Robust physical methods that enrich genomic regions identical by descent for linkage studies: confirmation of a locus for osteogenesis imperfecta

<p>Abstract</p> <p>Background</p> <p>The monogenic disease osteogenesis imperfecta (OI) is due to single mutations in either of the collagen genes ColA1 or ColA2, but within the same family a given mutation is accompanied by a wide range of disease severity. Although this phenotypic variability implies the existence of modifier gene variants, genome wide scanning of DNA from OI patients has not been reported. Promising genome wide marker-independent physical methods for identifying disease-related loci have lacked robustness for widespread applicability. Therefore we sought to improve these methods and demonstrate their performance to identify known and novel loci relevant to OI.</p> <p>Results</p> <p>We have improved methods for enriching regions of identity-by-descent (IBD) shared between related, afflicted individuals. The extent of enrichment exceeds 10- to 50-fold for some loci. The efficiency of the new process is shown by confirmation of the identification of the Col1A2 locus in osteogenesis imperfecta patients from Amish families. Moreover the analysis revealed additional candidate linkage loci that may harbour modifier genes for OI; a locus on chromosome 1q includes COX-2, a gene implicated in osteogenesis.</p> <p>Conclusion</p> <p>Technology for physical enrichment of IBD loci is now robust and applicable for finding genes for monogenic diseases and genes for complex diseases. The data support the further investigation of genetic loci other than collagen gene loci to identify genes affecting the clinical expression of osteogenesis imperfecta. The discrimination of IBD mapping will be enhanced when the IBD enrichment procedure is coupled with deep resequencing.</p

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Review of the distribution, causes for the decline and recommendations for management of the quokka, Setonix brachyurus (Macropodidae: Marsupialia), an endemic macropod marsupial from south-west Western Australia

The former and current distribution of the quokka, Setortix brachyurus, was mapped from published and all available unpublished records. At the time of European settlement the quokka was widespread and abundant and its distribution encompassed an area of approximatelyThe former and current distribution of the quokka, Setortix brachyurus, was mapped from published and all available unpublished records. At the time of European settlement the quokka was widespread and abundant and its distribution encompassed an area of approximately 41 200 km2 of south-west Western Australia inclusive of two offshore islands, Bald Island and Rottnest Island. Historical reports indicated an extensive population decline occurred in the 1930s. The decline continued, with a previously undocumented decline apparent in the period from 1980 to 1992. However, this decline may be an artefact of the time scales used for mapping and may well equate with a previously reported decline lor a suite of south -west mammals in the 1970s. By 1992 the quokka´s distribution had been reduced to an area of approximately 17800 km2. An increased awareness of the presence of the quokka on the mainland has resulted in numerous reportings of quokka presence since 1992, has confimled the existence of several populations at the northern extent of the quokka´´s known geographic range and indicated the cmrent, 2005, distribution to be similar to that in 1992. However, survey and population estimates at six of these mainland locations from the northem jarrah forest indicated low abundance. There have been no population estimates elsewhere on the mainland. Two populations have been reported tiom the Swan Coastal Plain, but neither has been confirmed extant. Predation by the introduced fox, Vulpes vulpes, is implicated as a major cause of the quokka´s initial decline, while ongoing predation, habitat destruction and modification through altered tire regimes have contributed to the continued decline. Specific conservation management actions are recommended, namely: (i) Implementing an active adaptive management program in the northern jarrah forest to determine quokka population response to habitat manipulation through the use of fIre, fox baiting and pig control; (ii) Surveying the Stirling fumge and Green Range populations with emphasis placed on determining population size and population genetic structure; (iii) Surveying the reported occurrences from the Swan Coastal Plain, with emphasis on unambiguously determining presence. If confirmed, priority should he directed to assessing population size and determining the management requirements to ensure persistence of the population; (iv) Surveying southem forest and south coast populations to assess quokka population size, the extent of movement between sllbpopulations and assessment of the range of habitat types used by quokkas. The latter should be combined with spatial analyses of known extant populations and suitable and potentially suitable habitat; (v) Determining the role of tire in establishing and maintaining preferred habitat of southern forest and south coast populations; and (vi) Establishing a program to assess the potential effects from management operations

Assessment of risks to non-target species from an encapsulated toxin in a bait proposed for control of feral cats

Context The CURIOSITY bait is the name coined for a variation of the existing sausage-style cat bait, ERADICAT. The latter is used under experimental permit in Western Australia for research associated with cat control. The CURIOSITY bait differs from ERADICAT by providing a pH-buffered (less acidic) medium and has been proposed to reduce the risk to non-target species by encapsulating a toxin in a pellet. We trialled a prototype pellet proposed for encapsulation of 1080 and/or alternative toxins, with delivery proposed through the CURIOSITY bait. Aim Our aim was to determine whether the pellet was consumed by non-target native species from south-west of Western Australia. Methods Trials involved use of a non-toxic biomarker, Rhodamine B, encapsulated within the pellet and inserted into the CURIOSITY bait. Uptake of the encapsulated biomarker was assessed in captive trials for the target species, the feral cat (Felis catus) and two non-target species of varanid lizard, Rosenberg's goanna (Varanus rosenbergi) and Gould's goanna (V. gouldii) and the non-target mammal species chuditch (Dasyurus geoffroii) and southern brown bandicoot (Isoodon obesulus). Uptake of the encapsulated biomarker was also assessed in field trials for a range of native species. Key results Captive trials demonstrated feral cats will consume the CURIOSITY bait and pellet. However, results from captive and field trials indicated several non-target species also consumed the bait and pellet. We also found the pellet itself was not sufficiently robust for use in a bait. As with previously reported studies, we found Rhodamine B to be an effective biomarker for use in cats. We also developed a technique whereby Rhodamine B can be used as a biomarker in reptiles. However, its use as a biomarker in other mammalian species was confounded by what appeared to be background, or pre-existing, levels of fluorescence, or banding, in their whiskers. Conclusion The prototype pellet is unsuitable in its current form for use with the CURIOSITY bait. We caution that the CURIOSITY bait has non-target issues in south-west of Western Australia and any proposed variations to this bait, or the ERADICAT bait, need to be rigorously assessed for their potential risk to non-target species and assessed for the level of uptake by cats, irrespective of their suitability/unsuitability as a medium for delivery of an encapsulated toxin. We believe the threat to biodiversity-conservation values from unmitigated feral-cat predation of native fauna poses a significant and real threat and we recommend urgent investment of resources to address the issue of cat predation in a coordinated and collaborative manner within Australia and New Zealand