WEHI (English: /wiːˈhaɪ/), previously known as the Walter and Eliza Hall Institute of Medical Research, and as the Walter and Eliza Hall Institute, is Australia's oldest medical research institute. Sir Frank Macfarlane Burnet, who won the Nobel Prize in 1960 for his work in immunology, was director from 1944 to 1965. Burnet developed the ideas of clonal selection and acquired immune tolerance. Later, Professor Donald Metcalf discovered and characterised colony-stimulating factors. As of 2015[update], the institute hosted more than 750 researchers who work to understand, prevent and treat diseases including blood, breast and ovarian cancers; inflammatory diseases (autoimmunity) such as rheumatoid arthritis, type 1 diabetes and coeliac disease; and infectious diseases such as malaria, HIV and hepatitis B and C.Located in Parkville, Melbourne, it is closely associated with The University of Melbourne and The Royal Melbourne Hospital. The institute also has a campus at La Trobe University. The Director of WEHI, since July 2009, is Professor Doug Hilton AO, FAA, a molecular biologist.
Mutations in the RNA-binding protein roquin-1 are known to result in humoral autoimmunity. Heissmeyer and colleagues show that MALT1 cleavage of roquin and regnase-1 downstream of TCR signaling releases cooperatively repressed targets to promote T H 17 cell differentiation
The tumour suppressor p53 transcriptionally regulates a range of target genes that control cell growth and survival. Mutations of p53 have been implicated in the development of ∼50% of human cancers, including those instigated by exposure to mutagens. Although numerically rare, cancers can arise as a consequence of inherited mutations, such as in the Li–Fraumeni syndrome, which is caused by mutation of one p53 allele. Gene-targeted mice deficient for p53 have been generated to study this familial cancer syndrome. On a C57BL/6 background, p53 -deficient mice develop primarily thymic lymphoma and more rarely sarcoma. Evasion of apoptosis is considered to be essential for neoplastic transformation. As proteins of the Bcl-2 family are the critical regulators of apoptosis, we investigated the role of the pro-survival members Bcl-2, Bcl-x L and Bcl-w in cancer development in p53 +/− and p53 −/− mice by testing whether ABT-737, a pharmacological inhibitor of these proteins, could prevent or delay tumourigenesis. Our studies showed that ABT-737 prophylaxis only caused a minor delay and reduction in γ -radiation-induced thymic lymphoma development in p53 −/− mice, but this was accompanied by a concomitant increase in sarcoma. These data show that, collectively, Bcl-2, Bcl-x L and Bcl-w have only minor roles in thymic lymphoma development elicited by defects in p53, and this may indicate that Mcl-1 and/or A1 may feature more prominently in this process.
Autism spectrum disorder (autism) describes a heterogeneous neurodevelopmental phenotype arising from the interplay of environmental and genetic factors in early life. In a general population birth cohort, we employed a scoping approach to identify prospective associations between prenatal and birth factors and a subsequent autism diagnosis. Factors associated with increased likelihood of autism included those related to i) maternal health (maternal pre-pregnancy body mass index, pre-existing maternal mental health conditions, maternal use of selective serotonin reuptake inhibitors) ii) environmental exposures (maternal passive tobacco smoke exposure, and exposure to vinyl floors) iii) demographic factors (socioeconomic disadvantage). Factors associated with a decreased likelihood of autism included maternal dietary nutrition and supplementation (higher folic acid, magnesium, and iron, as well as adherence to the Australian Dietary Guidelines). Our findings extend the evidence that autism may have a multifactorial origin in early life. Further studies should explore the composite effects of these prenatal and birth factors on autism outcomes via shared biological pathways, such as inflammation, and oxidative stress, in concert with genetic predisposition.
Genetic variants produce complex phenotypic effects that confound current assays and predictive models. We developed variant in situ sequencing (VIS-seq), a pooled, image-based method measuring variant effects on molecular and cellular phenotypes in diverse cell types. Applying VIS-seq to ∼3,000 LMNA and PTEN variants yielded high-dimensional morphological profiles capturing changes in protein abundance, localization, activity, and cell architecture. VIS-seq identified a subset of linker-subdomain LMNA variants that increase nuclear circularity, in contrast to aggregating or low-abundance rod-subdomain variants that decrease circularity. VIS-seq also identified autism-associated PTEN variants that mislocalize and accurately distinguished autism-linked from tumor syndrome-linked and gnomAD control variants. Most variants impacted a multidimensional phenotypic continuum not recapitulated by any single functional readout. By linking variants to cell images at scale, VIS-seq illuminates how variant effects cascade from molecules to subcellular structures to cells, providing a framework for resolving the complexity of variant function.
The D4Z4 locus is a macrosatellite array on Chromosome 4q normally comprising 8 to >100 3.3-kb repeat units. Its size and repetitiveness render it refractory to most sequencing technologies; consequently, its genetic and epigenetic architectures remain incompletely understood despite their relevance to facioscapulohumeral muscular dystrophy (FSHD). Current FSHD molecular testing relies on complex, multistep and low-resolution assays, which aim to identify contractions on permissive haplotypes (FSHD type 1) or epigenetic reactivation due to pathogenic variants in the epigenetic machinery, most often in SMCHD1 (FSHD type 2). Recent guideline updates highlight the need for more accurate and comprehensive diagnostic approaches. Here, we leverage ultra-long whole-genome and Cas9-targeted sequencing to develop a fast and accurate workflow, D4Z4End2End, for comprehensive genetic and methylation analysis of D4Z4 alleles. We apply it to samples from two controls, four FSHD1 patients, four FSHD2 patients, and two patients with Bosma arhinia microphthalmia syndrome (BAMS) caused by SMCHD1 variants, as well as publicly available data from 30 B-lymphoblastoid cell lines from the 1000 Genomes Project and Human Pangenome Reference Consortium. We attain high-depth sequencing of full-length D4Z4 arrays of up to 40 repeat units (∼132 kb), accurately capture contracted arrays, genetic mosaicism, and pathogenic SMCHD1 variants, and generate consensus sequences of all D4Z4 alleles. We identify new allelic variants, analyze complex D4Z4 rearrangements including in-cis duplications, and reveal length- and SMCHD1-dependent methylation patterns across the D4Z4 array. Our findings offer insights into D4Z4 genetics and epigenetics, and demonstrate the potential of long-read nanopore sequencing to accelerate FSHD research and diagnostics.
