Simon Foote

Genome-wide analysis of chemically induced mutations in mouse in phenotype-driven screens

Publisher: Springer Science and Business Media LLC

Date: 26-10-2015

DOI: 10.1186/S12864-015-2073-4

The influence of host genetics on erythrocytes and malaria infection: is there therapeutic potential?

Publisher: Springer Science and Business Media LLC

Date: 29-07-2015

DOI: 10.1186/S12936-015-0809-X

Ankyrin-1 gene exhibits allelic heterogeneity in conferring protection against malaria

Publisher: Cold Spring Harbor Laboratory

Date: 08-03-2017

DOI: 10.1101/114959

Abstract: Allelic heterogeneity is a common phenomenon where a gene exhibit different phenotype depending on the nature of its genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host-parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 ( Ank-1 ) which exhibits allelic-dependent heterogeneous phenotypes during malaria infections. We conducted an ENU mutagenesis screen on mice and identified two Ank-1 mutations, one resulted in an amino acid substitution (MRI95845), and the other a truncated Ank-1 protein (MRI96570). Both mutations caused hereditary spherocytosis-like phenotypes and confer differing protection against Plasmodium chabaudi infections. Upon further examination, the Ank-1 (MRI96570) mutation was found to inhibit intra-erythrocytic parasite maturation, whereas Ank-1 (MW95845) caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between two Ank-1 mutations. Despite the lack of direct evidence from population studies, this data further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasized the importance of such phenomenon to achieve a better understanding of host-parasite interactions, which could be the basis of future studies.

Stargazin and AMPA receptor membrane expression is increased in the somatosensory cortex of Genetic Absence Epilepsy Rats from Strasbourg

Publisher: Elsevier BV

Date: 04-2011

DOI: 10.1016/J.NBD.2011.01.003

Abstract: Absence-like seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model are believed to arise in hyperexcitable somatosensory cortical neurons, however the cellular basis of this increased excitability remains unknown. We have previously shown that expression of the Transmembrane AMPA receptor Regulatory Protein (TARP), stargazin, is elevated in the somatosensory cortex of GAERS. TARPs are critical regulators of the trafficking and function of AMPA receptors. Here we examine the developmental expression of stargazin and the impact this may have on AMPA receptor trafficking in the GAERS model. We show that elevated stargazin in GAERS is associated with an increase in AMPA receptor proteins, GluA1 and GluA2 in the somatosensory cortex plasma membrane of adult epileptic GAERS. Elevated stargazin expression is not seen in the epileptic WAG/Rij rat, which is a genetically distinct but phenotypically similar rat model also manifesting absence seizures, indicating that the changes seen in GAERS are unlikely to be a secondary consequence of the seizures. In juvenile (6 week old) GAERS, at the age when seizures are just starting to be expressed, there is elevated stargazin mRNA, but not protein expression for stargazin or the AMPA receptor subunits. In neonatal (7 day old) pre-epileptic GAERS there was no alteration in stargazin mRNA expression in any brain region examined. These data demonstrate that stargazin and AMPA receptor membrane targeting is altered in GAERS, potentially contributing to hyperexcitability in somatosensory cortex, with a developmental time course that would suggest a pathophysiological role in the epilepsy phenotype.

Leishmaniasis host response loci (lmr1-3) modify disease severity through a Th1/Th2-independent pathway

Publisher: Springer Science and Business Media LLC

Date: 11-12-2004

DOI: 10.1038/SJ.GENE.6364042

The wound repair response controls outcome to cutaneous leishmaniasis

Publisher: Proceedings of the National Academy of Sciences

Date: 13-10-2005

DOI: 10.1073/PNAS.0505630102

Abstract: 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.

New insights into the protective power of platelets in malaria infection

Publisher: Informa UK Limited

Date: 13-05-2013

DOI: 10.4161/CIB.23653

Structure of the RESA gene ofPiasmodium falciparum

Publisher: Oxford University Press (OUP)

Date: 1986

DOI: 10.1093/NAR/14.21.8265

Abstract: We have determined the nucleotide sequence of the gene encoding the ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum, an antigen that has been shown to confer protective immunity on monkeys. The sequence has enabled us to predict the structure of the RESA gene and the amino acid sequence of its protein product. The gene consists of two exons with a short intron located near the 5' end of the coding region. A hydrophobic amino acid segment predicted for the 3' end of exon 1 is consistent with the possibility that exon 1 encodes trafficking signal sequences. We show that restriction fragment length polymorphisms can be used to define two different alleles of RESA, represented by isolates FC27 and NF7, and compare the FC27 sequence with that of a long cDNA clone from NF7 described previously.

Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance

Publisher: Public Library of Science (PLoS)

Date: 22-04-2015

DOI: 10.1371/JOURNAL.PBIO.1002132

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

Publisher: Proceedings of the National Academy of Sciences

Date: 30-07-2002

DOI: 10.1073/PNAS.162566999

Abstract: 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 F 2 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.

Familial focal epilepsy with variable foci mapped to chromosome 22q12: Expansion of the phenotypic spectrum

Publisher: Wiley

Date: 10-07-2012

DOI: 10.1111/J.1528-1167.2012.03585.X

Abstract: We aimed to refine the phenotypic spectrum and map the causative gene in two families with familial focal epilepsy with variable foci (FFEVF). A new five-generation Australian FFEVF family (A) underwent electroclinical phenotyping, and the original four-generation Australian FFEVF family (B) (Ann Neurol, 44, 1998, 890) was re-analyzed, including new affected in iduals. Mapping studies examined segregation at the chromosome 22q12 FFEVF region. In family B, the original whole genome microsatellite data was reviewed. Five subjects in family A and 10 in family B had FFEVF with predominantly awake attacks and active EEG studies with a different phenotypic picture from other families. In family B, reanalysis excluded the tentative 2q locus reported. Both families mapped to chromosome 22q12. Our results confirm chromosome 22q12 as the solitary locus for FFEVF. Both families show a subtly different phenotype to other published families extending the clinical spectrum of FFEVF.

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

Publisher: Springer Science and Business Media LLC

Date: 20-05-2005

DOI: 10.1007/S00439-005-1296-X

Abstract: 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 in iduals 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 in iduals. These findings provide evidence of a new autosomal dominant glaucoma locus on the short arm of chromosome 3.

Host resistance to malaria: using mouse models to explore the host response.

Publisher: Springer Science and Business Media LLC

Date: 30-11-2011

DOI: 10.1007/S00335-010-9302-6

Abstract: Malaria is a disease that infects over 500 million people, causing at least 1 million deaths every year, with the majority occurring in developing countries. The current antimalarial arsenal is becoming dulled due to the rapid rate of resistance of the parasite. However, in populations living in malaria-endemic regions there are many ex les of genetic-based resistance to the severe effects of the parasite Plasmodium. Defining the genetic factors behind host resistance has been an area of great scientific interest over the last few decades this review summarizes the current knowledge of the genetic loci involved. Perhaps the lessons learned from the natural variation in both the human populations and experimental mouse models of infection may pave the way for novel resistance-proof antimalarials.

Evidence for a common genetic aetiology in high-risk families with multiple haematological malignancy subtypes

Publisher: Wiley

Date: 08-2010

DOI: 10.1111/J.1365-2141.2010.08267.X

Abstract: A family history of a haematological malignancy (HM) is known to be a risk factor for HMs. However, collections of large families with multiple cases of varied disease types are relatively rare. We describe a collection of 12 families with dense aggregations of multiple HM subtypes. Cases were ascertained from a population based study conducted between 1972 and 1980 in Tasmania, Australia. Diagnoses were confirmed through review and re-examination of stored tissue, pathology reports, Tasmanian Cancer Registry and flow cytometry records. Family trees were generated and kinship coefficients were calculated for all pairs of affected in iduals. 120 cases were found in these families. Cases diagnosed with chronic lymphocytic leukaemia (CLL) demonstrated the most significantly increased aggregation (P 53 years), did not aggregate together in families with disease that presented at an earlier age (<20 years) (P = 0.009).

A novel ENU-induced ankyrin-1 mutation impairs parasite invasion and increases erythrocyte clearance during malaria infection in mice

Publisher: Cold Spring Harbor Laboratory

Date: 31-08-2016

DOI: 10.1101/072587

Abstract: Genetic defects in various red blood cell (RBC) cytoskeletal proteins have been long associated with changes in susceptibility towards malaria infection. In particular, while ankyrin (Ank-1) mutations account for approximately 50% of hereditary spherocytosis (HS) cases, an association with malaria is not well-established, and conflicting evidence has been reported. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced ankyrin mutation MRI61689 that gives rise to two different ankyrin transcripts: one with an introduced splice acceptor site resulting a frameshift, the other with a skipped exon. Ank-1 (MRI61689/+) mice exhibit an HS-like phenotype including reduction in mean corpuscular volume (MCV), increased osmotic fragility and reduced RBC deformability. They were also found to be resistant to rodent malaria Plasmodium chabaudi infection. Parasites in Ank-1 (MRI61689/+) erythrocytes grew normally, but red cells showed resistance to merozoite invasion. Uninfected Ank-1 (MRI61689/+) erythrocytes were also more likely to be cleared from circulation during infection the “bystander effect”. This increased clearance is a novel resistance mechanism which was not observed in previous ankyrin mouse models. We propose that this bystander effect is due to reduced deformability of Ank-1 (MRI61689/+) erythrocytes. This paper highlights the complex roles ankyrin plays in mediating malaria resistance.

Mutation detection using mass spectrometric separation of tiny oligonucleotide fragments

Publisher: Cold Spring Harbor Laboratory

Date: 12-06-2002

DOI: 10.1101/GR.GR-1578R

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

Publisher: American Society of Hematology

Date: 12-2004

DOI: 10.1182/BLOOD-2004-06-2234

Abstract: In most myeloid leukemias induced in mice by γ-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.

Resistance to Leishmania major is linked to the H2 region on chromosome 17 and to chromosome 9

Publisher: Rockefeller University Press

Date: 05-05-1997

DOI: 10.1084/JEM.185.9.1705

Abstract: In Leishmaniasis, as in many infectious diseases, clinical manifestations are determined by the interaction between the genetics of the host and of the parasite. Here we describe studies mapping two loci controlling resistance to murine cutaneous leishmaniasis. Mice infected with L. major show marked genetic differences in disease manifestations: BALB/c mice are susceptible, exhibiting enlarging lesions that progress to systemic disease and death, whereas C57BL/6 are resistant, developing small, self-healing lesions. F2 animals from a C57BL/6 × BALB/c cross showed a continuous distribution of lesion score. Quantitative trait loci (QTL) have been mapped after a non-parametric QTL analysis on a genome-wide scan on 199 animals. QTLs identified were confirmed in a second cross of 271 animals. Linkage was confirmed to a chromosome 9 locus (D9Mit67–D9Mit71) and to a region including the H2 locus on chromosome 17. These have been named lmr2 and lmr1, respectively.

Fine Mapping of Leishmania major Susceptibility Locus lmr2 and Evidence of a Role for Fli1 in Disease and Wound Healing

Publisher: American Society for Microbiology

Date: 06-2010

DOI: 10.1128/IAI.00126-10

Abstract: Genetic linkage studies of the host response to Leishmania major , the causative agent of cutaneous leishmaniasis, have identified significant genetic complexity in humans and mice. In the mouse model, multiple loci have been implicated in susceptibility to infection, but to date, the genes underlying these loci have not been identified. We now describe the contribution of a novel candidate gene, Fli1 , to both L. major resistance and enhanced wound healing. We have previously mapped the L. major response locus, lmr2 , to proximal chromosome 9 in a genetic cross between the resistant C57BL/6 strain and the susceptible BALB/c strain. We now show that the presence of the resistant C57BL/6 lmr2 allele in susceptible BALB/c mice confers an enhanced L. major resistance and wound healing phenotype. Fine mapping of the lmr2 locus permitted the localization of the lmr2 quantitative trait locus to a 5-Mb interval comprising 21 genes, of which microarray analysis was able to identify differential expression in 1 gene— Fli1 . Analysis of Fli1 expression in wounded and L. major -infected skin and naïve and infected lymph nodes validated the importance of Fli1 in lesion resolution and wound healing and identified 3 polymorphisms in the Fli1 promoter, among which a GA repeat element may be the important contributor.

The advantages of dense marker sets for linkage analysis with very large families

Publisher: Springer Science and Business Media LLC

Date: 25-01-2007

DOI: 10.1007/S00439-007-0323-5

Abstract: Dense sets of hundreds of thousands of markers have been developed for genome-wide association studies. These marker sets are also beneficial for linkage analysis of large, deep pedigrees containing distantly related cases. It is impossible to analyse jointly all genotypes in large pedigrees using the Lander-Green Algorithm, however, as marker density increases it becomes less crucial to analyse all in iduals' genotypes simultaneously. In this report, an approximate multipoint non-parametric technique is described, where large pedigrees are split into many small pedigrees, each containing just two cases. This technique is demonstrated, using phased data from the International Hapmap Project to simulate sets of 10,000, 50,000 and 250,000 markers, showing that it becomes increasingly accurate as more markers are genotyped. This method allows routine linkage analysis of large families with dense marker sets and represents a more easily applied alternative to Monte Carlo Markov Chain methods.

Identity-by-descent approach to gene localisation in eight individuals affected by keratoconus from north-west Tasmania, Australia

Publisher: Springer Science and Business Media LLC

Date: 28-03-2002

DOI: 10.1007/S00439-002-0705-7

Abstract: The minimum physical distance surrounding a candidate gene has been determined in founder populations by studying allele sharing and then mapping historical recombination events. In this study, we developed a novel minimalistic approach by using the genetically isolated population of Tasmania, Australia, to identify candidate gene loci in a small number of in iduals of unknown genetic relationship affected by a dominant disorder. Keratoconus, an inheritable non-inflammatory progressive degeneration of the cornea, is present at a five-fold increased incidence in Burnie, a coastal town on the island of Tasmania. Based on the fundamental assumption that in iduals with keratoconus from this town are likely to be related through a founder effect, a 10-cM interval genome scan was conducted on six patients of undefined genetic relationship and one affected sib-pair to identify commonly shared chromosomal segments for the elucidation of candidate gene loci. Analysis of allele sharing revealed four markers on three chromosomes where all eight in iduals shared a common allele on at least one chromosome, and thirteen markers where all but one patient shared common alleles. No excess of allele sharing was observed at any marker tested on chromosome 21, a suggested candidate chromosome for keratoconus. Further analysis of positive loci revealed suggestive association at 20q12, where significant deviation in allele frequency D20S119 ( P=2.1 x 10(-5)) is observed when additional Tasmanian keratoconus s les are genotyped. Identification of a conserved minimal chromosomal haplotype around D20S119 in related Tasmanian patients suggests association with this locus, however association with the nearby candidate gene MMP-9 has been excluded.

Adenosine monophosphate deaminase 3 activation shortens erythrocyte half-life and provides malaria resistance in mice

Publisher: American Society of Hematology

Date: 09-2016

DOI: 10.1182/BLOOD-2015-09-666834

Abstract: AMPD3 activation reduces red blood cell half-life, which is associated with increased oxidative stress and phosphatidylserine exposure. AMPD3 activation causes malaria resistance through increased RBC turnover and increased RBC production.

Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major

Publisher: Springer Science and Business Media LLC

Date: 05-02-2004

DOI: 10.1038/SJ.GENE.6364056

Fragmentation reactions of all 64 protonated trimer oligodeoxynucleotides and 16 mixed base tetramer oligodeoxynucleotides via tandem mass spectrometry in an ion trap

Publisher: Elsevier BV

Date: 2000

DOI: 10.1016/S1387-3806(99)00150-5

Treatment of Erythrocytes with the 2-Cys Peroxiredoxin Inhibitor, Conoidin A, Prevents the Growth of Plasmodium falciparum and Enhances Parasite Sensitivity to Chloroquine

Publisher: Public Library of Science (PLoS)

Date: 03-04-2014

DOI: 10.1371/JOURNAL.PONE.0092411

B-cell-targeted therapy for systemic lupus erythematosus: An update

Publisher: Springer Science and Business Media LLC

Date: 2008

DOI: 10.2165/00063030-200822040-00003

Abstract: Systemic lupus erythematosus (SLE) is a classic autoimmune disease characterized by a myriad of immune system aberrations, most likely resulting from pathogenic autoantibody production, immune complex deposition, and subsequent end-organ damage. B cells play a key role in the pathogenesis therefore, B-cell-targeted therapies, including B-cell depletion and blockage of B-cell survival factors such as B-lymphocyte stimulator (BLyS), are potential therapeutic targets for SLE. In uncontrolled clinical trials from approximately 20 studies, rituximab--a mouse-human chimeric anti-CD20 monoclonal antibody that effectively depletes B cells--has been demonstrated to reduce disease activity and decrease serum autoantibodies, with a clinical response of 86% in a case series of approximately 400 SLE patients with refractory disease, with or without concomitant use of cyclophosphamide. Epratuzumab, a humanized anti-CD22 monoclonal antibody that partially depletes B cells, has also been shown to reduce disease activity but not to decrease autoantibody levels in patients with moderately active SLE. Randomized controlled phase I/II trials in patients with active SLE have documented that belimumab, a humanized anti-BLyS monoclonal antibody, reduces B-cell numbers, inhibits disease activity and decreases anti-double-stranded DNA autoantibody in SLE patients. All these therapies are well tolerated, but accompanying infectious complications have been observed. Other B-cell-targeted therapies such as 'humanized' monoclonal antibodies to CD20 (e.g. ocrelizumab) and agents that interrupt B-cell/T-cell interactions also have potential, and the efficacy of these, along with rituximab, belimumab and epratuzumab, needs to be determined by randomized controlled trials.

Decreases in HCN mRNA expression in the hippocampus after kindling and status epilepticus in adult rats

Publisher: Wiley

Date: 10-2008

DOI: 10.1111/J.1528-1167.2008.01593.X

Abstract: Studies in animal models and patients have implicated changes in hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) expression in the pathogenesis of temporal lobe epilepsy (TLE). However, the nature of HCN changes during the epileptogenic process and their commonality across different TLE models is unknown. Here HCN1 and HCN2 mRNA expression was quantitatively measured at different time points during epileptogenesis in two distinct animal models of TLE the kainic acid (KA)-induced status epilepticus (SE) and amygdala kindling models. Hippoc al subregions (CA1, CA3, and dentate gyrus [DG]) and entorhinal cortex were dissected at different time-points. For KA-induced SE animals this was 24 h, 7 days (preepileptic), and 6 weeks (epileptic) post status. For amygdala kindling animals this was 2 weeks after reaching either "partially kindled" (one class II/III seizure) or "fully kindled" (five class V seizures) states. Quantification of regional hippoc al neuronal loss in the KA-treated animals was done using NeuN immunofluorescence and confocal microscopy. HCN mRNA levels decreased in an isoform and region specific manner at all time points after KA-induced SE. The decrease in neuronal number could not account for all reductions in HCN mRNA levels post-KA insult, implicating transcriptional changes. A reduction in HCN2 mRNA levels was also observed in fully kindled animals in the CA3 region. A reduction in HCN mRNA levels is present in two different models of TLE. This supports the case that a reduction in HCN channel expression is an accompaniment of epileptogenesis in different adult models of TLE.

Identification of the Mhc Region as an Asthma Susceptibility Locus in Recombinant Congenic Mice

Publisher: American Thoracic Society

Date: 08-2011

DOI: 10.1165/RCMB.2009-0369OC

Risk analysis of prostate cancer in practical, a multinational consortium, using 25 known prostate cancer susceptibility loci

Publisher: American Association for Cancer Research (AACR)

Date: 07-2015

DOI: 10.1158/1055-9965.EPI-14-0317

Abstract: Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify in iduals by their risk of prostate cancer. Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 in iduals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev 24(7) 1121–9. ©2015 AACR.

Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with Multiple Sclerosis susceptibility

Publisher: Public Library of Science (PLoS)

Date: 08-02-2011

DOI: 10.1371/JOURNAL.PONE.0016964

Platelets Kill Intraerythrocytic Malarial Parasites and Mediate Survival to Infection

Publisher: American Association for the Advancement of Science (AAAS)

Date: 06-02-2009

DOI: 10.1126/SCIENCE.1166296

Abstract: Platelets play a critical role in the pathogenesis of malarial infections by encouraging the sequestration of infected red blood cells within the cerebral vasculature. But platelets also have well-established roles in innate protection against microbial infections. We found that purified human platelets killed Plasmodium falciparum parasites cultured in red blood cells. Inhibition of platelet function by aspirin and other platelet inhibitors abrogated the lethal effect human platelets exert on P. falciparum parasites. Likewise, platelet-deficient and aspirin-treated mice were more susceptible to death during erythrocytic infection with Plasmodium chabaudi . Both mouse and human platelets bind malarial-infected red cells and kill the parasite within. These results indicate a protective function for platelets in the early stages of erythrocytic infection distinct from their role in cerebral malaria.

A new standard for the assessment of disease progression in murine cutaneous leishmaniasis

Publisher: Wiley

Date: 05-2000

DOI: 10.1046/J.1365-3024.2000.00305.X

Abstract: Infection of mice with Leishmania major has been used both as a model for the cutaneous disease in humans and as a model for the more general control and function of helper T cells in immunity. In both cases, disease patterns and disease progression have been assessed by two complementary methods, lesion size and parasite burden in the draining lymph nodes. We propose a much improved method for the graphical representation of lesion development which conveys more information with better accuracy. We also describe a polymerase chain reaction method for determining parasite burden, which is faster and allows the analysis of larger numbers of experimental animals than the current limiting dilution analysis. Moreover, these methods are equally applicable to other infectious diseases, an obvious one being schistosomiasis.

Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease

Publisher: Springer Science and Business Media LLC

Date: 10-2009

DOI: 10.1038/EJHG.2008.171

Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1.

Publisher: American Society for Microbiology

Date: 11-2015

DOI: 10.1128/IAI.00926-15

Abstract: The treatment of iron deficiency in areas of high malaria transmission is complicated by evidence which suggests that iron deficiency anemia protects against malaria, while iron supplementation increases malaria risk. Iron deficiency anemia results in an array of pathologies, including reduced systemic iron bioavailability and abnormal erythrocyte physiology however, the mechanisms by which these pathologies influence malaria infection are not well defined. In the present study, the response to malaria infection was examined in a mutant mouse line, Tfrc MRI24910 , identified during an N -ethyl- N -nitrosourea (ENU) screen. This line carries a missense mutation in the gene for transferrin receptor 1 (TFR1). Heterozygous mice exhibited reduced erythrocyte volume and density, a phenotype consistent with dietary iron deficiency anemia. However, unlike the case in dietary deficiency, the erythrocyte half-life, mean corpuscular hemoglobin concentration, and intraerythrocytic ferritin content were unchanged. Systemic iron bioavailability was also unchanged, indicating that this mutation results in erythrocytic iron deficiency without significantly altering overall iron homeostasis. When infected with the rodent malaria parasite Plasmodium chabaudi adami , mice displayed increased parasitemia and succumbed to infection more quickly than their wild-type littermates. Transfusion of fluorescently labeled erythrocytes into malaria parasite-infected mice demonstrated an erythrocyte-autonomous enhanced survival of parasites within mutant erythrocytes. Together, these results indicate that TFR1 deficiency alters erythrocyte physiology in a way that is similar to dietary iron deficiency anemia, albeit to a lesser degree, and that this promotes intraerythrocytic parasite survival and an increased susceptibility to malaria in mice. These findings may have implications for the management of iron deficiency in the context of malaria.

Host porphobilinogen deaminase deficiency confers malaria resistance in Plasmodium chabaudi but not in Plasmodium berghei or Plasmodium falciparum during intraerythrocytic growth

Publisher: Cold Spring Harbor Laboratory

Date: 27-03-2019

DOI: 10.1101/589242

Abstract: An important component in host resistance to malaria infection are inherited mutations that give rise to abnormalities and deficiencies in erythrocyte proteins and enzymes. Understanding how such mutations confer protection against the disease may be useful for developing new treatment strategies. A mouse ENU-induced mutagenesis screen for novel malaria resistance-conferring mutations identified a novel nonsense mutation in the gene encoding porphobilinogen deaminase (PBGD) in mice, denoted here as Pbgd MRI58155 . Heterozygote Pbgd MRI58155 mice exhibited approximately 50% reduction in cellular PBGD activity in both mature erythrocytes and reticulocytes, although enzyme activity was approximately 10 times higher in reticulocytes than erythrocytes. When challenged with blood-stage P. chabaudi , which preferentially infects erythrocytes, heterozygote mice showed a modest but significant resistance to infection, including reduced parasite growth. A series of assays conducted to investigate the mechanism of resistance indicated that mutant erythrocyte invasion by P. chabaudi was normal, but that following intraerythrocytic establishment a significantly greater proportions of parasites died and therefore affected their ability to propagate. The Plasmodium resistance phenotype was not recapitulated in Pbgd -deficient mice infected with P. berghei , which prefers reticulocytes, or when P. falciparum was cultured in erythrocytes from patients with acute intermittent porphyria (AIP), which had modest (20-50%) reduced levels of PBGD. Furthermore, the growth of Pbgd -null P. falciparum and Pbgd -null P. berghei parasites, which grew at the same rate as their wild-type counterparts in normal cells, were not affected by the PBGD-deficient background of the AIP erythrocytes or Pbgd -deficient mice. Our results confirm the dispensability of parasite PBGD for P. berghei infection and intraerythrocytic growth of P. falciparum , but for the first time identify a requirement for host erythrocyte PBGD by P. chabaudi during in vivo blood stage infection. The causative agent of malaria, Plasmodium , adopts a parasitic lifestyle during erythrocyte infection, and as such relies on host cell factors for its survival and growth. Host-encoded mutations that alter the availability of these factors confer disease resistance, including several well-known genetic erythrocyte abnormalities that have arisen due to the historical evolutionary pressure of malaria. This study identified in mice a novel malaria resistance-conferring host mutation in the heme biosynthesis enzyme, porphobilinogen deaminase (PBGD), and compared the relative requirements by Plasmodium for the host versus parasite-encoded forms of PBGD in both in vivo and in vitro settings. The findings demonstrated that parasite PBGD was dispensable, but that the host enzyme was important specifically during in vivo infection by P. chabaudi , and collectively suggest that Plasmodium requires a certain threshold of the enzyme to sustain its intraerythrocytic growth. Plasmodium may therefore be vulnerable to other interventions that limit host PBGD activity.

What can bioinformatics do for parasitology research?

Publisher: Elsevier BV

Date: 09-1998

DOI: 10.1016/S0169-4758(98)01299-X

In vivo assessment of rodent Plasmodium parasitemia and merozoite invasion by flow cytometry.

Publisher: MyJove Corporation

Date: 05-04-2015

DOI: 10.3791/52736

Mapping of the plasmodium chabaudi resistance locus char2

Publisher: American Society for Microbiology

Date: 10-2006

DOI: 10.1128/IAI.01690-05

Abstract: 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.

No maternally inherited diabetes and deafness mutations in a sample of 193 Tasmanian diabetics with glaucoma

Publisher: Informa UK Limited

Date: 2007

DOI: 10.1080/13816810701201971

Anticipation in familial hematologic malignancies

Publisher: American Society of Hematology

Date: 27-01-2011

DOI: 10.1182/BLOOD-2010-07-296475

Abstract: We describe a collection of 11 families with ≥ 2 generations of family members whose condition has been diagnosed as a hematologic malignancy. In 9 of these families there was a significant decrease in age at diagnosis in each subsequent generation (anticipation). The mean age at diagnosis in the first generation was 67.8 years, 57.1 years in the second, and 41.8 years in the third (P .0002). This was confirmed in both direct parent-offspring pairs with a mean reduction of 19 years in the age at diagnosis (P = .0087) and when the analysis was repeated only including cases of mature B-cell neoplasm (P = .0007). We believe that these families provide further insight into the nature of the underlying genetic mechanism of predisposition in these families.

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

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 10-2005

DOI: 10.1167/IOVS.05-0312

Abstract: 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. 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 in iduals. 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. 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.

Complete amino acid sequence and maturation of the mouse submaxillary gland renin precursor

Publisher: Springer Science and Business Media LLC

Date: 07-1982

DOI: 10.1038/298090A0

Abstract: To assess how often older adults admitted to hospital for common non-cardiac conditions were discharged with intensified antihypertensive treatment, and to identify markers of appropriateness for these intensifications. Retrospective cohort study. US Veterans Administration Health System. Patients aged 65 years or over with hypertension admitted to hospital with non-cardiac conditions between 2011 and 2013. Intensification of antihypertensive treatment, defined as receiving a new or higher dose antihypertensive agent at discharge compared with drugs used before admission. Hierarchical logistic regression analyses were used to control for characteristics of patients and hospitals. Among 14 915 older adults (median age 76, interquartile range 69-84), 9636 (65%) had well controlled outpatient blood pressure before hospital admission. Overall, 2074 (14%) patients were discharged with intensified antihypertensive treatment, more than half of whom (1082) had well controlled blood pressure before admission. After adjustment for potential confounders, elevated inpatient blood pressure was strongly associated with being discharged on intensified antihypertensive regimens. Among patients with previously well controlled outpatient blood pressure, 8% (95% confidence interval 7% to 9%) of patients without elevated inpatient blood pressure, 24% (21% to 26%) of patients with moderately elevated inpatient blood pressure, and 40% (34% to 46%) of patients with severely elevated inpatient blood pressure were discharged with intensified antihypertensive regimens. No differences were seen in rates of intensification among patients least likely to benefit from tight blood pressure control (limited life expectancy, dementia, or metastatic malignancy), nor in those most likely to benefit (history of myocardial infarction, cerebrovascular disease, or renal disease). One in seven older adults admitted to hospital for common non-cardiac conditions were discharged with intensified antihypertensive treatment. More than half of intensifications occurred in patients with previously well controlled outpatient blood pressure. More attention is needed to reduce potentially harmful overtreatment of blood pressure as older adults transition from hospital to home.

Governing networks in tourism: what have we achieved, what is still to be done and learned?

Publisher: Emerald

Date: 16-11-2015

DOI: 10.1108/TR-04-2015-0013

Abstract: – Networks and networking are ubiquitous concepts in tourism, their importance appreciated by scholars and practitioners. Tourism research has developed elaborate methods and concepts to grasp the numerous variants of tourism networks and to gain insights into their governance. In particular, Association Internationale D’Experts Scientifiques Du Tourisme (AIEST) and its official journal, Tourism Review , have made significant contributions to the achievements in this research area. After approximately two decades of intensive research on tourism networks, it is appropriate to pause for a moment to critically assess the results achieved, to compare them with partly old, partly newly, emerging real-world challenges, and to explore future directions. – This paper provides a selective and critical overview of the state-of-the-art in research on governing networks in tourism. This overview of eight major achievements is combined with an exploratory, comparative analysis of qualitative interviews with tourism practitioners. – Considering the two sources mentioned above, the study derives seven suggestions for future directions in research on network governance in tourism. These relate to the big picture of tourism governance, e-governance, disparities within networks, negative aspects of networking, dynamism of networks, network moderators and means of network steering. – Due to its design, the paper is uniquely able to compare real-world issues with up-to-date theoretical achievements, and will contribute to bringing them closer together in future approaches. Hence, it is relevant for both academic readers and practitioners.

A Ca_v3.2 T-type calcium channel point mutation has splice-variant-specific effects on function and segregates with seizure expression in a polygenic rat model of absence epilepsy

Publisher: Society for Neuroscience

Date: 14-01-2009

DOI: 10.1523/JNEUROSCI.5295-08.2009

Abstract: Low-voltage-activated, or T-type, calcium (Ca 2+ ) channels are believed to play an essential role in the generation of absence seizures in the idiopathic generalized epilepsies (IGEs). We describe a homozygous, missense, single nucleotide (G to C) mutation in the Ca v 3.2 T-type Ca 2+ channel gene ( Cacna1h ) in the genetic absence epilepsy rats from Strasbourg (GAERS) model of IGE. The GAERS Ca v 3.2 mutation ( gcm ) produces an arginine to proline (R1584P) substitution in exon 24 of Cacna1h , encoding a portion of the III–IV linker region in Ca v 3.2. gcm segregates codominantly with the number of seizures and time in seizure activity in progeny of an F1 intercross. We have further identified two major thalamic Cacna1h splice variants, either with or without exon 25. gcm introduced into the splice variants acts “epistatically,” requiring the presence of exon 25 to produce significantly faster recovery from channel inactivation and greater charge transference during high-frequency bursts. This gain-of-function mutation, the first reported in the GAERS polygenic animal model, has a novel mechanism of action, being dependent on exonic splicing for its functional consequences to be expressed.

Genetic absence epilepsy rats from Strasbourg have increased corticothalamic expression of stargazin

Publisher: Elsevier BV

Date: 08-2008

DOI: 10.1016/J.NBD.2008.04.012

Abstract: Stargazin is membrane bound protein involved in trafficking, synapse anchoring and biophysical modulation of AMPA receptors. A quantitative trait locus in chromosome 7 containing the stargazin gene has been identified as controlling the frequency and duration of absence seizures in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Furthermore, mutations in this gene result in the Stargazer mouse that displays an absence epilepsy phenotype. GAERS stargazin mRNA expression is increased 1.8 fold in the somatosensory cortex and by 1.3 fold in the thalamus. The changes were present before and after the onset of absence seizures indicating that increases are not a secondary consequence of the seizures. Stargazin protein expression was also significantly increased in the somatosensory cortex after the onset of spontaneous seizures. The results are of significant importance beyond the GAERS model, as they are the first to show that an increase in stargazin expression may be pro-epileptic.

Genes and susceptibility to leishmaniasis

Publisher: Elsevier

Date: 2005

DOI: 10.1016/S0065-308X(05)59001-8

Ankyrin-1 gene exhibits allelic heterogeneity in conferring protection against malaria

Publisher: Oxford University Press (OUP)

Date: 09-0001

DOI: 10.1534/G3.117.300079

Abstract: Allelic heterogeneity is a common phenomenon where a gene exhibits a different phenotype depending on the nature of its genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host–parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 (Ank-1) which exhibits allelic-dependent heterogeneous phenotypes during malaria infections. We conducted an ENU mutagenesis screen on mice and identified two Ank-1 mutations, one resulting in an amino acid substitution (MRI95845), and the other a truncated Ank-1 protein (MRI96570). Both mutations caused hereditary spherocytosis-like phenotypes and confer differing protection against Plasmodium chabaudi infections. Upon further examination, the Ank-1(MRI96570) mutation was found to inhibit intraerythrocytic parasite maturation, whereas Ank-1(MRI95845) caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between two Ank-1 mutations. Despite the lack of direct evidence from population studies, this data further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasized the importance of such phenomena in achieving a better understanding of host–parasite interactions, which could be the basis of future studies.

Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status

Publisher: Public Library of Science (PLoS)

Date: 18-03-2016

DOI: 10.1371/JOURNAL.PGEN.1005853

Genetics of murine leishmaniasis

Publisher: Oxford University Press (OUP)

Date: 2005

DOI: 10.1093/BFGP/4.3.270

Abstract: 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 ex le, 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.

Host genetics in malaria: lessons from mouse studies

Publisher: Springer Science and Business Media LLC

Date: 28-03-2018

DOI: 10.1007/S00335-018-9744-9

Abstract: Malaria remains a deadly parasitic disease caused by Plasmodium, claiming almost half a million lives every year. While parasite genetics and biology are often the major targets in many studies, it is becoming more evident that host genetics plays a crucial role in the outcome of the infection. Similarly, Plasmodium infections in mice also rely heavily on the genetic background of the mice, and often correlate with observations in human studies, due to their high genetic homology with humans. As such, murine models of malaria are a useful tool for understanding host responses during Plasmodium infections, as well as dissecting host-parasite interactions through various genetic manipulation techniques. Reverse genetic approach such as quantitative trait loci studies and random mutagenesis screens have been employed to discover novel host genes that affect malaria susceptibility in mouse models, while other targeted studies utilize mouse models to validate observation from human studies. Herein, we review the findings from the past and present studies on murine models of hepatic and erythrocytic stages of malaria and speculate on how the current mouse models benefit from the recent development in CRISPR/Cas9 gene editing technology.

Isolation and regional mapping of 110 chromosome 22 STSs

Publisher: Elsevier BV

Date: 12-1994

DOI: 10.1006/GENO.1994.1671

Abstract: As part of a larger effort to create a complete physical map of the human genome, we have developed 110 new STSs specific for human chromosome 22. Clones isolated and sequenced from chromosome 22-enriched libraries provided a source of primers. These STSs were localized to regions of chromosome 22 using a panel of somatic cell hybrids. In building a refined physical map of chromosome 22, this set of STSs should provide a substantial backbone.

Identification and analysis of error types in high-throughput genotyping

Publisher: Elsevier BV

Date: 09-2000

DOI: 10.1086/303048

Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum.

Publisher: American Association for the Advancement of Science (AAAS)

Date: 07-12-2012

DOI: 10.1126/SCIENCE.1228892

Abstract: Activated platelets bound to malaria parasite–infected red blood cells were once thought to contribute to pathogenesis, but recently the platelets have been found to have a protective effect. McMorran et al. (p. 1348 see the Perspective by Engwerda and Good ) extended this discovery to show that platelet activation releases intracellular granules containing a chemokine, PF4, which is internalized by Plasmodium falciparum –infected red cells. Subsequently, mature parasites within the cells die. The Duffy blood-group factor on red blood cells is known to act as a nonspecific receptor for chemokines, such as PF4, as well as a receptor for cell invasion by other species of malaria parasite. When the Duffy antigen was blocked by antibody treatment, platelets and PF4 were less able to kill the P. falciparum parasites within.

Wound healing response is a major contributor to the severity of cutaneous leishmaniasis in the ear model of infection

Publisher: Wiley

Date: 19-09-2007

DOI: 10.1111/J.1365-3024.2007.00969.X

Abstract: In the conventional mouse model for cutaneous leishmaniasis involving infection with stationary phase Leishmania major promastigotes at the base of the tail, mice congenic for leishmaniasis resistance loci designated lmr1,2,3 cured their lesions more rapidly and laid down more ordered collagen fibres than the susceptible parental BALB/c mice, while the opposite was the case for the congenic mice carrying the susceptibility loci on the resistant C57BL/6 background. In that model, we showed that wound healing and not T cell responses played a major role in determining the resolution of skin infection. Here, we show a similar disease phenotype in the mouse model that mimics more closely the situation in humans, that is, strictly intradermal infection in the ear pinna with small numbers of metacyclic promastigotes. The data show that at the site of infection the innate and adaptive immune responses act in concert to clear parasites, and induce tissue repair and wound healing. Importantly, the data show that the host responses controlled by the lmr loci, which act locally to control infection in the skin, are distinct from the host responses operating systemically in the draining lymph node.

Mice That Are Congenic for the char2 Locus Are Susceptible to Malaria

Publisher: American Society for Microbiology

Date: 08-2002

DOI: 10.1128/IAI.70.8.4750-4753.2002

Abstract: A major advance has been made towards the positional cloning of char2 (a quantitative trait locus encoding resistance to Plasmodium chabaudi malaria). Mice congenic for the locus have been used to fine map the gene and to prove that char2 plays a significant role in the outcome of malarial infection, independently of other resistance loci.

A flow cytometric assay to quantify invasion of red blood cells by rodent Plasmodium parasites in vivo.

Publisher: Springer Science and Business Media LLC

Date: 17-03-2014

DOI: 10.1186/1475-2875-13-100

Generating mouse models of retinal disease using ENU mutagenesis

Publisher: Elsevier BV

Date: 02-2002

DOI: 10.1016/S0042-6989(01)00232-2

Abstract: We used the chemical mutagen, N-ethyl-N-nitrosourea, to induce random point mutations in the germline of the mouse strain C57BL/6 in order to generate models of retinal diseases. 1163 mutagenised first generation mice produced using this approach were examined for eye abnormalities. Approximately one-third (412) presented with some form of ocular abnormality. Most changes were unilateral and confined to the anterior segment of the eye. Less than 10% (44) of identified changes affected the posterior segment of the eye. 21 mice with varying ocular abnormalities, including 17 with retinal changes, were bred to produce second generation mice to confirm genetic inheritance. Genetic inheritance was confirmed in several of these lines including three with retinal changes.

Controlling malaria and African trypanosomiasis: The role of the mouse

Publisher: Oxford University Press (OUP)

Date: 2005

DOI: 10.1093/BFGP/4.3.214

Abstract: 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.

Human Leukocyte Antigen-DR15, Low Infant Sibling Exposure and Multiple Sclerosis: Gene-Environment Interaction

Publisher: Wiley

Date: 02-2010

DOI: 10.1002/ANA.21849

CTLA-4 and multiple sclerosis: The A49G single nucleotide polymorphism shows no association with multiple sclerosis in a Southern Australian population

Publisher: Elsevier BV

Date: 30-05-2008

DOI: 10.1016/J.JNEUROIM.2008.02.001

Can nature's defence against malaria be mimicked by the development of host-directed therapies?

Publisher: Springer Science and Business Media LLC

Date: 23-03-2004

DOI: 10.1038/SJ.TPJ.6500241

Improvements in allelic discrimination of microsatellite markers using denaturing polyacrylamide gel electrophoresis

Publisher: Springer Science and Business Media LLC

Date: 08-2000

DOI: 10.1007/S003350010122

Abstract: Poor resolution, retarded progress of DNA through gels, and variable sizing of DNA fragments between and within gels hinder accurate genotyping of some simple sequence length polymorphism (SSLP) markers with the Perkin Elmer Applied Biosystems 377 Sequenator. These problems are similar to renaturation related problems observed in DNA sequencing gels. PCR products especially susceptible to these problems are shown to have higher melting temperatures (T(m)) than others. Gels containing increased concentrations of denaturants allow greater accuracy in allelic discrimination. This is especially beneficial where quantification is necessary.

A Novel ENU-Mutation in Ankyrin-1 Disrupts Malaria Parasite Maturation in Red Blood Cells of Mice

Publisher: Public Library of Science (PLoS)

Date: 19-06-2012

DOI: 10.1371/JOURNAL.PONE.0038999

Familial recurrence risks for multiple sclerosis in Australia

Publisher: BMJ

Date: 07-05-2011

DOI: 10.1136/JNNP.2010.233064

Abstract: Genetic susceptibility to multiple sclerosis (MS) has been recognised for many years. Considerable data exist from the northern hemisphere regarding the familial recurrence risks for MS, but there are few data for the southern hemisphere and regions at lower latitude such as Australia. To investigate the interaction between environmental and genetic causative factors in MS, the authors undertook a familial recurrence risk study in three latitudinally distinct regions of Australia. Immediate and extended family pedigrees have been collected for three cohorts of people with MS in Queensland, Victoria and Tasmania spanning 15° of latitude. Age of onset data from Queensland were utilised to estimate age-adjusted recurrence rates. Recurrence risks in Australia were significantly lower than in studies from northern hemisphere populations. The age-adjusted risk for siblings across Australia was 2.13% compared with 3.5% for the northern hemisphere. A similar pattern was seen for other relatives. The risks to relatives were proportional to the population risks for each site, and hence the sibling recurrence-risk ratio (λ(s)) was similar across all sites. The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the λ(s) is similar to the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture.

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Publisher: Springer Science and Business Media LLC

Date: 08-2011

DOI: 10.1038/NATURE10251

The role of host genetics in leishmaniasis

Publisher: Elsevier BV

Date: 08-2009

DOI: 10.1016/J.PT.2009.05.004

Abstract: Leishmaniasis is one of the world's important infectious diseases. It is prevalent in tropical and subtropical regions of the world and endemic in 88 countries, with two million new cases of leishmaniasis reported annually. As a complex disease, the pathology of leishmaniasis varies and is determined by factors such as the environment, the insect vector, and parasite and host genetics. The contributing host genetics involve multiple genes thus, the mouse model of leishmaniasis has been exploited extensively in an attempt to identify and dissect the contribution of disease modifier genes to pathogenesis. This review summarizes recent advances in the identification of genetic loci involved in the host response to Leishmania spp. in the mouse model and in the human situation.

Menzies Research Institute Tasmania

Location: No location found

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University Of Tasmania

Location: Australia

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Whitehead Institute For Biomedical Research

Location: United States of America

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Menzies Research Institute Tasmania

Location: Australia

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Macquarie University

Location: Australia

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Australian National University

Location: Australia

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Walter And Eliza Hall Institute Of Medical Research

Location: Australia

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University Of Melbourne

Location: Australia

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Royal Melbourne Hospital Royal Park Campus

Location: Australia

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Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0882701

Start Date: 2008

End Date: 12-2008

Amount: $300,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP120100061

Start Date: 06-2012

End Date: 12-2014

Amount: $280,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0776744

Start Date: 05-2008

End Date: 03-2011

Amount: $400,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP130100517

Start Date: 09-2013

End Date: 09-2016

Amount: $427,510.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0775570

Start Date: 2007

End Date: 12-2007

Amount: $570,000.00

Funder: Australian Research Council