Identification of a shared, common haplotype cosegregating with an SGCB c.544A>C mutation in Indian patients affected with sarcoglycanopathy

Background Sarcoglycanopathies (SG) is the most frequent form of autosomal recessive limb-girdle muscular dystrophies (LGMD) leading to progressive muscle wasting and weakness, predominantly characterized by limb-girdle weakness. LGMDR4 is caused by mutations in SGCB encoding for the beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype cosegregating in 14 SG cases from 13 unrelated families with the likely pathogenic homozygous mutation c.544A>C (p.Thr182Pro) in SGCB. Methods The genotypes of five selected markers (rs10009426, rs6824707, rs2271046, rs35414474 and rs17611952) surrounding the c.544A>C (p.Thr182Pro) were extracted from the variant call format (VCF) generated from whole-exome sequencing (WES) of 14 cases and 14 related family members as controls. The linkage data file was constructed and linkage disequilibrium (LD) plots were generated using HaploView to visualize patterns of LD. Further, haplotype reconstructions based on the 6 markers were conducted using PLINK1.9. using the expectation-maximization (EM) algorithm, an iterative method to find maximum likelihood. Subsequently, the R programming language was used to determine and compare plots of the haplotype frequencies and percentages for both groups to infer the risk haplotypes. Results Four strong LD blocks were identified in control group: rs10009426 to rs6824707 (0.27 kb), rs6824707 to rs2271046 (41.6 kb), rs10009426 to rs2271046 (41.8 kb) and rs35414474 to rs17611952 (0.17 kb) which were absent in the case group. Similarly, a total of nine haplotypes were estimated in cases and controls of which haplotype H1= G, A, T, G, G, T showed significant statistical difference in the frequency between cases and controls. H1 is also observed to cosegregate with c.544A>C (p.Thr182Pro) in the pedigrees of all the cases. Conclusion The identification of c.544A>C (p.Thr182Pro) mutation in 14 cases from India indicates a probable event of founder effect. Further, the H1 haplotype, cosegregating with this mutation, convincingly sheds light on the recent developments in population genetics allowing insights into demographic and population history. This haplotype can also be used as a genetic marker to screen individuals with genetic susceptibility as carriers and provide genetically informed risk stratification and management in the prevention of SG.

Pertussis immunisation in infancy and atopic outcomes: A protocol for a population-based cohort study using linked administrative data

Introduction The burden of IgE-mediated food allergy in Australian born children is reported to be among the highest globally. This illness shares risk factors and frequently coexists with asthma, one of the most common noncommunicable diseases of childhood. Findings from a case-control study suggest that compared to immunisation with acellular pertussis vaccine, early priming of infants with whole-cell pertussis vaccine may be associated with a lower risk of subsequent IgE-mediated food allergy. If whole-cell vaccination is protective of food allergy and other atopic diseases, especially if protective against childhood asthma, the population-level effects could justify its preferential recommendation. However, the potential beneficial effects of whole-cell pertussis vaccination for the prevention of atopic diseases at a population-scale are yet to be investigated. Methods and analysis Analyses of population-based record linkage data will be undertaken to compare the rates of admissions to hospital for asthma in children aged between 5 and 15 years old, who were born in Western Australia (WA) or New South Wales (NSW) between 1997 and 1999 (329,831) when pertussis immunisation in Australia transitioned from whole-cell to acellular only schedules. In the primary analysis we will estimate hazard ratios and 95% confidence intervals for the time-to-first-event (hospital admissions as above) using Cox proportional hazard models in recipients of a first dose of whole-cell versus acellular pertussis-containing vaccine before 112 days old (~4 months of age). Similarly, we will also fit time-to-recurrent events analyses using Andersen-Gill models, and robust variance estimates to account for potential within-child dependence. Hospitalisations for all-cause anaphylaxis, food anaphylaxis, venom, all-cause urticaria and atopic dermatitis will also be examined in children who received at least one dose of pertussis-containing vaccine by the time of the cohort entry, using analogous statistical methods. Presentations to the emergency departments will be assessed separately using the same statistical approach.

Improving uptake of prevention of mother-to-child HIV transmission services in Benue State, Nigeria through a faith-based congregational strategy

Background Nigeria has low antiretroviral therapy (ART) coverage among HIV-positive pregnant women. In a previous cluster-randomized trial in Nigeria, Baby Shower events resulted in higher HIV testing coverage and linkage of pregnant women to ART; here, we assess outcomes of Baby Shower events in a non-research setting. Methods Baby Shower events, including a prayer ceremony, group education, music, gifting of a “mama pack” with safe delivery supplies, and HIV testing with ART linkage support for HIV-positive pregnant women, were conducted in eighty sites in Benue State, Nigeria. Client questionnaires (including demographics, ANC attendance, and HIV testing history), HIV test results, and reported linkage to ART were analyzed. Descriptive data on HIV testing and ART linkage data for facility-based care at ANC clinics in Benue State were also analyzed for comparison. Results Between July 2016 and October 2017, 10,056 pregnant women and 6,187 male partners participated in Baby Shower events; 61.5% of women attended with a male partner. Nearly half of female participants (n = 4515, 44.9%) were not enrolled in ANC for the current pregnancy, and 22.3% (n = 2,241) of female and 24.8% (n = 1,532) of male participants reported they had never been tested for HIV. Over 99% (n = 16,240) of participants had their HIV status ascertained, with 7.2% of females (n = 724) and 4.0% of males (n = 249) testing HIV-positive, and 2.9% of females (n = 274) and 2.3% of males (n = 138) receiving new HIV-positive diagnoses. The majority of HIV-positive pregnant women (93.0%, 673/724) were linked to ART. By comparison, at health facilities in Benue State during a similar time period, 99.7% of pregnant women had HIV status ascertained, 8.4% had a HIV-positive status, 2.1% were newly diagnosed HIV-positive, and 100% were linked to ART. Conclusion Community-based programs such as the faith-based Baby Shower intervention complement facility-based approaches and can reach individuals who would not otherwise access facility-based care. Future Baby Showers implementation should incorporate enhanced support for ART linkage and retention to maximize the impact of this intervention on vertical HIV transmission.

Assemblies of the genomes of parasitic wasps using meta-assembly and scaffolding with genetic linkage

Safe, effective biological-control introductions against invasive pests depend on narrowly host-specific natural enemies with the ability to adapt to a changing environment. As part of a project on the genetic architectures of these traits, we assembled and annotated the genomes of two aphid parasitoids, Aphelinus atriplicis and Aphelinus certus. We report here several assemblies of A. atriplicis made with Illumina and PacBio data, which we combined into a meta-assembly. We scaffolded the meta-assembly with markers from a genetic map of hybrids between A. atriplicis and A. certus. We used this genetic-linkage scaffolded (GLS) assembly of A. atriplicis to scaffold a de novo assembly of A. certus. The de novo assemblies of A. atriplicis differed in contiguity, and the meta-assembly of these assemblies was more contiguous than the best de novo assembly. Scaffolding with genetic-linkage data allowed chromosomal-level assembly of the A. atriplicis genome and scaffolding a de novo assembly of A. certus with this GLS assembly, greatly increased the contiguity of the A. certus assembly to the point where it was also at the chromosomal-level. However, completeness of the A. atriplicis assembly, as measured by % complete, single-copy BUSCO hymenopteran genes, varied little among de novo assemblies and was not increased by meta-assembly or genetic scaffolding. Furthermore, the greater contiguity of the meta-assembly and GLS assembly had little or no effect on the numbers of genes identified, the proportion with homologs or functional annotations. Increased contiguity of the A. certus assembly provided modest improvement in assembly completeness, as measured by % complete, single-copy BUSCO hymenopteran genes. The total genic sequence increased, and while the number of genes declined, gene length increased, which together suggest greater accuracy of gene models. More contiguous assemblies provide uses other than gene annotation, for example, identifying the genes associated with quantitative trait loci and understanding of chromosomal rearrangements associated with speciation.

Pedigree online: A New Web Server for Two-Way Interactive Pedigree Drawing

Pedigree drawing is of special importance for genetic counseling and research on documenting families with inherited disease. Current pedigree-drawing tools fall into two types: those build pedigree diagrams from input family data, and those provide a graphical interface to draw pedigree directly. Here we merge the two types of programs into one, and release a brand new pedigree-drawing web server, PedigreeOnline. Through introducing a novel pedigree-like-layout (PLL) family data format and taking advantage of HTML5 canvas element in development, this program is able to build two-way interactive connections between family data and graphical interface. Users can work on and switch easily between the graphical interface and the family data window. Currently this web server is compatible with Linkage data format and comma-separated value (CSV) data format. These features make PedigreeOnline a pedigree-drawing tool with outstanding user-friendliness and flexibility. PedigreeOnline is freely accessible for everyone at: http://www.ig.zju.edu.cn/PedigreeOnline/

Adjusting to precarity: how and why the Roslin Institute forged a leading role for itself in international networks of pig genomics research

From the 1980s onwards, the Roslin Institute and its predecessor organizations faced budget cuts, organizational upheaval and considerable insecurity. Over the next few decades, it was transformed by the introduction of molecular biology and transgenic research, but remained a hub of animal geneticists conducting research aimed at the livestock-breeding industry. This paper explores how these animal geneticists embraced genomics in response to the many-faceted precarity that the Roslin Institute faced, establishing it as a global centre for pig genomics research through forging and leading the Pig Gene Mapping Project (PiGMaP); developing and hosting resources, such as a database for genetic linkage data; and producing associated statistical and software tools to analyse the data. The Roslin Institute leveraged these resources to play a key role in further international collaborations as a hedge against precarity. This adoption of genomics was strategically useful, as it took advantage of policy shifts at the national and European levels towards funding research with biotechnological potential. As genomics constitutes a set of infrastructures and resources with manifold uses, the development of capabilities in this domain also helped Roslin to diversify as a response to precarity.

Does the suddenness matter? Antidepressant use before and after a spouse dies suddenly or expectedly of stroke

Aims: Changes in mental health at the time of widowhood may depend on the expectedness of spousal death, but scant evidence is available for spousal deaths attributable to stroke. Methods: Using register-linkage data for Finland, we assessed changes in antidepressant use before and after spousal death for those whose spouses died suddenly of stroke between 1998 and 2003 ( N=1820) and for those whose spouses died expectedly of stroke, with prior hospitalisation for cerebrovascular disease ( N=1636). We used both population-averaged logit models and individual fixed-effects linear probability models. The latter models control for unobserved time-invariant heterogeneity between the individuals. Results: Our study indicates that the suddenness of a spouse’s death from stroke plays a role in the well-being of the surviving spouse. Increases in antidepressant use appeared larger following widowhood for those whose spouses died suddenly of stroke relative to those whose spouses had a medical history of cerebrovascular disease. Conclusions: The suddenness of a spouse’s death from stroke plays a role for the surviving spouse. The results suggest multifaceted timings of distress surrounding spousal death, depending on the suddenness of a spouse’s death from stroke.

PedigreeOnline: a new web server for two-way interactive pedigree drawing

Pedigree drawing is of special importance for genetic counseling and research on documenting families with inherited disease. Current pedigree-drawing tools fall into two types: those build pedigree diagrams from input family data, and those provide a graphical interface to draw pedigree directly. Here we merge the two types of programs into one, and release a brand new pedigree-drawing web server, PedigreeOnline. Through introducing a novel pedigree-like-layout (PLL) family data format and taking advantage of HTML5 canvas element in development, this program is able to build two-way interactive connections between family data and graphical interface. Users can work on and switch easily between the graphical interface and the family data window. Currently this web server is compatible with Linkage data format and comma-separated value (CSV) data format. These features make PedigreeOnline a pedigree-drawing tool with outstanding user-friendliness and flexibility. PedigreeOnline is freely accessible for everyone at: http://www.ig.zju.edu.cn/PedigreeOnline/

Thousands of induced germline mutations affecting immune cells identified by automated meiotic mapping coupled with machine learning

Forward genetic studies use meiotic mapping to adduce evidence that a particular mutation, normally induced by a germline mutagen, is causative of a particular phenotype. Particularly in small pedigrees, cosegregation of multiple mutations, occasional unawareness of mutations, and paucity of homozygotes may lead to erroneous declarations of cause and effect. We sought to improve the identification of mutations causing immune phenotypes in mice by creating Candidate Explorer (CE), a machine-learning software program that integrates 67 features of genetic mapping data into a single numeric score, mathematically convertible to the probability of verification of any putative mutation–phenotype association. At this time, CE has evaluated putative mutation–phenotype associations arising from screening damaging mutations in ∼55% of mouse genes for effects on flow cytometry measurements of immune cells in the blood. CE has therefore identified more than half of genes within which mutations can be causative of flow cytometric phenovariation in Mus musculus. The majority of these genes were not previously known to support immune function or homeostasis. Mouse geneticists will find CE data informative in identifying causative mutations within quantitative trait loci, while clinical geneticists may use CE to help connect causative variants with rare heritable diseases of immunity, even in the absence of linkage information. CE displays integrated mutation, phenotype, and linkage data, and is freely available for query online.

Frequent short sickness absence, occupational health service utilisation and long-term sickness absence due to mental disorders among young employees

Objectives We examined whether frequent short-term sickness absence (FSTSA) and primary care use in occupational health service (OHS) were associated with medically-certified long-term sickness absence (LTSA) due to mental disorders among young employees. Methods We used record-linkage data covering the young employees (< 35 years) of the City of Helsinki, Finland (n = 8,282) from 2010 to 2014. The outcome was LTSA due to mental disorders. Cox regression models were fitted. Results FSTSAs were associated with subsequent LTSA. Also OHS use predicted LTSA due to mental disorders; however, this association was not found for those with prior FSTSA. Conclusions Both FSTSA and primary care use indicate subsequent LTSA independently, and together these indicators identify a larger proportion of individuals at risk of LTSA due to mental disorders.