Journal: Communications biology
Comparative genomics sequence data is an important source of information for interpreting genomes. Genome-wide annotations based on this data have largely focused on univariate scores or binary elements of evolutionary constraint. Here we present a complementary whole genome annotation approach, ConsHMM, which applies a multivariate hidden Markov model to learn de novo ‘conservation states’ based on the combinatorial and spatial patterns of which species align to and match a reference genome in a multiple species DNA sequence alignment. We applied ConsHMM to a 100-way vertebrate sequence alignment to annotate the human genome at single nucleotide resolution into 100 conservation states. These states have distinct enrichments for other genomic information including gene annotations, chromatin states, repeat families, and bases prioritized by various variant prioritization scores. Constrained elements have distinct heritability partitioning enrichments depending on their conservation state assignment. ConsHMM conservation states are a resource for analyzing genomes and genetic variants.
This scientometric review of genome-wide association studies (GWAS) from 2005 to 2018 (3639 studies; 3508 traits) reveals extraordinary increases in sample sizes, rates of discovery and traits studied. A longitudinal examination shows fluctuating ancestral diversity, still predominantly European Ancestry (88% in 2017) with 72% of discoveries from participants recruited from three countries (US, UK, Iceland). US agencies, primarily NIH, fund 85% and women are less often senior authors. We generate a unique GWAS H-Index and reveal a tight social network of prominent authors and frequently used data sets. We conclude with 10 evidence-based policy recommendations for scientists, research bodies, funders, and editors.
Understanding the age structure and population dynamics of harvested species is crucial for sustainability, especially in fisheries. The Bigmouth Buffalo (Ictiobus cyprinellus) is a fish endemic to the Mississippi and Hudson Bay drainages. A valued food-fish for centuries, they are now a prized sportfish as night bowfishing has become a million-dollar industry in the past decade. All harvest is virtually unregulated and unstudied, and Bigmouth Buffalo are declining while little is known about their biology. Using thin-sectioned otoliths and bomb-radiocarbon dating, we find Bigmouth Buffalo can reach 112 years of age, more than quadrupling previous longevity estimates, making this the oldest known freshwater teleost (~12,000 species). We document numerous populations that are comprised largely (85-90%) of individuals over 80 years old, suggesting long-term recruitment failure since dam construction in the 1930s. Our findings indicate Bigmouth Buffalo require urgent attention, while other understudied fishes may be threatened by similar ecological neglect.
The proliferation of invasive marine species is often explained by a lack of predators and opportunistic life history traits. For the invasive comb jelly Mnemiopsis leidyi, it has remained unclear how this now widely distributed species is able to overcome long periods of low food availability, particularly in their northernmost exotic habitats in Eurasia. Based on both field and laboratory evidence, we show that adult comb jellies in the western Baltic Sea continue building up their nutrient reserves after emptying the prey field through a shift to cannibalizing their own larvae. We argue, that by creating massive late summer blooms, the population can efficiently empty the prey field, outcompete intraguild competitors, and use the bloom events to build nutrient reserves for critical periods of prey scarcity. Our finding that cannibalism makes a species with typical opportunistic traits more resilient to environmental fluctuations is important for devising more effective conservation strategies.
Glioblastoma (GBM) is an aggressive primary human brain tumour that has resisted effective therapy for decades. Although glucose and glutamine are the major fuels that drive GBM growth and invasion, few studies have targeted these fuels for therapeutic management. The glutamine antagonist, 6-diazo-5-oxo-L-norleucine (DON), was administered together with a calorically restricted ketogenic diet (KD-R) to treat late-stage orthotopic growth in two syngeneic GBM mouse models: VM-M3 and CT-2A. DON targets glutaminolysis, while the KD-R reduces glucose and, simultaneously, elevates neuroprotective and non-fermentable ketone bodies. The diet/drug therapeutic strategy killed tumour cells while reversing disease symptoms, and improving overall mouse survival. The therapeutic strategy also reduces edema, hemorrhage, and inflammation. Moreover, the KD-R diet facilitated DON delivery to the brain and allowed a lower dosage to achieve therapeutic effect. The findings support the importance of glucose and glutamine in driving GBM growth and provide a therapeutic strategy for non-toxic metabolic management.
Tumor organoids maintain cell-cell interactions, heterogeneity, microenvironment, and drug response of the sample they originate from. Thus, there is increasing interest in developing tumor organoid models for drug development and personalized medicine applications. Although organoids are in principle amenable to high-throughput screenings, progress has been hampered by technical constraints and extensive manipulations required by current methods. Here we introduce a miniaturized method that uses a simplified geometry by seeding cells around the rim of the wells (mini-rings). This allows high-throughput screenings in a format compatible with automation as shown using four patient-derived tumor organoids established from two ovarian and one peritoneal high-grade serous carcinomas and one carcinosarcoma of the ovary. Using our automated screening platform, we identified personalized responses by measuring viability, number, and size of organoids after exposure to 240 kinase inhibitors. Results are available within a week from surgery, a timeline compatible with therapeutic decision-making.
Antimicrobial peptides (AMPs) constitute promising alternatives to classical antibiotics for the treatment of drug-resistant infections, which are a rapidly emerging global health challenge. However, our understanding of the structure-function relationships of AMPs is limited, and we are just beginning to rationally engineer peptides in order to develop them as therapeutics. Here, we leverage a physicochemical-guided peptide design strategy to identify specific functional hotspots in the wasp-derived AMP polybia-CP and turn this toxic peptide into a viable antimicrobial. Helical fraction, hydrophobicity, and hydrophobic moment are identified as key structural and physicochemical determinants of antimicrobial activity, utilized in combination with rational engineering to generate synthetic AMPs with therapeutic activity in a mouse model. We demonstrate that, by tuning these physicochemical parameters, it is possible to design nontoxic synthetic peptides with enhanced sub-micromolar antimicrobial potency in vitro and anti-infective activity in vivo. We present a physicochemical-guided rational design strategy to generate peptide antibiotics.
With the rise of new powerful genome engineering technologies, such as CRISPR/Cas9, cell models can be engineered effectively to accelerate basic and disease research. The most critical step in this procedure is the efficient delivery of foreign nucleic acids into cells by cellular transfection. Since the vectors encoding the components necessary for CRISPR/Cas genome engineering are always large (9-19 kb), they result in low transfection efficiency and cell viability, and thus subsequent selection or purification of positive cells is required. To overcome those obstacles, we here show a non-toxic and non-viral delivery method that increases transfection efficiency (up to 40-fold) and cell viability (up to 6-fold) in a number of hard-to-transfect human cancer cell lines and primary blood cells. At its core, the technique is based on adding exogenous small plasmids of a defined size to the transfection mixture.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently affects 36 million people worldwide with no effective treatment available. Development of AD follows a distinctive pattern in the brain and is poorly modelled in animals. Therefore, it is vital to widen the spatial scope of the study of AD and prioritise the study of human brains. Here we show that functionally distinct human brain regions display varying and region-specific changes in protein expression. These changes provide insights into the progression of disease, novel AD-related pathways, the presence of a gradient of protein expression change from less to more affected regions and a possibly protective protein expression profile in the cerebellum. This spatial proteomics analysis provides a framework which can underpin current research and open new avenues to enhance molecular understanding of AD pathophysiology, provide new targets for intervention and broaden the conceptual frameworks for future AD research.
Presence of the integrated endogenous banana streak virus (eBSV) in the B genome of plantain (AAB) is a major challenge for breeding and dissemination of hybrids. As the eBSV activates into infectious viral particles under stress, the progenitor Musa balbisiana and its derivants, having at least one B genome, cannot be used as parents for crop improvement. Here, we report a strategy to inactivate the eBSV by editing the virus sequences. The regenerated genome-edited events of Gonja Manjaya showed mutations in the targeted sites with the potential to prevent proper transcription or/and translational into functional viral proteins. Seventy-five percent of the edited events remained asymptomatic in comparison to the non-edited control plants under water stress conditions, confirming inactivation of eBSV into infectious viral particles. This study paves the way for the improvement of B genome germplasm and its use in breeding programs to produce hybrids that can be globally disseminated.