Systems-level immunomonitoring using self-sampled capillary blood, bioRxiv, 2019-07-08
AbstractComprehensive profiling of the human immune system in patients with cancer, autoimmune disease and during infections are providing valuable information that help us understand disease states and discriminate productive from inefficient immune responses and identify possible targets for immune modulation. Recent technical advances now allow for all immune cell populations and hundreds of plasma proteins to be detected using small volume blood samples. To democratize such systems-immunological analyses, further simplified blood sampling and preservation will be important. Here we describe that blood obtained via a nearly painless self-sampling device of 100 microliter of capillary blood that is preserved and frozen, can simplify systems-level immunomonitoring studies.
biorxiv immunology 100-200-users 2019Transcriptome assembly from long-read RNA-seq alignments with StringTie2, bioRxiv, 2019-07-08
AbstractRNA sequencing using the latest single-molecule sequencing instruments produces reads that are thousands of nucleotides long. The ability to assemble these long reads can greatly improve the sensitivity of long-read analyses. Here we present StringTie2, a reference-guided transcriptome assembler that works with both short and long reads. StringTie2 includes new computational methods to handle the high error rate of long-read sequencing technology, which previous assemblers could not tolerate. It also offers the ability to work with full-length super-reads assembled from short reads, which further improves the quality of assemblies. On 33 short-read datasets from humans and two plant species, StringTie2 is 47.3% more precise and 3.9% more sensitive than Scallop. On multiple long read datasets, StringTie2 on average correctly assembles 8.3 and 2.6 times as many transcripts as FLAIR and Traphlor, respectively, with substantially higher precision. StringTie2 is also faster and has a smaller memory footprint than all comparable tools.
biorxiv genomics 100-200-users 2019Aging is associated with a systemic length-driven transcriptome imbalance, bioRxiv, 2019-07-04
AbstractAging manifests itself through a decline in organismal homeostasis and a multitude of cellular and physiological functions1. Efforts to identify a common basis for vertebrate aging face many challenges; for example, while there have been documented changes in the expression of many hundreds of mRNAs, the results across tissues and species have been inconsistent2. We therefore analyzed age-resolved transcriptomic data from 17 mouse organs and 51 human organs using unsupervised machine learning3–5 to identify the architectural and regulatory characteristics most informative on the differential expression of genes with age. We report a hitherto unknown phenomenon, a systemic age-dependent length-driven transcriptome imbalance that for older organisms disrupts the homeostatic balance between short and long transcript molecules for mice, rats, killifishes, and humans. We also demonstrate that in a mouse model of healthy aging, length-driven transcriptome imbalance correlates with changes in expression of splicing factor proline and glutamine rich (Sfpq), which regulates transcriptional elongation according to gene length6. Furthermore, we demonstrate that length-driven transcriptome imbalance can be triggered by environmental hazards and pathogens. Our findings reinforce the picture of aging as a systemic homeostasis breakdown and suggest a promising explanation for why diverse insults affect multiple age-dependent phenotypes in a similar manner.
biorxiv systems-biology 100-200-users 2019Emergence of the Ug99 lineage of the wheat stem rust pathogen through somatic hybridisation, bioRxiv, 2019-07-04
AbstractParasexuality contributes to diversity and adaptive evolution of haploid (monokaryotic) fungi. However non-sexual genetic exchange mechanisms are not defined in dikaryotic fungi (containing two distinct haploid nuclei). Newly emerged strains of the wheat stem rust pathogen, Puccinia graminis f. sp. tritici (Pgt), such as Ug99, are a major threat to global food security. Here we show that Ug99 arose by somatic hybridisation and nuclear exchange between dikaryons. Fully haplotype-resolved genome assembly and DNA proximity analysis revealed that Ug99 shares one haploid nucleus genotype with a much older African lineage of Pgt, with no recombination or reassortment. Generation of genetic variation by nuclear exchange may favour the evolution of dikaryotism by providing an advantage over diploidy.
biorxiv genetics 100-200-users 2019Linking transcriptome and chromatin accessibility in nanoliter droplets for single-cell sequencing, bioRxiv, 2019-07-04
Linked profiling of transcriptome and chromatin accessibility from single cells can provide unprecedented insights into cellular status. Here we developed a droplet-based Single-Nucleus chromatin Accessibility and mRNA Expression sequencing (SNARE-seq) assay, that we used to profile neonatal and adult mouse cerebral cortices. To demonstrate the strength of single-cell dual-omics profiling, we reconstructed transcriptome and epigenetic landscapes of cell types, uncovered lineage-specific accessible sites, and connected dynamics of promoter accessibility with transcription during neurogenesis.
biorxiv genomics 100-200-users 2019Reconciling Dimensional and Categorical Models of Autism Heterogeneity a Brain Connectomics & Behavioral Study, bioRxiv, 2019-07-04
AbstractBackgroundHeterogeneity in autism spectrum disorder (ASD) has hindered the development of biomarkers, thus motivating subtyping efforts. Most subtyping studies divide ASD individuals into non-overlapping (categorical) subgroups. However, continuous inter-individual variation in ASD suggests the need for a dimensional approach.MethodsA Bayesian model was employed to decompose resting-state functional connectivity (RSFC) of ASD individuals into multiple abnormal RSFC patterns, i.e., categorical subtypes henceforth referred to as “factors”. Importantly, the model allowed each individual to express one or more factors to varying degrees (dimensional subtyping). The model was applied to 306 ASD individuals (age 5.2-57 years) from two multisite repositories. Posthoc analyses associated factors with symptoms and demographics.ResultsAnalyses yielded three factors with dissociable whole-brain hypohyper RSFC patterns. Most participants expressed multiple (categorical) factors, suggestive of a mosaic of subtypes within individuals. All factors shared abnormal RSFC involving the default network, but the directionality (hypohyper RSFC) differed across factors. Factor 1 was associated with core ASD symptoms, while factor 2 was associated with comorbid symptoms. Older males preferentially expressed factor 3. Factors were robust across multiple control analyses and not associated with IQ, nor head motion.ConclusionsThere exist at least three ASD factors with dissociable patterns of whole-brain RSFC, behaviors and demographics. Heterogeneous default network hypohyper RSFC across the factors might explain previously reported inconsistencies. The factors differentiated between core ASD and comorbid symptoms - a less appreciated domain of heterogeneity in ASD. These factors are co-expressed in ASD individuals with different degrees, thus reconciling categorical and dimensional perspectives of ASD heterogeneity.
biorxiv neuroscience 100-200-users 2019