eichingeri gave intense hybridization signals with all species of the O. officinalis complex. This 242 bp clone, named pOe.49, has a copy number from 0.9 to 4.0 x 10(4) in diploid species of this complex. Analysis of the primary structure and database searches revealed homology of pOe.49 to a number of sequences representing part of the integrase coding domain of retroviruses and gypsy-like retrotransposons. Sequencing of specific PCR products confirmed that pOe.49 is part of a gypsy-like retrotransposon. RFLP analysis was used to study the genomic organisation of pOe.49 among 30 accessions of the O. officinalis complex using 10 restriction enzymes. Diversity analysis based on 120 polymorphic fragments obtained from the RFLP assay grouped the O. officinalis complex accessions by genome, species and eco-geographic groups. The results suggest that, with further characterization, this retrotransposon-like DNA sequence may be useful for phylogenetic analysis of species in the O. officinalis complex.

Amino Acid Sequence↗

PubMed1987

KP elements repress P-induced hybrid dysgenesis in Drosophila melanogaster.

Molecular and genetic analysis has revealed a specific P factor deletion derivative (the KP element) which is able to repress P-induced hybrid dysgenesis. All naturally occurring strains lacking the P cytotype (M') that were examined, throughout the world contain up to 30 copies of KP per haploid genome together with complete P factors. The KP element is derived from the P factor by an internal deletion of 1753 bp removing nucleotides 808-2560 and is transcribed to yield an abundant 0.8-kb poly(A)+ RNA with the coding capacity for an in-frame 207 amino acid polypeptide. Genetic crosses show that KP elements preferentially accumulate in the presence of P factors and suppress hybrid dysgenesis. Suppression is transmitted through both sexes and is thus distinct from the maternally transmitted P cytotype mode of suppression. The spread of KP elements is probably due to the continual selection of individuals with the highest numbers of KP elements in which P-induced hybrid dysgenesis is suppressed.

Animals↗