Abstract
Hybridization between invasive and native species has raised global concern, given the dramatic increase in species range shifts and pest outbreaks due to anthropogenic dispersal. ...Nevertheless, secondary contact between sister lineages of local and invasive species provides a natural laboratory to understand the factors that determine introgression and the maintenance or loss of species barriers. Here, we characterize the early evolutionary outcomes following secondary contact between invasive Helicoverpa armigera and native H. zea in Brazil. We carried out whole-genome resequencing of Helicoverpa moths from Brazil in two temporal samples: during the outbreak of H. armigera in 2013 and 2017. There is evidence for a burst of hybridization and widespread introgression from local H. zea into invasive H. armigera coinciding with H. armigera expansion in 2013. However, in H. armigera, the admixture proportion and the length of introgressed blocks were significantly reduced between 2013 and 2017, suggesting selection against admixture. In contrast to the genome-wide pattern, there was striking evidence for adaptive introgression of a single region from the invasive H. armigera into local H. zea, including an insecticide resistance allele that increased in frequency over time. In summary, despite extensive gene flow after secondary contact, the species boundaries are largely maintained except for the single introgressed region containing the insecticide-resistant locus. We document the worst-case scenario for an invasive species, in which there are now two pest species instead of one, and the native species has acquired resistance to pyrethroid insecticides through introgression.
Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased ...sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Native to the Americas, the invasive Spodoptera frugiperda (fall armyworm; FAW) was reported in West Africa in 2016, followed by its chronological detection across the Old World and the hypothesis of ...an eastward Asia expansion. We explored population genomic signatures of American and Old World FAW and identified 12 maternal mitochondrial DNA genome lineages across the invasive range. 870 high-quality nuclear single nucleotide polymorphic DNA markers identified five distinct New World population clusters, broadly reflecting FAW native geographical ranges and the absence of host-plant preferences. We identified unique admixed Old World populations, and admixed and non-admixed Asian FAW individuals, all of which suggested multiple introductions underpinning the pest's global spread. Directional gene flow from the East into eastern Africa was also detected, in contrast to the west-to-east spread hypothesis. Our study demonstrated the potential of population genomic approaches via international partnership to address global emerging pest threats and biosecurity challenges.
A hypermutated subtype of advanced prostate cancer was recently described, but prevalence and mechanisms have not been well-characterized. Here we find that 12% (7 of 60) of advanced prostate cancers ...are hypermutated, and that all hypermutated cancers have mismatch repair gene mutations and microsatellite instability (MSI). Mutations are frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 epigenetic silencing. Our findings identify parallels and differences in the mechanisms of hypermutation in prostate cancer compared with other MSI-associated cancers.
Inherited loss-of-function mutations in the tumor suppressor genes BRCA1, BRCA2, and multiple other genes predispose to high risks of breast and/or ovarian cancer. Cancer-associated inherited ...mutations in these genes are collectively quite common, but individually rare or even private. Genetic testing for BRCA1 and BRCA2 mutations has become an integral part of clinical practice, but testing is generally limited to these two genes and to women with severe family histories of breast or ovarian cancer. To determine whether massively parallel, "next-generation" sequencing would enable accurate, thorough, and cost-effective identification of inherited mutations for breast and ovarian cancer, we developed a genomic assay to capture, sequence, and detect all mutations in 21 genes, including BRCA1 and BRCA2, with inherited mutations that predispose to breast or ovarian cancer. Constitutional genomic DNA from subjects with known inherited mutations, ranging in size from 1 to >100,000 bp, was hybridized to custom oligonucleotides and then sequenced using a genome analyzer. Analysis was carried out blind to the mutation in each sample. Average coverage was >1200 reads per base pair. After filtering sequences for quality and number of reads, all single-nucleotide substitutions, small insertion and deletion mutations, and large genomic duplications and deletions were detected. There were zero false-positive calls of nonsense mutations, frameshift mutations, or genomic rearrangements for any gene in any of the test samples. This approach enables widespread genetic testing and personalized risk assessment for breast and ovarian cancer.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Helicoverpa armigera has recently invaded South and Central America, and appears to be spreading rapidly. We update a previously developed potential distribution model to highlight the global ...invasion threat, with emphasis on the risks to the United States. The continued range expansion of H. armigera in Central America is likely to change the invasion threat it poses to North America qualitatively, making natural dispersal from either the Caribbean islands or Mexico feasible. To characterise the threat posed by H. armigera, we collated the value of the major host crops in the United States growing within its modelled potential range, including that area where it could expand its range during favourable seasons. We found that the annual value of crops that would be exposed to H. armigera totalled approximately US$78 billion p.a., with US$843 million p.a. worth growing in climates that are optimal for the pest. Elsewhere, H. armigera has developed broad-spectrum pesticide resistance; meaning that if it invades the United States, protecting these crops from significant production impacts could be challenging. It may be cost-effective to undertake pre-emptive biosecurity activities such as slowing the spread of H. armigera throughout the Americas, improving the system for detecting H. armigera, and methods for rapid identification, especially distinguishing between H. armigera, H. zea and potential H. armigera x H. zea hybrids. Developing biological control programs, especially using inundative techniques with entomopathogens and parasitoids could slow the spread of H. armigera, and reduce selective pressure for pesticide resistance. The rapid spread of H. armigera through South America into Central America suggests that its spread into North America is a matter of time. The likely natural dispersal routes preclude aggressive incursion responses, emphasizing the value of preparatory communication with agricultural producers in areas suitable for invasion by H. armigera.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The clinical and histopathological distinctions between inherited versus acquired bone marrow failure and myelodysplastic syndromes are challenging. The identification of inherited bone marrow ...failure/myelodysplastic syndromes is critical to inform appropriate clinical management. To investigate whether a subset of pediatric and young adults undergoing transplant for aplastic anemia or myelodysplastic syndrome have germline mutations in bone marrow failure/myelodysplastic syndrome genes, we performed a targeted genetic screen of samples obtained between 1990-2012 from children and young adults with aplastic anemia or myelodysplastic syndrome transplanted at the Fred Hutchinson Cancer Research Center. Mutations in inherited bone marrow failure/myelodysplastic syndrome genes were found in 5.1% (5/98) of aplastic anemia patients and 13.6% (15/110) of myelodysplastic syndrome patients. While the majority of mutations were constitutional, a RUNX1 mutation present in the peripheral blood at a 51% variant allele fraction was confirmed to be somatically acquired in one myelodysplastic syndrome patient. This highlights the importance of distinguishing germline versus somatic mutations by sequencing DNA from a second tissue or from parents. Pathological mutations were present in DKC1, MPL, and TP53 among the aplastic anemia cohort, and in FANCA, GATA2, MPL, RTEL1, RUNX1, SBDS, TERT, TINF2, and TP53 among the myelodysplastic syndrome cohort. Family history or physical examination failed to reliably predict the presence of germline mutations. This study shows that while any single specific bone marrow failure/myelodysplastic syndrome genetic disorder is rare, screening for these disorders in aggregate identifies a significant subset of patients with inherited bone marrow failure/myelodysplastic syndrome.
Objective
Musculoskeletal conditions of the foot and ankle are common, yet the cost‐effectiveness of the variety of treatments available is not well defined. The aim of this systematic review was ...therefore to identify, appraise, and synthesize the literature pertaining to the cost‐effectiveness of interventions for musculoskeletal foot and ankle conditions.
Methods
Electronic databases were searched for studies presenting economic evaluations of nonsurgical and surgical treatments for acute or chronic musculoskeletal conditions of the foot and ankle. Data on cost, incremental cost‐effectiveness, and quality‐adjusted life years for each intervention and comparison were extracted. Risk of bias was assessed using the Drummond checklist for economic studies (range 0–35).
Results
Thirty‐six studies were identified reporting nonsurgical interventions (n = 10), nonsurgical versus surgical interventions (n = 14), and surgical interventions (n = 12). The most common conditions were osteoarthritis, ankle fracture, and Achilles tendon rupture. The strongest economic evaluations were for interventions managing end‐stage ankle osteoarthritis, ankle sprain, ankle fracture, calcaneal fracture, and Achilles tendon rupture. Total ankle replacement and ankle arthrodesis for end‐stage ankle osteoarthritis, in particular, have been demonstrated through high‐quality studies to be cost‐effective compared to the nonsurgical alternative.
Conclusion
Selected interventions for musculoskeletal foot and ankle conditions dominate comparators, whereas others require thoughtful consideration as they provide better clinical improvements, but at an increased cost. Researchers should consider measuring and reporting costs alongside clinical outcome to provide context when determining the appropriateness of interventions for other foot and ankle symptoms to best inform future clinical practice guidelines.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the ...number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants’ pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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