Publications by authors named "Lois Balmer"

12 Publications

  • Page 1 of 1

Mapping of Diabetes Susceptibility Loci in a Domestic Cat Breed with an Unusually High Incidence of Diabetes Mellitus.

Genes (Basel) 2020 Nov 19;11(11). Epub 2020 Nov 19.

Centre for Diabetes Research, Harry Perkins Institute for Medical Research, University of Western Australia, Nedlands 6009, Australia.

Genetic variants that are associated with susceptibility to type 2 diabetes (T2D) are important for identification of individuals at risk and can provide insights into the molecular basis of disease. Analysis of T2D in domestic animals provides both the opportunity to improve veterinary management and breeding programs as well as to identify novel T2D risk genes. Australian-bred Burmese (ABB) cats have a 4-fold increased incidence of type 2 diabetes (T2D) compared to Burmese cats bred in the United States. This is likely attributable to a genetic founder effect. We investigated this by performing a genome-wide association scan on ABB cats. Four SNPs were associated with the ABB T2D phenotype with values <0.005. All exons and splice junctions of candidate genes near significant single-nucleotide polymorphisms (SNPs) were sequenced, including the genes and . Six candidate polymorphisms were followed up in a larger cohort of ABB cats with or without T2D and also in Burmese cats bred in America, which exhibit low T2D incidence. The original SNPs were confirmed in this cohort as associated with the T2D phenotype, although no novel coding SNPs in any of the seven candidate genes showed association with T2D. The identification of genetic markers associated with T2D susceptibility in ABB cats will enable preventative health strategies and guide breeding programs to reduce the prevalence of T2D in these cats.
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http://dx.doi.org/10.3390/genes11111369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699364PMC
November 2020

Variants of innate CD8 T cells are associated with Grip2 and Klf15 genes.

Cell Mol Immunol 2020 Sep 9;17(9):1007-1009. Epub 2020 Jan 9.

Department of Anatomy, Pusan National University School of Medicine, Yangsan, 50612, South Korea.

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http://dx.doi.org/10.1038/s41423-019-0357-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608311PMC
September 2020

Genetic characterization of early renal changes in a novel mouse model of diabetic kidney disease.

Kidney Int 2019 10 30;96(4):918-926. Epub 2019 May 30.

Centre for Diabetes Research, Harry Perkins Institute of Medical Research, the University of Western Australia, Perth, Western Australia, Australia. Electronic address:

Genetic factors influence susceptibility to diabetic kidney disease. Here we mapped genes mediating renal hypertrophic changes in response to diabetes. A survey of 15 mouse strains identified variation in diabetic kidney hypertrophy. Strains with greater (FVB/N(FVB)) and lesser (C57BL/6 (B6)) responses were crossed and diabetic F2 progeny were characterized. Kidney weights of diabetic F2 mice were broadly distributed. Quantitative trait locus analyses revealed diabetic mice with kidney weights in the upper quartile shared alleles on chromosomes (chr) 6 and 12; these loci were designated as Diabetic kidney hypertrophy (Dkh)-1 and -2. To confirm these loci, reciprocal congenic mice were generated with defined FVB chromosome segments on the B6 strain background (B6.Dkh1/2f) or vice versa (FVB.Dkh1/2b). Diabetic mice of the B6.Dkh1/2f congenic strain developed diabetic kidney hypertrophy, while the reciprocal FVB.Dkh1/2b congenic strain was protected. The chr6 locus contained the candidate gene; Ark1b3, coding aldose reductase; the FVB allele has a missense mutation in this gene. Microarray analysis identified differentially expressed genes between diabetic B6 and FVB mice. Thus, since the two loci identified by quantitative trait locus mapping are syntenic with regions identified for human diabetic kidney disease, the congenic strains we describe provide a valuable new resource to study diabetic kidney disease and test agents that may prevent it.
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http://dx.doi.org/10.1016/j.kint.2019.04.031DOI Listing
October 2019

Variable outcomes of human heart attack recapitulated in genetically diverse mice.

NPJ Regen Med 2019 4;4. Epub 2019 Mar 4.

1Australian Regenerative Medicine Institute, Monash University, Clayton, VIC Australia.

Clinical variation in patient responses to myocardial infarction (MI) has been difficult to model in laboratory animals. To assess the genetic basis of variation in outcomes after heart attack, we characterized responses to acute MI in the Collaborative Cross (CC), a multi-parental panel of genetically diverse mouse strains. Striking differences in post-MI functional, morphological, and myocardial scar features were detected across 32 CC founder and recombinant inbred strains. Transcriptomic analyses revealed a plausible link between increased intrinsic cardiac oxidative phosphorylation levels and MI-induced heart failure. The emergence of significant quantitative trait loci for several post-MI traits indicates that utilizing CC strains is a valid approach for gene network discovery in cardiovascular disease, enabling more accurate clinical risk assessment and prediction.
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http://dx.doi.org/10.1038/s41536-019-0067-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399323PMC
March 2019

Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma.

Elife 2019 01 25;8. Epub 2019 Jan 25.

Drug Discovery Group, QIMR Berghofer Medical Research Institute, Herston, Australia.

Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this idea to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset to , a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit gene . Ribosome biogenesis was upregulated in skin shortly after UVR exposure. Mechanistically, variation in the 'usual suspects' by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.
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http://dx.doi.org/10.7554/eLife.42424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428585PMC
January 2019

Common Heritable Immunological Variations Revealed in Genetically Diverse Inbred Mouse Strains of the Collaborative Cross.

J Immunol 2019 02 26;202(3):777-786. Epub 2018 Dec 26.

Department of Immunology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada;

Variations in the proportion and number of specific immune cell types among healthy individuals are influenced by both heritable and nonheritable factors. Mouse models, subjected to fewer nonheritable factors than humans, allow the identification of genetic factors that shape the immune system. We characterized immunological trait variability in the Collaborative Cross (CC), a powerful genetic resource of recombinant inbred mouse strains derived from eight diverse founder strains. Of the 18 immunological traits studied in more than 60 CC strains, eight showed genome-wide significant linkage, revealing new genetic loci linked to specific immune traits. We also found that these traits were highly subject to heritable influences. As for humans, mouse immunological traits varied as a continuum rather than as discrete immunophenotypes. The CC thus represents a useful resource to identify factors that determine immunological variations, as well as defining other immune traits likely to be heritable in humans.
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http://dx.doi.org/10.4049/jimmunol.1801247DOI Listing
February 2019

Variable cardiac α-actin (Actc1) expression in early adult skeletal muscle correlates with promoter methylation.

Biochim Biophys Acta Gene Regul Mech 2017 Oct 26;1860(10):1025-1036. Epub 2017 Aug 26.

Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia; School of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Western Australia, QEII Medical Centre, Nedlands, Western Australia, Australia. Electronic address:

Different genes encode the α-actin isoforms that are predominantly expressed in heart and skeletal muscle. Mutations in the skeletal muscle α-actin gene (ACTA1) cause muscle diseases that are mostly lethal in the early postnatal period. We previously demonstrated that the disease phenotype of ACTA1 mouse models could be rescued by transgenic over-expression of cardiac α-actin (ACTC1). ACTC1 is the predominant striated α-actin isoform in the heart but is also expressed in developing skeletal muscle. To develop a translatable therapy, we investigated the genetic regulation of Actc1 expression. Using strains from The Collaborative Cross (CC) genetic resource, we found that Actc1 varies in expression by up to 24-fold in skeletal muscle. We defined significant expression quantitative trait loci (eQTL) associated with early adult Actc1 expression in soleus and heart. eQTL in both heart and soleus mapped to the Actc1 locus and replicate an eQTL mapped for Actc1 in BXD heart and quadriceps. We built on this previous work by analysing genes within the eQTL peak regions to prioritise likely candidates for modifying Actc1 expression. Additionally we interrogated the CC founder haplotype contributions to enable prioritisation of genetic variants for functional analyses. Methylation around the Actc1 transcriptional start site in early adult skeletal muscle negatively correlated with Actc1 expression in a strain-dependent manner, while other marks of regulatory potential (histone modification and chromatin accessibility) were unaltered. This study provides novel insights into the complex genetic regulation of Actc1 expression in early adult skeletal muscles.
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http://dx.doi.org/10.1016/j.bbagrm.2017.08.004DOI Listing
October 2017

Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice.

J Endocrinol 2016 Jan 22;228(1):61-73. Epub 2015 Oct 22.

Department of Medicine (AH)Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, AustraliaWalter and Eliza Hall Institute of Medical ResearchParkville, 3010 Victoria, AustraliaHarry Perkins Institute of Medical ResearchNedlands, Western Australia 6009, AustraliaThe School of Medical Sciences Edith Cowan UniversityJoondalup Western Australia 6027, Australia.

Type 2 diabetes (T2D) is associated with defective insulin secretion, which in turn contributes to worsening glycaemic control and disease progression. The genetic cause(s) associated with impaired insulin secretion in T2D are not well elucidated. Here we used the polygenic New Zealand Obese (NZO) mouse model, which displays all the cardinal features of T2D including hyperglycaemia to identify genes associated with β-cell dysfunction. A genome-wide scan identified a major quantitative trait locus (QTL) on chromosome 7 associated with defective glucose-mediated insulin secretion. Using congenic strains, the locus was narrowed to two candidate genes encoding the components of the KATP channel: Abcc8 (SUR1) and Kcnj11 (Kir6.2). The NZO Abcc8 allele was associated with a ∼211 bp deletion in its transcript and reduced expression of SUR1. Transgenic NZO mice were generated that expressed the WT Abcc8/Kcnj11 genes and displayed significant improvements in early-phase glucose-mediated insulin secretion and glucose tolerance, confirming Abcc8 as a causative gene. Importantly, we showed that despite improving β-cell function in the NZO transgenic mice, there was no enhancement of insulin sensitivity or body weight. This study provides evidence for a role of Abcc8 in early-phase glucose-mediated insulin secretion and validates this gene as a contributor to β-cell dysfunction in T2D.
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http://dx.doi.org/10.1530/JOE-15-0290DOI Listing
January 2016

Characterization of Retinal Vascular and Neural Damage in a Novel Model of Diabetic Retinopathy.

Invest Ophthalmol Vis Sci 2015 Jun;56(6):3721-30

Centre for Diabetes Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Western Australia, Australia 2Centre of Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.

Purpose: Diabetic retinopathy (DR) is a major cause of blindness globally. Investigating the underlying mechanisms of DR would be aided by a suitable mouse model that developed key features seen in the human disease, and did so without carrying genetic modifications. This study was undertaken to produce such a model.

Methods: Our panel of Collaborative Cross strains was screened for DR-like features after induction of diabetes by intravenous injection with alloxan or streptozotocin. Both flat-mounted whole-retina and histologic sections were studied for the presence of retinal lesions. Progression of DR was also studied by histologic examination of the retinal vascular and neural structure at various time points after diabetes onset. In addition, microarray investigations were conducted on retinas from control and diabetic mice.

Results: Features of DR such as degenerated pericytes, acellular capillaries, minor vascular proliferation, gliosis of Müller cells, and loss of ganglion cells were noted as early as day 7 in some mice. These lesions became more evident with time. After 21 days of diabetes, severe vascular proliferation, microaneurysms, preretinal damage, increased Müller cell gliosis, and damage to the outer retina were all obvious. Microarray studies found significant differential expression of multiple genes known to be involved in DR.

Conclusions: The FOT_FB strain provides a useful model to investigate the pathogenesis of DR and to develop treatments for this vision-threatening disease.
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http://dx.doi.org/10.1167/iovs.14-16289DOI Listing
June 2015

Rapid identification of major-effect genes using the collaborative cross.

Genetics 2014 Sep;198(1):75-86

Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Nedlands 6009, WA, Australia Centre of Medical Research, University of Western Australia, Nedlands 6009, WA, Australia

The Collaborative Cross (CC) was designed to facilitate rapid gene mapping and consists of hundreds of recombinant inbred lines descended from eight diverse inbred founder strains. A decade in production, it can now be applied to mapping projects. Here, we provide a proof of principle for rapid identification of major-effect genes using the CC. To do so, we chose coat color traits since the location and identity of many relevant genes are known. We ascertained in 110 CC lines six different coat phenotypes: albino, agouti, black, cinnamon, and chocolate coat colors and the white-belly trait. We developed a pipeline employing modifications of existing mapping tools suitable for analyzing the complex genetic architecture of the CC. Together with analysis of the founders' genome sequences, mapping was successfully achieved with sufficient resolution to identify the causative genes for five traits. Anticipating the application of the CC to complex traits, we also developed strategies to detect interacting genes, testing joint effects of three loci. Our results illustrate the power of the CC and provide confidence that this resource can be applied to complex traits for detection of both qualitative and quantitative trait loci.
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http://dx.doi.org/10.1534/genetics.114.163014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174955PMC
September 2014

Establishment of "The Gene Mine": a resource for rapid identification of complex trait genes.

Mamm Genome 2008 Jun 21;19(6):390-3. Epub 2008 Aug 21.

Centre for Diabetes Research, The Western Australian Institute for Medical Research, and Centre for Medical Research, University of Western Australia, MRF Building, Level 6, 50 Murray St., Perth, WA 6000, Australia.

Identification of genes underlying complex traits presents a challenge to which geneticists have responded with many diverse approaches. A common feature of these approaches is that different research groups must, on a case-by-case basis, replicate similar efforts in recruitment, genetic characterization, and analyses. To avoid this expensive "churning," an alternative approach has been proposed: production of an experimental genetic reference population, the Collaborative Cross, in which both genetic diversity and mapping power are maximized. Since this population consists of inbred mouse strains, further advantages are that it is essentially infinitely reproducible; genetic characterization needs to be performed only once; and the founder strains' genomes have been or will be sequenced, allowing imputation of allele sequences of all members of the reference population. Here we describe the establishment of such a genetic reference population, which we dub "The Gene Mine." Over 1000 genetically distinct lines have been established, descended from eight diverse founder strains. Preliminary phenotypic ascertainment of these strains indicates unexpected variability arising from independent assortment of genetic variants. The Gene Mine will be a powerful resource for characterization of essentially any mouse phenotype that has a genetic basis.
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http://dx.doi.org/10.1007/s00335-008-9134-9DOI Listing
June 2008

The influence of ontogeny and light environment on the expression of visual pigment opsins in the retina of the black bream, Acanthopagrus butcheri.

J Exp Biol 2008 May;211(Pt 9):1495-503

School of Animal Biology, University of Western Australia, Crawley, WA 6009, Australia.

The correlation between ontogenetic changes in the spectral absorption characteristics of retinal photoreceptors and expression of visual pigment opsins was investigated in the black bream, Acanthopagrus butcheri. To establish whether the spectral qualities of environmental light affected the complement of visual pigments during ontogeny, comparisons were made between fishes reared in: (1) broad spectrum aquarium conditions; (2) short wavelength-reduced conditions similar to the natural environment; or (3) the natural environment (wild-caught). Microspectrophotometry was used to determine the wavelengths of spectral sensitivity of the photoreceptors at four developmental stages: larval, post-settlement, juvenile and adult. The molecular sequences of the rod (Rh1) and six cone (SWS1, SWS2A and B, Rh2Aalpha and beta, and LWS) opsins were obtained and their expression levels in larval and adult stages examined using quantitative RT-PCR. The changes in spectral sensitivity of the cones were related to the differing levels of opsin expression during ontogeny. During the larval stage the predominantly expressed opsin classes were SWS1, SWS2B and Rh2Aalpha, contrasting with SWS2A, Rh2Abeta and LWS in the adult. An increased proportion of long wavelength-sensitive double cones was found in fishes reared in the short wavelength-reduced conditions and in wild-caught animals, indicating that the expression of cone opsin genes is also regulated by environmental light.
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http://dx.doi.org/10.1242/jeb.012047DOI Listing
May 2008