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R M Harding

Publications and source records attributed to R M Harding.

At least 55 records · Page 3Linked to original sources
PubMed1993

Why are some genetic diseases common? Distinguishing selection from other processes by molecular analysis of globin gene variants.

Various processes (selection, mutation, migration and genetic drift) are known to determine the frequency of genetic disease in human populations, but so far it has proved almost impossible to decide to what extent each is responsible for the presence of a particular genetic disease. The techniques of gene and haplotype analysis offer new hope in addressing this issue, and we review relevant studies of three haemoglobinopathies: sickle cell anaemia, and alpha and beta thalassaemia. We show how for each disease it is possible to recognize a pattern of regionally specific mutations, found in association with one or a few haplotypes, that is best explained as the result of selection; other patterns are due to population migration and genetic drift. However, we caution that such conclusions can be drawn in special circumstances only. In the case of the haemoglobinopathies it is possible because a selective agent (malaria) was already suspected, and the investigations could be carried out in relatively genetically homogenous populations whose migratory histories are known. Moreover, some data reviewed here suggest that gene conversion and the haplotype composition of a population may affect the frequency of a mutation, making interpretation of gene frequencies difficult on the basis of standard population genetics theory. Hence attempts to use the same approaches with other genetic diseases are likely to be frustrated by a lack of suitably untrammelled populations and by difficulties accounting for poorly understood genetic processes. We conclude that although this combination of molecular and population genetics is successful when applied to the study of haemoglobinopathies, it may not be so easy to apply it to the study of other genetic diseases.

Africa, Northern↗
PubMed1993

The population genetics of the haemoglobinopathies.

The haemoglobinopathies are the commonest single gene disorders known, and are so common in some regions of the world that the majority of the population carries at least one genetic abnormality affecting the structure or synthesis of the haemoglobin molecule. The prevalence of the common haemoglobinopathies (the alpha- and beta-thalassaemias, HbS, HbC and HbE) is almost certainly a result of the protection they provide against malaria, as the epidemiological evidence reviewed in this chapter shows. World-wide, the distributions of malaria and the common haemoglobinopathies largely overlap, and micro-epidemiological surveys have confirmed the close relationship between the disorders. However, there are complications to this picture which appear to undermine the malaria hypothesis. First, in some areas, malaria and haemoglobinopathies are not coincident. Second, the malaria hypothesis does not easily explain why no two regions of the world have the same haemoglobinopathy or combination of haemoglobinopathies. The majority of mutations have arisen only once and are regionally specific. By using molecular characterization of mutations and the analysis of haplotypes on haemoglobinopathy-bearing chromosomes it is possible to show how a combination of selection by malaria, genetic drift and population movements can explain the first complication. In order to explain the second, we have argued that malaria selection has operated relatively recently on human populations (within the last 5000 years). The present distribution is then seen as the result of selection elevating sporadic mutations in local populations. In the absence of sufficient gene flow to spread all mutations to all populations, the consequence is a patchwork distribution of haemoglobinopathies. Given time, we would expect the mutations that protect and do not compromise the health of their carriers to become widely disseminated, but it is likely that human intervention will alter this process of natural selection.

Africa↗
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↗
PubMed1993

Nucleotide sequence of one component of the banana bunchy top virus genome contains a putative replicase gene.

One DNA component of the banana bunchy top virus (BBTV) genome was cloned and sequenced. This component is present as a circular, ssDNA in the virions and consists of 1111 nucleotides. It contains one large open reading frame (ORF) of 858 nucleotides in the virion sense; this ORF encodes a putative replicase based on the presence of a dNTP-binding motif (GGEGKT). Two smaller ORFs (249 and 366 nucleotides), in the complementary orientation, could not be assigned any obvious function. Neither of these ORFs had significant sequence homology with any known DNA plant virus gene or gene product. Computer analysis of this component-predicted a strong stem-loop structure in the virion sense putative untranslated region; a nonanucleotide sequence in the loop was nearly identical to the nonanucleotide invariant loop sequence of geminiviruses and coconut foliar decay virus. There is strong evidence that the genome of BBTV consists of more than one component because no ORF was found that would encode a protein the size of the BBTV coat protein. BBTV has some characteristics in common with geminiviruses but cannot be classified as one. Rather, BBTV probably belongs to an undescribed plant virus group which could also include subterranean clover stunt virus and coconut foliar decay virus.

Amino Acid Sequence↗
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↗
PubMed1992

Interethnic genetic differentiation in Africa: HLA class I antigens in The Gambia.

A total of 752 individuals from The Gambia, west Africa who are representative of the major ethnic groups in the capital, Banjul, were serologically typed for HLA-A, -B, and -C antigens. Although all were typically "African" in their antigenic profiles, some marked frequency differences were found between the ethnic groups. Genetic distance comparisons with several other African populations showed that, although these west African populations clustered closely together, the positions of the various ethnic groups in The Gambia were consistent with historical and linguistic evidence of their affinities with one another and with other African populations. Despite the potential confounding effects both of selection by infectious diseases and of genetic drift caused by local differences in population structure, HLA frequencies appear to be of value in measuring inter- and intraregional population affinities in sub-Saharan Africa.

Africa↗
PubMed1991

Stability and extractability of double-stranded RNA of pangola stunt and sugarcane Fiji disease viruses in dried plant tissues.

When leaves infected with pangola stunt virus (PaSV) were dried at 23, 37, 50, 70 or 105 degrees C, the dsRNA was stable and could be extracted after aerobic storage at room temperature for 1 month, although at 105 degrees C the amount obtained was reduced. The dsRNA was also recovered after leaves were freeze dried and stored in vacuo at room temperature for 6 months, or were dried and stored aerobically at room temperature for 10.5 months. dsRNA of sugarcane Fiji disease virus (FDV) was also stable when infected leaves were dried at 23, 37, 50 or 105 degrees C and stored aerobically for 3 months or for at least 6 months when infected leaves were dried at 70 degrees C. The unexpected high stability and extractability of both PaSV and FDV dsRNA when dried in leaves at low or high temperatures and stored at room temperature indicate that these, and probably other plant-infecting reoviruses, can be transported readily in desiccated host tissue between different countries for later extraction and comparison of their dsRNAs.

Desiccation↗
PubMed1991

Virus-like particles associated with banana bunchy top disease contain small single-stranded DNA.

Virus-like particles were purified from banana plants with banana bunchy top disease. These particles were isometric with a diameter of 18 to 20 nm and a density of 1.28 to 1.30 g/ml in caesium sulphate. Associated with these particles were an ssDNA of about 1 kb and one major protein of Mr 20,100. DsDNA was synthesized from nucleic acid extracts from these particles and cloned. One clone, pBT338, hybridized specifically (i) with sap extracts from plants infected with banana bunchy top virus (BBTV) but not with sap extracts from healthy plants and (ii) with the small ssDNA in nucleic acid extracts from infected plants and virus-like particles. Banana bunchy top disease was transmitted from infected to healthy bananas by aphid inoculation and it was demonstrated that the small ssDNA was transmitted with the disease. It is probable that these particles represent the virions of BBTV containing small ssDNA and that the virus resembles subterranean clover stunt virus more than any other known virus.

Blotting, Southern↗
PubMed1991

Spatial differentiation of RH and GM haplotype frequencies in Sub-Saharan Africa and its relation to linguistic affinities.

This study analyzes patterns of variation in eight GM and seven Rhesus (RH) haplotypes across sub-Saharan Africa. We examine the concordance with genetic patterns of both geographic and language-family relationships by spatial analysis and ordination techniques. The genetic variation has significant spatial structure, but positive autocorrelation declines neither asymptotically nor proportionally with increasing distance. Evidently, neither isolation by distance with increasing distance. Evidently, neither isolation by distance nor clinical migration-selection models account for the observed genetic structure. Language-family relationship is the best predictor of genetic relationship and may reflect historic migrations and expansions of ethnically different peoples within sub-Saharan Africa. Yet the greatest part of the genetic variance remains unexplained by the models we have tested.

Africa, Central↗
PubMed1990

Peak expiratory flow at altitude.

The mini Wright peak flow meter is a useful, portable instrument for field studies but being sensitive to air density will under-read at altitude. True peak expiratory flow will increase at altitude, however, because of the decreased air density, given that dynamic resistance is unchanged. The effect of simulated altitude on peak expiratory flow (PEF) was determined in six subjects with both the mini Wright meter and a volumetric spirometer (which is unaffected by air density). With increasing altitude PEF as measured by the spirometer increased linearly with decreasing pressure, so that at a barometric pressure of 380 mm Hg* (half an atmosphere, corresponding to an altitude of 5455 m) there was a 20% increase over sea level values. The mini Wright flow meter gave readings 6% below sea level values for this altitude--that is, under-reading by 26%. Measurements of PEF made at altitude with the mini Wright meter should be corrected by adding 6.6% per 100 mm Hg drop in barometric pressure.

Altitude↗
PubMed1990

Rapid decompression to 50,000 feet: effect on heart rate response.

Interest in Molecular Sieve Oxygen Generation Systems (MSOGS) for use in military aircraft has demonstrated a need to study physiological effects of MSOGS product gas in the worst case scenario, a rapid decompression (RD). In this paper we report the heart rate (HR) response to positive pressure breathing (PPB) during and after RD from 6,096 to 15,239 m (20,000 to 50,000 ft) in a hypobaric chamber while breathing gas mixtures that simulate the product gas from MSOGS. Interbeat (R-R) intervals were recorded in 10 subjects while they breathed either Aviators' Breathing Oxygen (ABO), that is 99.5% oxygen, or 93% oxygen at two regulator settings: dilution and non-dilution. Additional experimental profiles on six subjects isolated the effects of hypoxia, anxiety, and PPB on HR changes after RD. Anxiety appeared to have the greatest effect. Most of the subjects showed increased HR and reduced HR variability after the onset of pressure breathing (immediately after decompression). As the exposure continued, HR variability increased as the HR began to decline. No consistent change in the HR response could be attributed to the modest increase in hypoxia produced by substitution of 93% oxygen for ABO.

Adult↗
PubMed1990

Positive pressure breathing for acceleration protection and its role in prevention of inflight G-induced loss of consciousness.

That pressure breathing for G protection (PBG) can improve both tolerance and endurance to high sustained +Gz acceleration is now well established. It is not surprising, therefore, that the undoubted potential benefits of PBG in an operational environment have been greeted with enthusiasm by aircrew and their commanders. In some quarters, the use of positive pressure breathing (PPB) during periods of high sustained +Gz acceleration is being hailed as a potential cure for the problem of G-induced loss of consciousness (G-LOC). We believe, however, that confidence in the technique for this purpose in modern, highly agile fighter aircraft is misplaced. This article reviews PPB's background and present use as protection against +Gz acceleration, and summarizes the physiologic basis for its effectiveness, before relating it to its undoubted role in support of other anti-G strategies. From theoretical considerations supported by published evidence, we conclude that while PPB, if used correctly and when combined with other strategies, can enhance tolerance to +Gz acceleration, its principal influence on the occurrence of G-LOC will be by virtue of its ability to increase endurance by decreasing aircrew fatigue.

Acceleration↗
PubMed1990

Modern European cranial variables and blood polymorphisms show comparable spatial patterns.

Spatial patterns in cranial traits for modern European populations are compared with patterns described by Sokal et al. (1989) for blood polymorphisms. Spatial patterns in these variables are described from both one-dimensional and directional autocorrelation correlograms. Manhattan distances computed among one-dimensional correlograms are used (1) to cluster variables with similar patterns and (2) to test the hypothesis that these clusters are to some extent accounted for by the type of variable. The one-dimensional correlograms for cranial traits do not show a significant contrast with either red cell antigens or the set of blood polymorphisms that excludes HLA. The only contrast that accounts for any of the cluster structure among one-dimensional correlograms is that between HLA and non-HLA variables. A cluster analysis of the directional correlograms demonstrates that cranial traits reflect patterns comparable to those for blood polymorphisms. This finding implies that patterns in cranial variables can be accounted for by the same, or similar, population processes as those inferred from patterns in blood polymorphisms. The implications of this finding for the likely origin of the northwest-southeast cline seen in some modern blood polymorphisms and modern cranial variables, but not in Neolithic cranial variables, are discussed.

Antigens↗
PubMed1989

Spatial patterns of human gene frequencies in Europe.

The aims of this study of spatial patterns of human gene frequencies in Europe are twofold. One is to present new methodology developed for the analysis of such data. The other is to report on the diversity of spatial patterns observed in Europe and their interpretation as evidence of population processes. Spatial variation in 59 allele and haplotype frequencies (26 genetic systems) for polymorphisms in blood antigens, enzymes, and proteins is analyzed for an aggregate of 3,384 localities, using homogeneity tests, one-dimensional and directional spatial correlograms, and SYMAP interpolated surfaces. The data matrices are reduced to reveal the principal patterns by clustering techniques. The findings of this study can be summarized as follows: 1) There is significant heterogeneity in allele frequencies among the localities for all but one genetic system. 2) There are significant spatial patterns for most allele frequencies. 3) There is a substantial minority of clinal patterns in these populations. Clinal trends are found more frequently in HLA alleles than for other variables. North-south and northwest-southwest gradients predominate. 4) There is a strong decline in overall genetic similarity with geographic distance for most variables. 5) There are few, if any, appreciable correlations in pairs of allele frequencies over the continent, and there is little interesting correlation structure in the resulting correlation matrix. 6) Few spatial correlograms are markedly similar to each other, yet they form well-defined clusters. Spatial variation patterns, therefore, differ among allele frequencies. Patterns of human gene frequencies in modern Europe are diverse and complex. No single model suffices for interpretation of the observed genetic structure. Some clinal patterns reported here support the Neolithic demic-expansion hypothesis, others suggest latitudinal selection. Most of the clinal patterns are in HLA alleles, but there is also evidence from ABO for east-west migration diffusion. The majority of patterns are patchy, consistent with hypotheses of isolation by distance or of settlement of genetically differing, subsequently expanding ethnic groups. While undoubtedly there has been an ongoing stochastic process of differentiation consistent with the isolation-by-distance model, this has not obscured the directional patterns caused by migration (demic diffusion), and has perhaps only reinforced the contribution from settlement of ethnic units to patterns of genetic variation. However, the impact of the latter is most difficult to discern and requires further methodological developments.

ABO Blood-Group System↗
PubMed1988

Classification of the European language families by genetic distance.

Genetic distances among speakers of the European language families were computed by using gene-frequency data for human blood group antigens, enzymes, and proteins of 26 genetic systems. Each system was represented by a different subset of 3369 localities across Europe. By subjecting the matrix of distances to numerical taxonomic procedures, we obtained a grouping of the language families of Europe by their genetic distances as contrasted with their linguistic relationships. The resulting classification largely reflects geographic propinquity rather than linguistic origins. This is evidence for the primary importance of short-range interdemic gene flow in shaping the modern gene pools of Europe. Yet, some language families--i.e., Basque, Finnic (including Lappish), and Semitic (Maltese)--have distant genetic relationships with their geographic neighbors. These results indicate that European gene pools still reflect the remote origins of some ethnic units subsumed by these major linguistic groups.

Ethnicity↗