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Biomedical subjects

D M Baird

Publications and source records attributed to D M Baird.

12 recordsLinked to original sources
PubMed2006

Effects of hTERT on metal ion-induced genomic instability.

There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longer-term genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERT- cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased beta-galactosidase staining and apoptosis. This instability was not present in telomerase-positive hTERT+ cells. In contrast, in hTERT+ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERT- cells. The growth and survival of both metal-exposed hTERT+ and hTERT- cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.

Apoptosis↗
PubMed2006

Intra-allelic mutation at human telomeres.

The maintenance of telomere length is important in upholding the integrity of the genome. However, it is clear from detailed observations of both telomere length and internal repeat structure that human telomeres are extremely dynamic structures and are subjected to multiple processes that create considerable heterogeneity. Genetic evidence suggests that meiotic recombination within telomeres is rare. However, there are various lines of evidence that implicate the involvement of intra-allelic processes in human telomere dynamics. In this paper, we briefly review some of this evidence and the putative mechanisms of intra-allelic telomeric mutation.

Alleles↗
PubMed2000

High levels of sequence polymorphism and linkage disequilibrium at the telomere of 12q: implications for telomere biology and human evolution.

The human Xp/Yp telomere-junction region exhibits high levels of sequence polymorphism and linkage disequilibrium. To determine whether this is a general feature of human telomeres, we have undertaken sequence analysis at the 12q telomere and have extended the analysis at Xp/Yp. A total of 22 single-nucleotide polymorphisms (SNPs) and one 30-bp duplication were detected in the 1,870 bp adjacent to the 12q telomere. Twenty polymorphic positions were in almost complete linkage disequilibrium, creating three common diverged haplotypes accounting for 80% of 12q telomeres in the white population. A further 6% of 12q telomeres contained a 1,439-bp deletion in the DNA flanking the telomere. The remaining 13% of 12q telomeres did not amplify with the primers used (nulls). The distribution of telomere (TTAGGG) and variant repeats within 12q telomeres was hypervariable, but alleles with similar distribution patterns were associated with the same haplotype in the telomere-adjacent DNA. These data suggest that 12q telomeres, like Xp/Yp telomeres, exhibit low levels of homologous recombination and evolve along haploid lineages. In contrast, high levels of homologous recombination occur in the adjacent proterminal regions of human chromosomes. This suggests that there is a localized telomere-mediated suppression of recombination. In addition, the genetic characteristics of these regions may provide a source of deep lineages for the study of early human evolution, unaffected by both natural selection and recombination. To explain the presence of a few diverged haplotypes adjacent to the Xp/Yp and 12q telomeres, we propose a model that involves the hybridization of two archaic hominoid lineages ultimately giving rise to modern Homo sapiens.

Base Sequence↗
PubMed1999

The plasticity of human telomeres demonstrated by a hypervariable telomere repeat array that is located on some copies of 16p and 16q.

Human telomeres are composed of tandem arrays of TTAGGG repeats with many variant repeats at the proximal ends. Comparison of the interspersion of variant and TTAGGG repeats between alleles can be used to study telomere instability, but the difficulty in identifying chromosome-specific sequences close to the start of autosomal telomeres has hampered such investigations. A chromosome end, including a telomere and adjacent sequence, that is polymorphic for its presence or absence in unrelated individuals has been identified. The telomere-adjacent DNA shows strong homology (92-99%) to sequences, including two expressed sequence tags, that are usually located in subterminal regions of human chromosomes but not adjacent to telomeres. Since this chromosome end arose, it has relocated at least once. In Caucasians, it forms the telomere of approximately 6% of 16q and 2% of 16p chromosome arms. The mechanism of relocation is unknown but must have involved the telomere-adjacent DNA rather than the telomere itself, as copies on 16p and 16q share the same telomere-adjacent sequence. The interspersion patterns of TTAGGG with TGAGGG, TTGGGG and non-amplifying repeat sequences revealed extensive allelic variation, such that 47 different alleles were observed among the 50 alleles mapped. Closely related alleles differ by small changes in copy number at blocks of adjacent like repeats, as seen at the Xp/Yp pseudoautosomal telomere. Such differences are compatible with a model in which the majority of mutations arise by intra-allelic mechanisms, in individuals hemizygous for a single copy of the chromosome end.

Base Sequence↗
PubMed1997

Sequences from higher primates orthologous to the human Xp/Yp telomere junction region reveal gross rearrangements and high levels of divergence.

A high level of sequence polymorphism combined with linkage disequilibrium has created a limited number of highly diverged haplotypes across the human Xp/Yp telomere junction region. To gain insight into the unusual genetic characteristics of this region, we have examined the orthologous sequences in the common chimpanzee (Pan troglodytes ), the gorilla (Gorilla gorilla) and the orang-utan (Pongo pygmaeus). Divergence from the human Xp/Yp sequence is higher (average 2.6-fold) than that observed at other loci. The position of the human Xp/Yp telomere is unique, as additional sequences are present at this location in the other three species. These included an array of subterminal satellite in the chimpanzee and, in the gorilla a small interstitial array of telomere-like repeats followed by sequences with strong homology to the human 18p subterminal region. In the orang-utan, two alleles with different structures were identified. These differ by the presence or absence of a short interspersed nuclear element (SINE) sequence just proximal to long arrays of telomere-like repeat sequences that probably represent the proximal end of the orang-utan Xp/Yp telomere. In addition, a high level of sequence divergence between the two orang-utan structures was identified. This divergence is similar to that observed between the human Xp/Yp telomere-adjacent haplotypes. The high sequence divergence and evidence of gross rearrangements indicate that the Xp/Yp telomeric region has evolved faster than the rest of the genome.

Alleles↗
PubMed1995

Mechanisms underlying telomere repeat turnover, revealed by hypervariable variant repeat distribution patterns in the human Xp/Yp telomere.

Sequences immediately adjacent to the human Xp/Yp telomere exhibit a high frequency of base substitutional polymorphisms, together with almost complete linkage disequilibrium, to create only a few diverged haplotypes. This sequence divergence has been used to develop a PCR-based system for mapping the distribution of the telomere (TTAGGG) and variant repeats (TGAGGG and TCAGGG) at the proximal end of the telomere repeat array. The distribution of these repeats is extremely variable. Almost all Xp/Yp telomeres are different, indicating a high mutation rate. Some telomere maps associated with the same flanking haplotype show similarities, identifying subsets of telomeres that share a recent common ancestry. Mechanisms underlying the rapid turnover of repeats at the proximal end of the Xp/Yp telomere include intra-allelic processes, such as slippage during replication. Inter-allelic exchanges may occur occasionally, but telomerase activity probably plays only a minor role in the germline turnover of proximally located telomere and variant repeats.

Alleles↗
PubMed1994

A subterminal satellite located adjacent to telomeres in chimpanzees is absent from the human genome.

One of the significant unresolved differences between the karyotypes of humans and African apes is the presence of positively staining G-bands at the ends of many chromosome arms in the chimpanzee and gorilla but absent from human chromosomes. Using a telomere anchored PCR strategy, we have isolated DNA from a subterminal satellite, composed of a 32 basepair A-T rich repeat, from the chimpanzee genome that hybridizes to all the additional terminal bands and at two interstitial sites. The satellite is more abundant in gorillas and is not detected in humans or orangutans. Furthermore, there is no similarity between other chimpanzee telomere-junction clones and human subterminal sequences, and therefore the organization of sequences adjacent to telomeres is very different between these closely related primates.

Animals↗
PubMed1983

Tobacco smoking among students at the University of the Witwatersrand, Johannesburg.

The epidemiology of smoking, factors which motivated students at the University of the Witwatersrand, Johannesburg, to smoke, to continue smoking or to stop smoking, and student awareness of the health hazards of smoking were investigated. Analysis of a random sample comprising 13% of the 12426 full-time undergraduate students at the university revealed that 22% smoked, 17% were ex-smokers and 61% had never smoked. Most of the smokers smoked between 10 and 20 cigarettes a day. The years between the ages of 17 and 19 years appear to be important in determining whether students become regular smokers or stop smoking.

Adolescent↗