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PubMed2005

Coordination of bowing and fingering in violin playing.

Playing string instruments implies motor skills including asymmetrical interlimb coordination. How special is musical skill as compared to other bimanually coordinated, non-musical skillful performances? We succeeded for the first time to measure quantitatively bimanual coordination in violinists playing repeatedly a simple tone sequence. A motion analysis system was used to record finger and bow trajectories for assessing the temporal structure of finger-press, finger-lift (left hand), and bow stroke reversals (right arm). The main results were: (1) fingering consisted of serial and parallel (anticipatory) mechanisms; (2) synchronization between finger and bow actions varied from -12 ms to 60 ms, but these 'errors' were not perceived. The results suggest that (1) bow-finger synchronization varied by about 50 ms from perfect simultaneity, but without impairing auditory perception; (2) the temporal structure depends on a number of combinatorial mechanisms of bowing and fingering. These basic mechanisms were observed in all players, including all amateurs. The successful biomechanical measures of fingering and bowing open a vast practical field of assessing motor skills. Thus, objective assessment of larger groups of string players with varying musical proficiency, or of professional string players developing movement disorders, may be helpful in music education.

Adult↗

PubMed2006

Instability of expanded simple tandem repeats is induced in cell culture by a variety of agents: N-Nitroso-N-ethylurea, benzo(a)pyrene, etoposide and okadaic acid.

Expanded simple tandem repeat (ESTR) sequences have proven useful biomarkers to detect genotoxicity in vivo. Their high sensitivity has been used to assess environmentally relevant doses of mutagens such as ionizing radiation, DNA alkylating agents and airborne particulate pollution, for germline mutations in mouse assays. The mutagenic response involves size alteration of these ESTR loci induced by agents causing a variety of cellular damage. The mechanistic aspects of this induced instability remain unclear and have not been studied in detail. Mechanistic knowledge is important to help understand the relevance of increased ESTR mutation frequencies. In this study, we applied a murine cell culture system to examine induced response to four agents exhibiting different modes of toxic action including: N-nitroso-N-ethylurea (ENU), benzo(a)pyrene (BaP), okadaic acid and etoposide at slightly sub-toxic levels. We used single-molecule-polymerase chain reaction (SM-PCR) to assess the relative mutant frequency after 4-week chemical treatments at the Ms6-hm ESTR sequence of cultured C3H/10T1/2 cells (a mouse embryonic cell line). Increased mutation was observed with both 0.64 mM ENU (1.95-fold increase, P<0.0001), 1 microM benzo(a)pyrene (1.87-fold increase, P=0.0006) and 3 nM etoposide (1.89-fold increase, P=0.0003). The putative ESTR mutagen okadaic acid (1.27-fold increase, P=0.2289), administered at 0.5 nM, did not affect the C3H/10T1/2 Ms6-hm locus. Therefore, agents inducing small and bulky adducts, and indirectly causing strand breaks through inhibition of topoisomerase, caused similar induction of instability at an ESTR locus at matched toxicities. As size spectra for induced mutations were identical, the data indicate that although these chemicals exhibit distinct modes of action, a similar indirect process is influencing ESTR instability. In contrast, a potent tumour promoter that is a kinase inhibitor does not contribute to induced ESTR instability in cell culture.

Animals↗

PubMed1998

Analysis of a variant surface glycoprotein gene expression site promoter of Trypanosoma brucei by remodelling the promoter region.

Trypanosoma brucei survives in the mammalian bloodstream by antigenic variation of its variant surface glycoprotein (VSG) coat. VSG genes are found in telomeric expression sites (ESs), and only one ES is fully transcribed at a time. The parasite changes its coat by either bringing another VSG gene into the active ES, or by switching on another ES and silencing the first. It has previously been shown that the promoter of an active ES can be replaced by a ribosomal promoter without affecting the function of the ES. This study has now analysed the conserved sequences flanking the ES promoter by deletion or replacement of these sequences in intact trypanosomes. The results show that the sequences 3' of the promoter and extending down to the first protein-coding gene, ESAG 7, are not required in the bloodstream-form parasite either for high-level transcription or for switching of the ES. Transformants in which the sequences 5' of the promoter extending up to simple-sequence 50-bp repeats had been removed were not obtained unless the 5' ES sequences were replaced with exogenous DNA, or unless the ES promoter was replaced by a ribosomal promoter, and even these transformants were rare. Transformants lacking the 5' ES sequences displayed a less complete transcriptional repression of silent ESs. These results indicate that the area 5' of an ES promoter is required for optimal functioning of an ES.

Animals↗

PubMed2000

Genomic instability in multistage carcinogenesis.

For a normal cell to accumulate multiple genetic changes during multistage carcinogenesis, the induction of genomic instability is considered advantageous. Since most human cancers are associated with exposure to environmental carcinogens, it is likely that environmental carcinogens interact with genomic instability. Our results indeed suggest that carcinogens contribute to the induction of microsatellite instability and induce more mutations in those cells which show microsatellite instability. We have recently developed a sensitive method to clearly detect changes in simple repeats of coding sequences of cancer genes and the results suggest that such sequences of different genes are mutated in different tumors.

Animals↗

PubMed1998

Hybrid oligomer duplexes formed with phosphorothioate DNAs: CD spectra and melting temperatures of S-DNA.RNA hybrids are sequence-dependent but consistent with similar heteronomous conformations.

Knowledge of the relative stabilities of S-DNA.RNA hybrids of different sequences is important for choosing RNA targets for hybridization with antisense phosphorothioate oligodeoxyribonucleotides (S-DNAs). It is also important to know how hybrid secondary structure varies with sequence, since different structures could influence thermal stability and the activity of RNase H. Our approach has been to study relatively simple sequences consisting of repeating di-, tri-, and tetranucleotides, which allow the maximum resolution of nearest-neighbor effects. Circular dichroism (CD) spectra and melting temperatures were acquired for 16 hybrid sequences that could be formed by mixing S-DNA and RNA oligomers of 24 nucleotides in length. CD spectra of S-DNA.RNA hybrids were sequence-dependent and were similar to those of analogous unmodified hybrids. From singular value decomposition, the major CD spectral component was like that of the A-conformation. Three nearest-neighbor relationships among the hybrid CD spectra were in as good agreement as are such relationships among spectra of duplex RNAs. Tm values ranged from 44.1 degrees C for S-d(ACT)8. r(AGU)8 to 66.6 degrees C for S-d(CCT)8.r(AGG)8 (in 0.15 M K+, phosphate buffer, pH 7). The S-DNA.RNA hybrids had a sequence-dependence of melting temperatures that was approximately the same as that calculated using published data for normal DNA.RNA hybrids [Sugimoto, N., Nakano, S., Katoh, M., Matsumura, A., Nakamuta, H., Ohmichi, T.,Yoneyama, M., & Sasaki, M. (1995) Biochemistry 34, 11211-11216]. In general, sequence-dependent CD spectra and Tm values of S-DNA.RNA hybrids appear to reflect the unique nearest-neighbor interactions of adjacent base pairs, where the S-DNA and RNA strands are in different, but relatively uniform, conformations.

Base Composition↗

PubMed2002

Transposable elements and the evolution of genome size in eukaryotes.

It is generally accepted that the wide variation in genome size observed among eukaryotic species is more closely correlated with the amount of repetitive DNA than with the number of coding genes. Major types of repetitive DNA include transposable elements, satellite DNAs, simple sequences and tandem repeats, but reliable estimates of the relative contributions of these various types to total genome size have been hard to obtain. With the advent of genome sequencing, such information is starting to become available, but no firm conclusions can yet be made from the limited data currently available. Here, the ways in which transposable elements contribute both directly and indirectly to genome size variation are explored. Limited evidence is provided to support the existence of an approximately linear relationship between total transposable element DNA and genome size. Copy numbers per family are low and globally constrained in small genomes, but vary widely in large genomes. Thus, the partial release of transposable element copy number constraints appears to be a major characteristic of large genomes.

DNA Transposable Elements↗

PubMed2003

Distinct macroscopic structures developed from solutions of chemical compounds and periodic proteins.

By controlling the growth of inorganic crystals, macro-biomolecules, including proteins, play pivotal roles in modulating biomineralization. Natural proteins that promote biomineralization are often composed of simple repeats of peptide sequences; however, the relationship between these repetitive structures and their functions remains largely unknown. Here we show that an artificial protein containing a repeated peptide sequence allows NaCl, KCl, CuSO(4) and sucrose to form a variety of macroscopic structures, as represented by their dendritic configurations. Mutational analyses revealed that the physicochemical characteristics of the protein, not the peptide sequence per se, were responsible for formation of the dendritic structures. This suggests that proteins that modulate crystal growth may have evolved as repeat-containing forms at a relatively high rate. These observations could serve as the basis for developing new genetic programming systems for creation of artificial proteins able to modulate crystal growth from inorganic compounds, and may thus provide a new tool for nano-biotechnology.

Crystallization↗

PubMed1998

Polymorphic microsatellite markers for population analysis of a tephritid pest species, Bactrocera tryoni.

To obtain a set of microsatellite markers for the Queensland fruit fly Bactrocera tryoni, a genomic library was screened with a number of simple repeat oligonucleotide probes. Sequencing recovered 22 repeat loci. The microsatellite sequences were short, with repeat numbers ranging from five to 11. Of these, 16 polymerase chain reaction (PCR) primer sets yielded amplifiable products, which were tested on 53 flies from five widely separated sites. All loci showed polymorphism in the population sample, with the number of alleles ranging from two to 16. Several dinucleotide repeats showed alleles separated by single-base differences and multiple steps, suggesting a mutation process more complex than the stepwise mutation model.

Alleles↗

PubMed1998

Computerized polymorphic marker identification: experimental validation and a predicted human polymorphism catalog.

A computational system for the prediction of polymorphic loci directly and efficiently from human genomic sequence was developed and verified. A suite of programs, collectively called POMPOUS (polymorphic marker prediction of ubiquitous simple sequences) detects tandem repeats ranging from dinucleotides up to 250 mers, scores them according to predicted level of polymorphism, and designs appropriate flanking primers for PCR amplification. This approach was validated on an approximately 750-kilobase region of human chromosome 3p21.3, involved in lung and breast carcinoma homozygous deletions. Target DNA from 36 paired B lymphoblastoid and lung cancer lines was amplified and allelotyped for 33 loci predicted by POMPOUS to be variable in repeat size. We found that among those 36 predominately Caucasian individuals 22 of the 33 (67%) predicted loci were polymorphic with an average heterozygosity of 0.42. Allele loss in this region was found in 27/36 (75%) of the tumor lines using these markers. POMPOUS provides the genetic researcher with an additional tool for the rapid and efficient identification of polymorphic markers, and through a World Wide Web site, investigators can use POMPOUS to identify polymorphic markers for their research. A catalog of 13,261 potential polymorphic markers and associated primer sets has been created from the analysis of 141,779,504 base pairs of human genomic sequence in GenBank. This data is available on our Web site (pompous.swmed.edu) and will be updated periodically as GenBank is expanded and algorithm accuracy is improved.

Computer Communication Networks↗

PubMed1994

Two 5q13 simple tandem repeat loci are in linkage disequilibrium with type 1 spinal muscular atrophy.

The gene for the common recessive neuromuscular disorder spinal muscular atrophy (SMA) has been previously mapped to chromosome 5q. We report here linkage disequilibrium analyses of two polymorphic simple tandem repeat (STR) sequences which map into the critical region of 5q13 containing the SMA gene. The polymorphisms presented are constituents of CATT-1, a complex STR which is present in as many as four or more copies per chromosome 5. The PCR can amplify as many as eight CATT-1 products of different sizes from genomic DNA samples due to differing numbers of CA dinucleotides at each STR location (sublocus). Oligonucleotide primers for two of these subloci have been developed for specific PCR assays; a variety of allele sizes can be generated with each assay and, in some cases, no amplification products are detected due to null alleles. The genotyping of 149 SMA Type 1 chromosomes and 142 normal chromosomes from Canadian and American kindreds reveals the presence of significant linkage disequilibrium between the null allele of the sublocus referred to as CATT-40G1 and mutation(s) causing SMA Type 1 (Werdnig-Hoffmann disease). Allele 2 of the second sublocus, CATT-192F7, is also in linkage disequilibrium with SMA Type 1 although the degree of this association is less than that found for CATT-40G1. The proximal and distal STRs from the critical region, D5S435 and D5S351, showed no linkage disequilibrium with SMA. The data presented here will serve as a framework for future linkage disequilibrium analyses, expediting the final stage of the search for the SMA gene.

Alleles↗

PubMed1976

Studies on silk fibroin of Bombyx mori. I. Fractionation of fibroin prepared from the posterior silk gland.

1. Fractionation of fibroin prepared from the posterior silk glands of Bombyx mori was carried out. After carboxymethylation of the fibroin, it was fractionated by ammonium sulfate precipitation, Sephadex G-200 gel filtration and DEAE-cellulose column chromatography. 2. The fibroin was composed of at least two protein groups of large molecular size and three or four components of small molecular size, and, in addition, a mixture of proteins ranging in size from about 25,000 to more than 100,000 daltons with almost the same amino acid compositions. 3. The latter proteins contained about 48% glycine, 32% alanine, 11% serine, 4.5% tyrosine, 2% valine, and other minor amino acids. The sum of these main five amino acids accounts for more than 97% of the total amino acid residues of the proteins. 4. The present results indicate major heterogeneity in the molecular size of posterior silk gland fibroin, and, in addition, suggest the possibility of repeating sequences with relatively simple amino acid compositions in major peptide chains of fibroin.

Amino Acids↗

PubMed2000

A 39-kb sequence around a blackbird Mhc class II gene: ghost of selection past and songbird genome architecture.

To gain an understanding of the evolution and genomic context of avian major histocompatibility complex (Mhc) genes, we sequenced a 38.8-kb Mhc-bearing cosmid insert from a red-winged blackbird (Agelaius phoeniceus). The DNA sequence, the longest yet retrieved from a bird other than a chicken, provides a detailed view of the process of gene duplication, divergence, and degeneration ("birth and death") in the avian Mhc, as well as a glimpse into major noncoding features of a songbird genome. The peptide-binding region (PBR) of the single Mhc class II B gene in this region, Agph-DAB2, is almost devoid of polymorphism, and a still-segregating single-base-pair deletion and other features suggest that it is nonfunctional. Agph-DAB2 is estimated to have diverged about 40 MYA from a previously characterized and highly polymorphic blackbird Mhc gene, Aph-DAB1, and is therefore younger than most mammalian Mhc paralogs and arose relatively late in avian evolution. Despite its nonfunctionality, Agph-DAB2 shows very high levels of nonsynonymous divergence from Agph-DAB1 and from reconstructed ancestral sequences in antigen-binding PBR codons-a strong indication of a period of adaptive divergence preceding loss of function. We also found that the region sequenced contains very few other unambiguous genes, a partial Mhc- class II gene fragment, and a paucity of simple-sequence and other repeats. Thus, this sequence exhibits some of the genomic streamlining expected for avian as compared with mammalian genomes, but is not as densely packed with functional genes as is the chicken Mhc.

Amino Acid Sequence↗

PubMed1994

Patterns of differentiation and hybridization in North American wolflike canids, revealed by analysis of microsatellite loci.

Genetic divergence and gene flow among closely related populations are difficult to measure because mutation rates of most nuclear loci are so low that new mutations have not had sufficient time to appear and become fixed. Microsatellite loci are repeat arrays of simple sequences that have high mutation rates and are abundant in the eukaryotic genome. Large population samples can be screened for variation by using the polymerase chain reaction and polyacrylamide gel electrophoresis to separate alleles. We analyzed 10 microsatellite loci to quantify genetic differentiation and hybridization in three species of North American wolflike canids. We expected to find a pattern of genetic differentiation by distance to exist among wolflike canid populations, because of the finite dispersal distances of individuals. Moreover, we predicted that, because wolflike canids are highly mobile, hybrid zones may be more extensive and show substantial changes in allele frequency, relative to nonhybridizing populations. We demonstrate that wolves and coyotes do not show a pattern of genetic differentiation by distance. Genetic subdivision in coyotes, as measured by theta and Gst, is not significantly different from zero, reflecting persistent gene flow among newly established populations. However, gray wolves show significant subdivision that may be either due to drift in past Ice Age refugia populations or a result of other causes. Finally, in areas where gray wolves and coyotes hybridize, allele frequencies of gray wolves are affected, but those of coyotes are not. Past hybridization between the two species in the south-central United States may account for the origin of the red wolf.

Alleles↗

PubMed1994

[A new polymorphism in the human factor IX gene, useful for determining carriers of hemophilia B].

A new Taq I polymorphism in Alu repeat 4 of the human factor IX gene is reported. This polymorphism is associated with a C-T transition at the 72-bp position of the Alu repeat consensus sequence. A simple PCR system for testing of this structural anomaly, with internal control of restriction hydrolysis, was developed. The frequency of the new polymorphic site and its linkage with other polymorphisms of the factor IX gene were also evaluated. The new polymorphism was used for establishing hemophilia B carriers.

Base Sequence↗

PubMed1995

Human minisatellite loci composed of interspersed GGA-GGT triplet repeats.

We have isolated two tandemly repeated loci from human DNA which contain long blocks of GGA and GGT trinucleotide repeats. These two repeat unit types, together with other less common variants, are apparently irregularly interspersed along each repeat array. Genotyping methods have been developed for these highly polymorphic loci, including typing by polymerase chain reaction followed by Southern blot hybridization. Linkage analysis in Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees has been used to map the loci to chromosomes 15 and 22. In normal individuals, alleles at these loci can contain thousands of repeats, greatly exceeding repeat copy number at most trinucleotide and other simple repeat loci. No evidence for longer, higher-order repeats was observed among the limited number of repeats sequenced. These loci may represent a transitional state between simple repeat loci and some minisatellites.

Animals↗

PubMed2000

Class switch recombination of the chicken IgH chain genes: implications for the primordial switch region repeats.

In mammals and the amphibian, Xenopus, isotypes of antibodies have been shown to be changed through class switch recombination within the IgH chain gene locus. Here, we identified switch (S) repetitive sequences in the 5' introns of the Ig C(mu) and C(gamma) genes of the chicken. The S(mu) region is composed of two homologous regions, S(mu)1 and S(mu)2. The S(mu)1 region is an upstream 3.7 kb sequence composed of 37 repeats of a consensus sequence containing tandem repeats of the decamer ACCAGTATGG. The S(mu)2 region is a downstream 1.4 kb sequence consisting of simple tandem repeats of a decamer CCCAGTACAG. The S(gamma) region contains repeats of the decamer TATGGGGCAG. Analysis of chicken IgG-producing hybridomas revealed that the C(mu) gene was deleted from the chromosome by the recombination occurring between the S(mu) and S(gamma) regions. Recombination breakpoints at the C(mu) gene of splenocytes from an immunized chicken were scattered around the S(mu) region and two such breakpoints, the precise position of which were determined, were located within possible hairpin loop structures at the palindromic sequence of S(mu)1. A primordial palindromic sequence from which the prevalent switch repeat motifs of mammals, chickens and amphibians may have diverged is presented.

Animals↗

PubMed1993

Subtelomeric as well as telomeric sequences are lost from chromosomes in proliferating B lymphocytes.

B lymphocytes purified from peripheral blood can be normally cultured in vitro for only one doubling. They can undergo an unlimited number of cell divisions after transformation with a DNA tumor virus such as the Epstein-Barr virus. We have shown that the terminal restriction fragments of virus transformed B lymphocytes are shortened in the course of proliferation and that this process is accompanied by structural modifications. We have identified the sequences that are lost during the shortening process by hybridization to the canonical human telomeric simple repeat TTAGGG, to other simple sequences that are found at the ends of human chromosomes, and to a human subtelomeric sequence. We have observed that by 20 doublings over half the TTAGGG sequences, but few or no TGAGGG sequences, are lost from the TRFs. The subtelomeric sequence was removed from most of the TRFs on which it was present. The implications that these observations have on the problems of cell senescence and oncology are discussed.

B-Lymphocytes↗

PubMed1995

Simple tandem DNA repeats and human genetic disease.

The human genome contains many repeated DNA sequences that vary in complexity of repeating unit from a single nucleotide to a whole gene. The repeat sequences can be widely dispersed or in simple tandem arrays. Arrays of up to 5 or 6 nt are known as simple tandem repeats, and these are widely dispersed and highly polymorphic. Members of one group of the simple tandem repeats, the trinucleotide repeats, can undergo an increase in copy number by a process of dynamic mutation. Dynamic mutations of the CCG trinucleotide give rise to one group of fragile sites on human chromosomes, the rare folate-sensitive group. One member of this group, the fragile X (FRAXA) is responsible for the most common familial form of mental retardation. Another member of the group FRAXE is responsible for a rarer mild form of mental retardation. Similar mutations of AGC repeats give rise to a number of neurological disorders. The expanded repeats are unstable between generations and somatically. The intergenerational instability gives rise to unusual patterns of inheritance--particularly anticipation, the increasing severity and/or earlier age of onset of the disorder in successive generations. Dynamic mutations have been found only in the human species, and possible reasons for this are considered. The mechanism of dynamic mutation is discussed, and a number of observations of simple tandem repeat mutation that could assist in understanding this phenomenon are commented on.

Chromosome Mapping↗