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Simon J Foote

Publications and source records attributed to Simon J Foote.

At least 19 recordsLinked to original sources
PubMed2006

Comparative genomics profiling of clinical isolates of Aeromonas salmonicida using DNA microarrays.

BACKGROUND: Aeromonas salmonicida has been isolated from numerous fish species and shows wide variation in virulence and pathogenicity. As part of a larger research program to identify virulence genes and candidates for vaccine development, a DNA microarray was constructed using a subset of 2024 genes from the draft genome sequence of A. salmonicida subsp. salmonicida strain A449. The microarray included genes encoding known virulence-associated factors in A. salmonicida and homologs of virulence genes of other pathogens. We used microarray-based comparative genomic hybridizations (M-CGH) to compare selected A. salmonicida sub-species and other Aeromonas species from different hosts and geographic locations. RESULTS: Results showed variable carriage of virulence-associated genes and generally increased variation in gene content across sub-species and species boundaries. The greatest variation was observed among genes associated with plasmids and transposons. There was little correlation between geographic region and degree of variation for all isolates tested. CONCLUSION: We have used the M-CGH technique to identify subsets of conserved genes from amongst this set of A. salmonicida virulence genes for further investigation as potential vaccine candidates. Unlike other bacterial characterization methods that use a small number of gene or DNA-based functions, M-CGH examines thousands of genes and/or whole genomes and thus is a more comprehensive analytical tool for veterinary or even human health research.

Aeromonas salmonicida↗
PubMed2006

On the utility of data from the International HapMap Project for Australian association studies.

We compare patterns of linkage disequilibrium (LD) for 633 SNPs in two regions between samples collected in two Australian states and HapMap samples collected from Utah residents of Northern and Western (NW) European ancestry (CEU). Patterns of LD in the Australian and HapMap samples are similar, and tag SNPs chosen using HapMap genotypes perform almost as well on Australian samples as tags chosen using Australian genotypes.

Europe↗
PubMed2006

Mapping of the Plasmodium chabaudi resistance locus char2.

Animals congenic for the char2 host response locus to the murine malarial parasite Plasmodium chabaudi have been bred, and they demonstrated a phenotypic difference from the parental lines. These congenic lines have been crossed back to the parental line to generate recombinants across the congenic intervals. The recombinants were inbred, and the subcongenic intervals were fixed. These lines were then challenged with parasites and assessed as being either resistant or susceptible. From the analysis of many subcongenic lines, it has become obvious that there are at least two loci underlying the char2 locus and that both of these mediate resistance when the haplotype derives from the resistant C57BL/6 strain.

Animals↗
PubMed2005

Detecting genome wide haplotype sharing using SNP or microsatellite haplotype data.

Genome wide association studies using high throughput technology are already being conducted despite the significant hurdles that need to be overcome (Nat Rev Genet 6:95-108, 2005; Nat Rev Genet 6:109-118, 2005). Methods for detecting haplotype association signals in genome wide haplotype datasets are as yet very limited. Much methodological research has already been devoted to linkage disequilibrium (LD) fine mapping where the focus is the identification of the disease locus rather than the detection of a disease signal. Applications of these approaches to genome wide scanning are limited by the strong model assumptions of the sharing process, which lead to computational complexity. We describe a new algorithm for the initial identification of disease susceptibility loci in genome wide haplotype association studies. Excess sharing of ancestral haplotypes, which indicates the presence of a disease locus, is detected with a simple, easy to interpret, chi2 based statistic. The method allows genome wide scanning for qualitative traits within reasonable computational timeframes and can serve as a first pass analysis prior to the usage of likelihood based methods, providing candidate regions and inferred susceptibility haplotypes. Our method makes no assumptions regarding the population history or the pattern of background LD. Statistical significance is evaluated with permutation tests. The method is illustrated on simulated and real data where it is applied to simple (cystic fibrosis) and complex disease (multiple sclerosis) examples. The statistic has low type I error and greater power to map disease loci over conventional single marker tests for low to moderate levels of LD.

Algorithms↗
PubMed2005

The wound repair response controls outcome to cutaneous leishmaniasis.

Chronic microbial infections are associated with fibrotic and inflammatory reactions known as granulomas showing similarities to wound-healing and tissue repair processes. We have previously mapped three leishmaniasis susceptibility loci, designated lmr1, -2, and -3, which exert their effect independently of T cell immune responses. Here, we show that the wound repair response is critically important for the rapid cure in murine cutaneous leishmaniasis caused by Leishmania major. Mice congenic for leishmaniasis resistance loci, which cured their lesions more rapidly than their susceptible parents, also expressed differentially genes involved in tissue repair, laid down more ordered collagen fibers, and healed punch biopsy wounds more rapidly. Fibroblast monolayers from these mice repaired in vitro wounds faster, and this process was accelerated by supernatants from infected macrophages. Because these effects are independent of T cell-mediated immunity, we conclude that the rate of wound healing is likely to be an important component of innate immunity involved in resistance to cutaneous leishmaniasis.

Animals↗
PubMed2005

Evidence for a novel glaucoma locus at chromosome 3p21-22.

Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the world. It is a clinically variable group of diseases with the majority of cases presenting as the late onset adult type. Several chromosomal loci have been implicated in disease aetiology, but causal mutations have only been identified in a small proportion of glaucoma. We have previously described a large six-generation Tasmanian family with POAG exhibiting genetic heterogeneity. In this family, approximately one third of affected individuals presented with a glutamine-368-STOP (Q368STOP) mutation in the myocilin gene. We now use a Markov Chain Monte Carlo (MCMC) method to identify a second disease region in this family on the short arm of chromosome 3. This disease locus was initially mapped to the marker D3S1298 and a subsequent minimum disease region of 9 cM between markers D3S1298 and D3S1289 was identified through additional mapping. The region did not overlap with any previously described locus for POAG. Using a multiplicative relative risk model, we identified a positive association between this region and the Q368STOP mutation of myocilin on chromosome 1 in affected individuals. These findings provide evidence of a new autosomal dominant glaucoma locus on the short arm of chromosome 3.

Chromosome Mapping↗
PubMed2005

Identifying nineteenth century genealogical links from genotypes.

We have developed a likelihood method to identify moderately distant genealogical relationships from genomewide scan data. The aim is to compare the genotypes of many pairs of people and identify those pairs most likely to be related to one another. We have tested the algorithm using the genotypes of 170 Tasmanians with multiple sclerosis recruited into a haplotype association study. It is estimated from genealogical records that approximately 65% of Tasmania's current population of 470,000 are direct descendants of the 13,000 female founders living in this island state of Australia in the mid-nineteenth century. All cases and four to five relatives of each case have been genotyped with microsatellite markers at a genomewide average density of 4 cM. Previous genealogical research has identified 51 pairwise relationships linking 56 of the 170 cases. Testing the likelihood calculation on these known relative pairs, we have good power to identify relationships up to degree eight (e.g. third cousins once removed). Applying the algorithm to all other pairs of cases, we have identified a further 61 putative relative pairs, with an estimated false discovery rate of 10%. The power to identify genealogical links should increase when the new, denser sets of SNP markers are used. Except in populations where there is a searchable electronic database containing virtually all genealogical links in the past six generations, the algorithm should be a useful aid for genealogists working on gene-mapping projects, both linkage studies and association studies.

Algorithms↗
PubMed2005

Controlling malaria and African trypanosomiasis: the role of the mouse.

Malaria and trypanosomiasis are vector-borne protozoal diseases which disproportionately affect the poor. Both give rise to immense human suffering; malaria exerts its effect directly on human health, while trypanosomiasis causes damage largely though its effect on the health and productivity of the livestock on which so many poor people depend. These diseases both have multifaceted and poorly understood mechanisms of pathogenesis, combined with relatively complex life cycles characterised by multiple stages in both insect vector and mammalian host. In both cases, there is a dramatic effect of host genotype on disease progression. This effect is apparent in both the human and cattle hosts and among inbred mouse strains. This provides an opportunity to use the mouse to probe the mechanisms underlying resistance or susceptibility to pathology. The availability of high-density linkage maps, the genome sequence and transcriptomics tools has transformed the power of the mouse to illuminate such fundamental aspects of the host--parasite interaction.

Animals↗
PubMed2005

Genetics of murine leishmaniasis.

Leishmaniasis encompasses a number of disease syndromes, caused by several species of the digenetic protozoan Leishmania, and is transmitted by sandflies. The mouse model of the disease has been used to identify genes involved in disease susceptibility--for example, the Slc11a1 gene, important in resistance to Leishmania donovani--and to map loci important in Leishmania major infection. The genetics of the host response to L. major has been shown to be complex and to involve much more than the T helper cell response.

Animals↗
PubMed2005

Linkage to 10q22 for maximum intraocular pressure and 1p32 for maximum cup-to-disc ratio in an extended primary open-angle glaucoma pedigree.

PURPOSE: The purpose of this study was to identify genetic contributions to primary open-angle glaucoma (POAG) through investigations of two quantitative components of the POAG phenotype. METHODS: Genome-wide multipoint variance-components linkage analyses of maximum recorded intraocular pressure (IOP) and maximum vertical cup-to-disc ratio were conducted on data from a single, large Australian POAG pedigree that has been found to segregate the myocilin Q368X mutation in some individuals. RESULTS: Multipoint linkage analysis of maximum recorded IOP produced a peak LOD score of 3.3 (P = 0.00015) near marker D10S537 on 10q22, whereas the maximum cup-to-disc ratio produced a peak LOD score of 2.3 (P = 0.00056) near markers D1S197 to D1S220 on 1p32. Inclusion of the myocilin Q368X mutation as a covariate provided evidence of an interaction between this mutation and the IOP and cup-to-disc ratio loci. CONCLUSIONS: Significant linkage has been identified for maximum IOP and suggestive linkage for vertical cup-to-disc ratio. Identification of genes contributing to the variance of these traits will enhance understanding of the pathophysiology of POAG as a whole.

Chromosomes, Human, Pair 1↗
PubMed2005

Multiple sclerosis: a haplotype association study.

Results are presented from a genomewide haplotype association study on multiple sclerosis (MS) cases from Tasmania, an island state of Australia. Cases were ascertained on strict clinical and radiological grounds and on the fact that they had at least one grandparent born in the state. This enriched for early settler chromosomes among present day Tasmanians with MS and increased the chances of finding common haplotype sharing at disease predisposition loci in distant relatives sharing common ancestral haplotypes. Four-to-five close relatives were also collected for each of 170 cases and 105 population-based controls. All were genotyped at a 5cM resolution, haplotypes reconstructed and sharing estimated using an empirical approach based on sorting haplotypes to find the most common at each locus and then generating a test statistic for excess sharing in the cases based on permutation testing. Five initial loci were found where there was an excess sharing in the cases. These were fine-mapped with 10-12 additional markers. Only loci on chromosomes 6 and 10 remained after fine mapping. These loci demonstrate an increase in sharing of multi-marker haplotypes in MS cases compared to both population control transmitted haplotypes and case non-transmitted haplotypes.

Haplotypes↗
PubMed2004

PU.1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA binding domain.

In most myeloid leukemias induced in mice by gamma-radiation, one copy of chromosome 2 has suffered a deletion. To search for a potential tumor suppressor gene in that region, we have delineated the deletions in a panel of these tumors. A commonly deleted region of 2 megabase pairs (Mbp) includes the gene encoding the PU.1 transcription factor, a powerful inducer of granulocytic/monocytic differentiation. Significantly, in 87% of these tumors the remaining PU.1 allele exhibited point mutations in the PU.1 DNA binding domain. Surprisingly, 86% of these mutations altered a single CpG, implicating deamination of deoxycytidine, a common mutational mechanism, as the origin of this lesion. The "hot spot" resides in the codon for a contact residue essential for DNA binding by PU.1. In keeping with a tumor suppressor role for PU.1, enforced expression of wild-type PU.1 in the promyelocytic leukemia cells inhibited their clonogenic growth, induced monocytic differentiation, and elicited apoptosis. The mutant PU.1 found in tumors retained only minimal growth suppressive function. The results suggest that PU.1 normally suppresses development of myeloid leukemia by promoting differentiation and that the combination of gene deletion and a point mutation that impairs its ability to bind DNA is particularly leukemogenic.

Animals↗
PubMed2004

Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis.

In order to resolve a multiple sclerosis (MS) susceptibility locus that we had identified in earlier work at the telomeric end of the HLA complex, we genotyped another 34 microsatellite markers (47 in total) across the class I/extended class I region in 166 Tasmanian MS case and 104 control families (D6S299-D6S265). Extended MS susceptibility haplotypes, up to 9 Mb in length, were observed in 11% of MS cases and 4% of controls. Direct comparison of the telomerically extended portion of the MS susceptibility haplotype in HFE-Cys282Tyr (C282Y)-homozygous haemochromatosis patients identified a common ancestry for this genomic segment, which translated into an increased frequency of the C282Y allele in 489 MS cases from Tasmania and Victoria (10.2%) compared with controls (6.7%). Six C282Y homozygotes (1.2%), a three-fold increased rate over the general population, and 88 heterozygotes (18%) were identified. One C282Y-homozygous female was identified who had MS and was being treated for symptoms of iron overload. Interestingly, for 71 Victorian MS cases not of north western European (NWE) ancestry, a DR15-independent reduction in the frequency of the C282Y allele was observed, supporting the theory of a NWE origin for the C282Y-variant of the DR15 ancestral haplotype (C282Y-HLA-A*0301-B*0702-DRB1*1501-DQB1*0602). The results of linkage disequilibrium (LD) and log linear modelling analyses suggest that C282Y is increased in MS cases of NWE ancestry because it is in LD with the ancestral DR15 susceptibility haplotype (7.1) and that it does not play an independent role in predisposition to MS. However, our findings provide the impetus for further investigations into the role of iron metabolism in the severity of MS.

DNA Primers↗
PubMed2002

Analysis of 15 primary open-angle glaucoma families from Australia identifies a founder effect for the Q368STOP mutation of myocilin.

Primary open-angle glaucoma (POAG) is a leading cause of blindness in the world. A number of mutations in the myocilin gene have been identified that predispose to glaucoma. The most frequent of these is the Glutamine368STOP (Q368STOP) mutation. It has been postulated that individuals with the Q368STOP mutation are derived from a common founder. To clarify this situation, we studied 15 unrelated POAG families who carried the Q368STOP mutation, from south eastern Australia. In one large family, nine affected and ten unaffected individuals were identified with the Q368STOP mutation. Closely linked polymorphic microsatellite markers were used to establish a disease haplotype in this family. Additional genotyping of markers in another 14 unrelated Q368STOP families revealed the presence of the same disease haplotype. These findings indicate that the Q368STOP mutation in all 15 families shared a common origin prior to the European settlement of Australia in the early 1800s.

Alleles↗
PubMed2002

Multiple genetic loci modify susceptibility to plasmacytoma-related morbidity in E(mu)-v-abl transgenic mice.

There is a great difference in susceptibility to v-abl transgene-induced plasmacytoma between the BALB/cAn and the relatively resistant C57BL/6J mouse strains. We have used the Mapmaker/SURVIVOR algorithm to analyze genome-wide scans on over 800 transgenic F2 hybrid mice, and have mapped at least six loci on chromosomes 2, 4, 11, 17, and 18 that modify tumor-related morbidity. As in human multiple myeloma, males were found to be more prone to plasmacytomagenesis. Different loci influence tumor susceptibility in male and female mice. Survival in females may be largely controlled by a pair of interacting loci on chromosomes 2 and 17.

Algorithms↗
PubMed2002

Genetic dissection of the human leukocyte antigen region by use of haplotypes of Tasmanians with multiple sclerosis.

Association of multiple sclerosis (MS) with the human leukocyte antigen (HLA) class II haplotype DRB1*1501-DQB1*0602 is the most consistently replicated finding of genetic studies of the disease. However, the high level of linkage disequilibrium (LD) in the HLA region has hindered the identification of other loci that single-marker tests for association are unlikely to resolve. In order to address this issue, we generated haplotypes spanning 14.754 Mb (5 cM) across the entire HLA region. The haplotypes, which were inferred by genotyping relatives of 152 patients with MS and 105 unaffected control subjects of Tasmanian ancestry, define a genomic segment from D6S276 to D6S291, including 13 microsatellite markers integrated with allele-typing data for DRB1 and DQB1. Association to the DRB1*1501-DQB1*0602 haplotype was replicated. In addition, we found that the class I/extended class I region, defined by a genomic segment of approximately 400 kb between MOGCA and D6S265, harbors genes that independently increase risk of, or provide protection from, MS. Log-linear modeling analysis of constituent haplotypes that represent genomic regions containing class I (MOGCA-D6S265), class III (TNFa-TNFd-D6S273), and class II (DRB1-DQB1) genes indicated that having class I and class II susceptibility variants on the same haplotype provides an additive effect on risk. Moreover, we found no evidence for a disease locus in the class III region defined by a 150-kb genomic segment containing the TNF locus and 14 other genes. A global overview of LD performed using GOLD identified two discrete blocks of LD in the HLA region that correspond well with previous findings. We propose that the analysis of haplotypes, by use of the types of approaches outlined in the present article, should make it possible to more accurately define the contribution of the HLA to MS.

Alleles↗