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Biomedical subjects

W Amos

Publications and source records attributed to W Amos.

At least 37 records · Page 2Linked to original sources
PubMed2000

Genetic susceptibility to tuberculosis in Africans: a genome-wide scan.

Human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis. We have conducted a two-stage genome-wide linkage study to search for regions of the human genome containing tuberculosis-susceptibility genes. This approach uses sibpair families that contain two full siblings who have both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis-susceptibility gene, affected sibpairs inherit the same parental alleles more often than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sibpairs from The Gambia and South Africa. Seven chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis were identified. To identify whether any of these regions contained a potential tuberculosis-susceptibility gene, 22 markers from these regions were genotyped in a second set of 81 sibpairs from the same countries. Markers on chromosomes 15q and Xq showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. The potential identification of susceptibility loci on both chromosomes 15q and Xq was supported by an independent analysis designated common ancestry using microsatellite mapping. These results indicate that genome-wide linkage analysis can contribute to the mapping and identification of major genes for multifactorial infectious diseases of humans. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in many different populations.

Adolescent↗
PubMed2000

Conditional ETDT analysis of the human leukocyte antigen region in type 1 diabetes.

Several studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non- DR/DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1.

Adolescent↗
PubMed2000

Patterns of paternal relatedness in British grey seal colonies.

Previous studies of breeding behaviour in the grey seal, Halichoerus grypus, have painted conflicting pictures. Behavioural observations suggest a classical polygynous system with a small number of dominant males fathering most of the offspring. However, genetic analysis suggests that many potential fathers spend little time ashore, that some pairs of seals show partner fidelity and that the dominant males are not as successful as their behaviour would suggest. Here we used paternal relatedness between pups with known mothers, sampled over an 11-year period, to show that behavioural dominance leading to enhanced fitness is a feature of only a handful of males located near the centre of the breeding colony. The vast majority of pups are fathered by any of a large number of males who all share approximately equal success, including virtually all those males who have previously escaped our best sampling efforts. As expected, the frequency of full-sibs is reduced in this longer time series relative to the original study. However, absolute estimates of the frequency of full-sibs seem to be confounded by a tendency for females who produce paternally unrelated pups to have conceived to males who are more genetically dissimilar from each other than expected by chance alone. Together, these elements of breeding behaviour would help to maintain maximum genetic diversity and to minimize the effects of inbreeding.

Animals↗
PubMed2000

Population structure of long-finned pilot whales in the North Atlantic: a correlation with sea surface temperature?

The long-finned pilot whale, Globicephala melas, is a social, pelagic odontocete distributed widely in the cold temperate waters of the North Atlantic. Despite genetic, morphometric, physiological and observational studies, it remains unclear whether any population substructure exists. We have used eight highly polymorphic microsatellite loci to analyse samples from four disparate sampling sites: USA East Coast (Cape Cod), West Greenland, the Faeroe Islands and the UK. Our results indicate that substructure does exist, and is particularly pronounced between West Greenland and other sites. The magnitudes of the various pairwise comparisons do not support a simple isolation-by-distance model. Instead, the patterns of genetic differentiation suggest that population isolation occurs between areas of the ocean which differ in sea surface temperature. Such a mechanism is supported by the observation that temperature is a primary factor determining the relative distributions of two short-finned pilot whale (G. macrorhynchus) populations off the Pacific coast of Japan.

Animals↗
PubMed1999

Markov chain Monte Carlo analysis of human Y-chromosome microsatellites provides evidence of biased mutation.

We describe a Markov Chain Monte Carlo analysis of five human Y- chromosome microsatellite polymorphisms based on samples from five diverse populations. Our analysis provides strong evidence for mutational bias favoring increase in length at all loci. Estimates of population coalescent times and population size from our two largest samples, one African and one European, suggest that the African population is older but smaller and that the English East Anglian population has undergone significant expansion, being larger but younger. We conclude that Markov Chain Monte Carlo analysis of microsatellite haplotypes can uncover information not apparent when the microsatellites are considered independently. Incorporation of population size as a variable should allow us to estimate the timing and magnitude of major historical population trends.

Algorithms↗
PubMed1999

Where have all the fathers gone? An extensive microsatellite analysis of paternity in the grey seal (Halichoerus grypus).

Microsatellites were used to conduct an extensive analysis of paternity of grey seals from two Scottish breeding colonies at North Rona (n = 1189) and the Isle of May (n = 694), spanning more than a decade. A maximum of 46% of pups at North Rona and 29% of pups at the Isle of May could be allocated a father, even though the majority of candidate males for specific study sites within each colony were believed to have been sampled. Based on the paternities which could be assigned, both colonies showed evidence of reproductive skew, apparently due to the presence of approximately five males who were exceptionally successful. Some males were assigned paternities at least 10 years before, and colleagues 10 years after, being sampled, implying a reproductive lifespan of at least 10 years, and there are indications that the real maximum lies in the range 15-20 years. Male grey seals appear to have at least two breeding strategies they can adopt. On land, some males benefit from a traditionally polygynous system. However, between 50 and 70% of grey seal pups born at a particular colony are not fathered by males who are likely to be sampled by us, implying that these males seldom venture ashore here. We conclude that aquatic mating may play a much larger role in the grey seal than has previously been thought.

Animals↗
PubMed1999

Mitochondrial genetic analyses suggest selection against maternal lineages in bipolar affective disorder.

Previous reports of preferential transmission of bipolar affective disorder (BP) from the maternal versus the paternal lines in families suggested that this disorder may be caused by mitochondrial DNA mutations. We have sequenced the mitochondrial genome in 25 BP patients with family histories of psychiatric disorder that suggest matrilineal inheritance. No polymorphism identified more than once in this sequencing showed any significant association with BP in association studies using 94 cases and 94 controls. To determine whether our BP sample showed evidence of selection against the maternal lineage, we determined genetic distances between all possible pairwise comparisons within the BP and control groups, based on multilocus mitochondrial polymorphism haplotypes. These analyses revealed fewer closely related haplotypes in the BP group than in the matched control group, suggesting selection against maternal lineages in this disease. Such selection is compatible with recurrent mitochondrial mutations, which are associated with slightly decreased fitness. Although such mismatch distribution comparisons have been used previously for analyses of population histories, this is, as far as we are aware, the first report of this method being used to study disease.

Alleles↗
PubMed1999

An empirical exploration of the (delta mu)2 genetic distance for 213 human microsatellite markers.

Microsatellites are now used ubiquitously as genetic markers. One important application is to the assessment of population subdivision and phylogenetic relatedness. Such applications require a method of estimation of genetic distance. Here we examine the most widely used measure of microsatellite genetic distance, Goldstein et al.'s delta-mu squared ([delta mu]2), with respect to a large data set of 213 markers typed across samples from four diverse human populations. We find that (delta mu)2 yields plausible interpopulation distances. For the first time, we report significant interpopulation differences in mean microsatellite length, although the effect of these differences on (delta mu)2 is negligible. However, we also show that the method is extremely sensitive to one or two loci that contribute extreme values, even when a sample size of >200 loci is used. Some of these extreme loci can be removed on the grounds that some alleles carry large indels, but for others there is no clear justification for exclusion a priori. Our data suggest a rather recent African/non-African split, with an upper limit of some 70,000-80,000 years ago.

Africa↗
PubMed1998

Factors affecting levels of genetic diversity in natural populations.

Genetic variability is the clay of evolution, providing the base material on which adaptation and speciation depend. It is often assumed that most interspecific differences in variability are due primarily to population size effects, with bottlenecked populations carrying less variability than those of stable size. However, we show that population bottlenecks are unlikely to be the only factor, even in classic case studies such as the northern elephant seal and the cheetah, where genetic polymorphism is virtually absent. Instead, we suggest that the low levels of variability observed in endangered populations are more likely to result from a combination of publication biases, which tend to inflate the level of variability which is considered 'normal', and inbreeding effects, which may hasten loss of variability due to drift. To account for species with large population sizes but low variability we advance three hypotheses. First, it is known that certain metapopulation structures can result in effective population sizes far below the census size. Second, there is increasing evidence that heterozygous sites mutate more frequently than equivalent homozygous sites, plausibly because mismatch repair between homologous chromosomes during meiosis provides extra opportunities to mutate. Such a mechanism would undermine the simple relationship between heterozygosity and effective population size. Third, the fact that related species that differ greatly in variability implies that large amounts of variability can be gained or lost rapidly. We argue that such cases are best explained by rapid loss through a genome-wide selective sweep, and suggest a mechanism by which this could come about, based on forced changes to a control gene inducing coevolution in the genes it controls. Our model, based on meiotic drive in mammals, but easily extended to other systems, would tend to facilitate population isolation by generating molecular incompatabilities. Circumstances can even be envisioned in which the process could provide intrinsic impetus to speciation.

Animals↗
PubMed1998

Molecular analysis of the efficiency of sloughed skin sampling in whale population genetics.

Sloughed whale skin contains enough DNA for genetic analysis, and offers a non-intrusive method for collecting tissue. Here, we examine the efficiency of sloughed skin sampling using 1460 samples collected from free-ranging humpback whales. Samples were sexed and screened for up to 10 microsatellite markers. The vast majority of samples appear genetically compatible with field observations. About 1% of groups revealed more genotypes than whales, but we argue that this is more likely to be due to unobserved whales than to contamination. Sloughed skin sampling is particularly effective when applied to active groups and offers a viable alternative to biopsy darting in regions where darting is either not permitted or otherwise undesirable.

Alleles↗
PubMed1998

Ascertainment bias cannot entirely account for human microsatellites being longer than their chimpanzee homologues.

A large majority of human microsatellite markers are longer than their homologues in chimpanzees, suggesting that more expansion mutations have occurred in the lineage leading to humans. However, such a length difference has also been explained as arising from the selection of unusually long microsatellites as genetic markers. In order to resolve this controversy and to establish the true source of the observed length differences, we have now conducted the necessary reciprocal study. We have compared the lengths of size-selected markers cloned from chimpanzees between this species and humans. We find that of 19 markers which were informative and polymorphic in both species, 13 are longer in humans. This result is incompatible with ascertainment bias being the sole explanation for the inter-specific length differences. We estimate that dinucleotide repeat microsatellites are an average of 3.2 repeat units longer in humans than in chimpanzees, implying a mutational bias in favour of microsatellite expansions and a higher average genome-wide microsatellite mutation rate in the human lineage.

Animals↗
PubMed1997

Molecular scatology: the use of molecular genetic analysis to assign species, sex and individual identity to seal faeces.

Seals and commercial fisheries are potential competitors for fish and cephalopods. Research into the diet of British seal species has been based on conventional dietary analyses, but these methods often do not allow assignment of species identity to scat samples. We present a protocol for obtaining DNA from seal scat (faecal) samples which can be used in polymerase chain reactions to amplify both nuclear and mitochondrial DNA. This can provide a method of identifying the species, sex and individual identity of the seal, from a particular scat sample. Combined with conventional dietary analyses these techniques will allow us to assess sources of variation in seal diet composition. Scat samples have been collected from intertidal haul-out sites around the inner Moray Firth, north-east Scotland. We have assessed methods to extract and purify faecal DNA, a combination of DNA from the individual seal, prey items, and gut bacteria, for use in PCR. Controls using faecal and blood samples from the same individual have enabled microsatellite primer sets from four pinniped species to be tested. Approximately 200 scat samples have been examined for species identity and individual matches. This study will provide essential information for the assessment of interactions between seals and commercial or recreational fisheries.

Animals↗
PubMed1996

Network analysis of human Y microsatellite haplotypes.

To investigate the utility of Y chromosome microsatellites for studying human male-lineage evolution, we typed samples from three populations for five tetranucleotide repeats and an Alu insertion polymorphism. We found very high levels of haplotype diversity and evidence that most mutations involve the gain or loss of only one repeat unit, implying that any given microsatellite haplotype may have arisen independently on two or more Y-chromosome lineages. Together, these factors suggest that interpretation of small sample sizes (< 30) will be problematic. By typing a large sample of individuals (n = 174) from one population, East Anglia, we were able to construct a haplotype network. The network exhibits a well-connected core structure of commoner haplotypes. Computer simulations based on this network estimate the convergence time for African and Caucasian groups may be between 1.4 and 1.8 times as long as the convergence of the East Anglian population. Based on our comparison between large and small sample sizes, we suggest that large sample sizes are necessary in order to interpret Y-microsatellite haplotypes, and that a network analysis of the type we describe may prove informative in future studies.

Base Sequence↗