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Biomedical subjects

J B Clegg

Publications and source records attributed to J B Clegg.

At least 73 records · Page 4Linked to original sources
PubMed1993

A computer simulation study of VNTR population genetics: constrained recombination rules out the infinite alleles model.

Extensive allelic diversity in variable numbers of tandem repeats (VNTRs) has been discovered in the human genome. For population genetic studies of VNTRs, such as forensic applications, it is important to know whether a neutral mutation-drift balance of VNTR polymorphism can be represented by the infinite alleles model. The assumption of the infinite alleles model that each new mutant is unique is very likely to be violated by unequal sister chromatid exchange (USCE), the primary process believed to generate VNTR mutants. We show that increasing both mutation rates and misalignment constraint for intrachromosomal recombination in a computer simulation model reduces simulated VNTR diversity below the expectations of the infinite alleles model. Maximal constraint, represented as slippage of single repeats, reduces simulated VNTR diversity to levels expected from the stepwise mutation model. Although misalignment rule is the more important variable, mutation rate also has an effect. At moderate rates of USCE, simulated VNTR diversity fluctuates around infinite alleles expectation. However, if rates of USCE are high, as for hypervariable VNTRs, simulated VNTR diversity is consistently lower than predicted by the infinite alleles model. This has been observed for many VNTRs and accounted for by technical problems in distinguishing alleles of neighboring size classes. We use sampling theory to confirm the intrinsically poor fit to the infinite alleles model of both simulated VNTR diversity and observed VNTR polymorphisms sampled from two Papua New Guinean populations.

Alleles↗
PubMed1992

The evolution of tandemly repetitive DNA: recombination rules.

Variable numbers of tandem repeats (VNTRs), which include hypervariable regions, minisatellites and microsatellites, can be assigned together with satellite DNAs to define a class of noncoding tandemly repetitive DNA (TR-DNA). The evolution of TR-DNA is assumed to be driven by an unbiased recombinational process. A simulation model of unequal exchange is presented and used to investigate the evolutionary persistence of single TR-DNA lineages. Three different recombination rules are specified to govern the expansion and contraction of a TR-DNA lineage from an initial array of two repeats to, finally, a single repeat allele, which cannot participate in a misalignment and exchange process. In the absence of amplification or selection acting to bias array evolution toward expansion, the probability of attaining a target array size is a function only of the initial number of repeats. We show that the proportions of lineages attaining a targeted array size are the same irrespective of recombination rule and rate, demonstrating that our simulation model is well behaved. The time taken to attain a target array size, the persistence of the target array, and the total persistence time of repetitive array structure, are functions of the initial number of repeats, the rate of recombination, and the rules of misalignment preceding recombinational exchange. These relationships are investigated using our simulation model. While misalignment constraint is probably greatest for satellite DNA it also seems important in accounting for the evolution of VNTR loci including minisatellites. This conclusion is consistent with the observed nonrandom distributions of VNTRs and other TR-DNAs in the human genome.

Biological Evolution↗
PubMed1991

Analysis of ancient bone DNA: techniques and applications.

The analysis of DNA from ancient bone has numerous applications in archaeology and molecular evolution. Significant amounts of genetic information can be recovered from ancient bone: mitochondrial DNA sequences of 800 base pairs have been amplified from a 750-year-old human femur by using the polymerase chain reaction. DNA recovery varies considerably between bone samples and is not dependent on the age of the specimen. We present the results of a study on a small number of bones from a mediaeval and a 17th-century cemetery in Abingdon showing the relation between gross preservation, microscopic preservation and DNA recovery.

Bone and Bones↗
PubMed1991

Isolation and characterization of DNA from archaeological bone.

DNA was extracted from human and animal bones recovered from archaeological sites and mitochondrial DNA sequences were amplified from the extracts using the polymerase chain reaction. Evidence is presented that the amplified sequences are authentic and do not represent contamination by extraneous DNA. The results show that significant amounts of genetic information can survive for long periods in bone, and have important implications for evolutionary genetics, anthropology and forensic science.

Animals↗
PubMed1990

Molecular basis for dominantly inherited inclusion body beta-thalassemia.

Analysis of the molecular basis of dominantly inherited beta-thalassemia in four families has revealed different mutations involving exon 3 of the beta-globin gene. It is suggested that the phenotypic difference between this condition and the more common recessive forms of beta-thalassemia lies mainly in the length and stability of the abnormal translation products that are synthesized and, in particular, whether they are capable of binding heme and producing aggregations that are relatively resistant to proteolytic degradation.

Amino Acid Sequence↗
PubMed1990

Globin genes in Micronesia: origins and affinities of Pacific Island peoples.

DNA polymorphisms and copy-number variants of alpha-, zeta-, and gamma-globin genes have been studied in seven Micronesian island populations and have been compared with those in populations from Southeast Asia, Melanesia, and Polynesia. Micronesians are not significantly different from Polynesians at these loci and appear to be intermediate between Southeast Asians and Melanesians. There is evidence of significant Melanesian input into the Micronesian gene pool and of substantial proto-Polynesian contact with Melanesia.

Black People↗
PubMed1989

Population bottlenecks in Polynesia revealed by minisatellites.

Tandem-repetitive highly variable loci in the human genome (minisatellites) have been used in gene mapping and as DNA "fingerprints", but they have not yet found much application in population genetics. We have investigate the capacity of six minisatellites to discriminate between four populations in Oceania. We find that in comparison to Melanesians, Polynesians have a significant loss of heterozygosity (or gene diversity), not noted using more traditional markers. We show also that the number of alleles, the allele distribution and the mutation rates at the Polynesian minisatellite loci do not deviate from those predicted by the neutral mutation/infinite allele model. The low gene diversity is therefore likely to be a result of the maintenance of small population sizes and bottleneck effects during the colonization of the Pacific.

Alleles↗
PubMed1988

Genetic factors as determinants of infectious disease transmission in human communities.

Genetic factors may play an important role in individual susceptibility to infection. Hitherto this problem has been investigated by attempting to relate the distribution of genetic polymorphisms in populations to present or past infection, or by analysing specific infections by classical twin studies or group comparisons. There is reasonable evidence that the common red-cell polymorphisms involving haemoglobin, enzymes or membrane have been maintained by relative resistance to malaria. Blood-group heterogeneity, including secretor status, may reflect varying susceptibility to bacterial, virus and yeast infection. There is increasing evidence that the HLA-DR system may be involved in modifying the clinical course of bacterial, virus and parasitic infection. So far no specific resistance or susceptibility loci similar to those found in murine models have been found in man. DNA analysis, particularly involving restriction fragment length polymorphism associations with candidate genes, offers a valuable new approach to this problem.

Communicable Diseases↗
PubMed1988

Structure and evolution of the horse zeta globin locus.

The equine zeta globin gene locus consists of an intact 5' gene and a truncated 3' pseudogene (psi zeta) that has only 5' control sequences and a first exon and intron. Nevertheless, the psi zeta gene has retained almost perfect homology with its neighbour, presumably by gene conversion. The first introns of both zeta and psi zeta genes contain a number of degenerate tandem repeats of a 14 base-pair sequence that has been found in the zeta genes of goats and humans and that is related to a family of human minisatellite sequences. Comparisons of sequences flanking the zeta and psi zeta genes reveal areas of considerable interspecies homology, which can be explained by a zeta gene duplication that pre-dated the mammalian radiation.

Animals↗
PubMed1988

Novel alpha haemoglobin haplotypes in horses.

Four minor haplotypes that produce abnormal haemoglobin phenotypes in horses have been characterized. Two of them, AIIb and V, are copy number variants with, respectively, one and three alpha genes instead of the normal complement of two. The AIIa and C haplotypes, on the other hand, each have two alpha genes but, as a result of probable gene conversions, they now encode identical, though haplotype specific, globins. Two out of 60 unrelated and phenotypically normal horses studied had an unusual triplicated rearrangement in the embryonic zeta-gene locus. Each of these variants appears to have been produced by aberrant recombination events.

Animals↗
PubMed1988

Beta thalassemia in Melanesia: association with malaria and characterization of a common variant (IVS-1 nt 5 G----C).

Data on the distribution of beta thalassemia among over 6,000 Melanesians reveals a major difference in the carrier rates between populations in the malarious coastal regions of New Guinea and those living in the historically malaria-free Highlands. The island of Maewo in Vanuatu has a particularly high incidence of beta + thalassemia associated with a single restriction enzyme haplotype. Direct cloning into a plasmid vector and sequence analysis demonstrate that the mutation is a G to C transversion at position 5 of intron 1 of the beta-globin gene. Oligonucleotide probe surveys indicate that this variant accounted for all cases of beta thalassemia studied from Maewo. It is also common in coastal Papua New Guinea where haplotype and oligonucleotide probe data suggest that the molecular basis of beta thalassmia is more heterogeneous.

Alleles↗
PubMed1988

The polyadenylation site mutation in the alpha-globin gene cluster.

In a previous study, we described a form of nondeletion alpha-thalassemia (alpha T Saudi alpha) found in subjects of Saudi Arabian origin. In the current study, using synthetic oligoprobe hybridization and restriction enzyme analysis, we have demonstrated that the molecular basis of alpha T Saudi alpha is due solely to a single base mutation (AATAAA----AATAAG) in the polyadenylation signal of the alpha 2 gene and that the frameshift mutation in codon 14 of the linked alpha 1 gene is the result of a cloning artefact. The alpha 2 polyadenylation signal mutation occurs in other Middle Eastern and the Mediterranean populations and is responsible for the clinical phenotype of Hb H disease in some Saudi Arabian individuals with five alpha genes (alpha T Saudi alpha/(alpha alpha alpha)T Saudi). Evidence suggests that the (alpha alpha alpha)T Saudi haplotype has arisen as a result of a recombination between two misaligned chromosomes bearing the alpha T Saudi alpha defect.

Alleles↗
PubMed1987

Ahaptoglobinaemia in Melanesia: DNA and malarial antibody studies.

To assess the relative contributions of genetic and acquired factors, particularly malaria, to the high frequencies of ahaptoglobinaemia found in Melanesia we have performed DNA and malarial antibody studies in a population from Vanuatu. No gene deletion or rearrangement was found on gene mapping in any ahaptoglobinaemic individual and the frequencies of the Hp1 and Hp2 alleles in the ahaptoglobinaemic group were similar to controls. However, antibodies to Plasmodium falciparum were significantly elevated in the ahaptoglobinaemics. These data suggest that malaria rather than genetic factors is the major cause of ahaptoglobinaemia in Melanesia.

Adult↗