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Extreme purifying selection against point mutations in the human genome
Get PDFGenome sequencing of tens of thousands of humans has enabled the measurement of large selective effects for mutations to protein-coding genes. Here we describe a new method, called ExtRaINSIGHT, for measuring similar selective effects in noncoding as well as in coding regions of the human genome. ExtRaINSIGHT estimates the prevalance of strong purifying selection, or “ultraselection” (λs), as the fractional depletion of rare single-nucleotide variants in target genomic sites relative to matched sites that are putatively free from selection, after controlling for local variation and neighbor-dependence in mutation rate. We show using simulations that λs is closely related to the average site-specific selection coefficient against heterozygous point mutations, as predicted at mutation-selection balance. Applying ExtRaINSIGHT to 71,702 whole genome sequences from gnomAD v3, we find strong evidence of ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. By contrast, we find weak evidence in other noncoding RNAs and transcription factor binding sites, and only modest evidence in ultraconserved elements and human accelerated regions. We estimate that ~0.3–0.5% of the human genome is ultraselected, implying ~0.3–0.4 lethal or nearly lethal de novo mutations per potential human zygote. Overall, our study sheds new light on the genome-wide distribution of fitness effects for new point mutations by combining deep new sequencing data sets and classical theory from population genetics
Discovery of Ongoing Selective Sweeps within Anopheles Mosquito Populations Using Deep Learning.
Get PDFIdentification of partial sweeps, which include both hard and soft sweeps that have not currently reached fixation, provides crucial information about ongoing evolutionary responses. To this end, we introduce partialS/HIC, a deep learning method to discover selective sweeps from population genomic data. partialS/HIC uses a convolutional neural network for image processing, which is trained with a large suite of summary statistics derived from coalescent simulations incorporating population-specific history, to distinguish between completed versus partial sweeps, hard versus soft sweeps, and regions directly affected by selection versus those merely linked to nearby selective sweeps. We perform several simulation experiments under various demographic scenarios to demonstrate partialS/HIC's performance, which exhibits excellent resolution for detecting partial sweeps. We also apply our classifier to whole genomes from eight mosquito populations sampled across sub-Saharan Africa by the Anopheles gambiae 1000 Genomes Consortium, elucidating both continent-wide patterns as well as sweeps unique to specific geographic regions. These populations have experienced intense insecticide exposure over the past two decades, and we observe a strong overrepresentation of sweeps at insecticide resistance loci. Our analysis thus provides a list of candidate adaptive loci that may be relevant to mosquito control efforts. More broadly, our supervised machine learning approach introduces a method to distinguish between completed and partial sweeps, as well as between hard and soft sweeps, under a variety of demographic scenarios. As whole-genome data rapidly accumulate for a greater diversity of organisms, partialS/HIC addresses an increasing demand for useful selection scan tools that can track in-progress evolutionary dynamics
Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network
Get PDFUsing the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism
Quantitative towers in finite difference calculus approximating the continuum
No full textAbstract
Multivector fields and differential forms at the continuum level have respectively two commutative associative products, a third composition product between them and various operators like , d and ‘*’ which are used to describe many nonlinear problems. The point of this paper is to construct consistent direct and inverse systems of finite dimensional approximations to these structures and to calculate combinatorially how these finite dimensional models differ from their continuum idealizations. In a Euclidean background, there is an explicit answer which is natural statistically.</jats:p
The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies.
Get PDFMonoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting
Single-cell alternative polyadenylation analysis delineates GABAergic neuron types.
Get PDFBACKGROUND: Alternative polyadenylation (APA) is emerging as an important mechanism in the post-transcriptional regulation of gene expression across eukaryotic species. Recent studies have shown that APA plays key roles in biological processes, such as cell proliferation and differentiation. Single-cell RNA-seq technologies are widely used in gene expression heterogeneity studies; however, systematic studies of APA at the single-cell level are still lacking. RESULTS: Here, we described a novel computational framework, SAPAS, that utilizes 3'-tag-based scRNA-seq data to identify novel poly(A) sites and quantify APA at the single-cell level. Applying SAPAS to the scRNA-seq data of phenotype characterized GABAergic interneurons, we identified cell type-specific APA events for different GABAergic neuron types. Genes with cell type-specific APA events are enriched for synaptic architecture and communications. In further, we observed a strong enrichment of heritability for several psychiatric disorders and brain traits in altered 3' UTRs and coding sequences of cell type-specific APA events. Finally, by exploring the modalities of APA, we discovered that the bimodal APA pattern of Pak3 could classify chandelier cells into different subpopulations that are from different laminar positions. CONCLUSIONS: We established a method to characterize APA at the single-cell level. When applied to a scRNA-seq dataset of GABAergic interneurons, the single-cell APA analysis not only identified cell type-specific APA events but also revealed that the modality of APA could classify cell subpopulations. Thus, SAPAS will expand our understanding of cellular heterogeneity
Treatment with granulocyte-colony stimulating factor (G-CSF) is not associated with increased risk of brain metastasis in patients with de novo stage IV breast cancer
Get PDFBackground: Survival outcome after developing brain metastasis is poor and there is an unmet need to identify factors that can promote brain metastasis. Granulocyte-colony stimulating factor (G-CSF) is given to support neutrophil recovery after myelosuppressive chemotherapy to some patients. However, there is emerging evidence that neutrophils can promote metastasis, including through the formation of neutrophil extracellular traps (NETs), scaffolds of chromatin with enzymes expelled from neutrophils to the extracellular space. In animal models, G-CSFs can induce NETs to promote liver and lung metastasis. The primary objective of this study was to test the association between G-CSF use and the later incidence of brain metastasis. Methods: Patients with de novo Stage IV breast cancer, without known brain metastasis at the time of initial diagnosis, were identified from electronic medical records covering the period from 1/1/2013 to 12/31/2020 at Northwell Health. Univariate and multivariate logistic regression models were used to test the association between variables of interest, including G-CSF use, and brain metastasis. Results: A total of 78 patients were included in the final analysis. Among those 78 patients, 24 patients (30.8%) had received G-CSF along with chemotherapy at least once. In logistic regression models, G-CSF use was not a significant factor to predict brain metastasis (OR 1.89 [95%CI 1.89-5.33]; P=0.23). Interestingly, in multivariate logistic models, pulmonary embolism (PE)/deep venous thrombosis (DVT) was a significant predictive factor of brain metastasis (OR 6.74 [95%CI 1.82-25.01]; P=0.004) (38.5% vs 21.5%). Conclusions: The use of G-CSF was not associated with increased risk of brain metastasis in patients with de novo Stage IV breast cancer. Interestingly, PE/DVT, which can be associated with elevated NETs, was associated with brain metastasis. Further studies are warranted to determine whether DVT/PE with or without elevated NETs levels in the blood, is predictive of developing brain metastasis in patients with de novo Stage IV breast cancer
An amygdalo-cortical circuit for multisensory processing in maternal behavior
No full textSocial encounters are commonly constructed from stimuli of more than one modality. The ability to integrate separate streams of information from conspecifics likely improves the fidelity of social communication, yet the neural circuitry that supports this operation is poorly understood. Much of the research investigating the neural correlates of multisensory integration has focused on the binding of visual and auditory stimuli and has largely ignored the contribution of olfactory input. Mice, however, rely heavily on odors to communicate social information, which can significantly modify neural activity across sensory modalities and alter the behavioral output of the animal. Because social behaviors like reproduction and parental care are essential for survival, the underlying circuits are evolutionarily conserved, allowing animal models to provide detailed insight on neural circuits with real implications for human health.
Studies of maternal behavior in mice have revealed incredible detail about hypothalamic and neuroendocrine systems that underlie a repertoire of stereotyped behaviors in natural mothers. However, the neural networks that support maternal behavior are not solely dependent on hormonal input. Instead, prolonged exposure to novel multisensory cues provided by pups is suspected to be the essential component enhancing the salience of specific stimuli. For example, in maternally experienced females, odor presentation enhances auditory responses to ethologically relevant stimuli. In this scenario, olfactory signaling conveys the context in which to detect and respond to certain auditory stimuli. Though compelling, this theory did not possess an anatomical substrate to support this function.
Here we identify a pathway from neurons in the basal amygdala to the auditory cortex (BA-AC) by which female mice may merge olfactory and auditory signals from pups to guide maternal behavior. BA-AC neurons both detect pup odor and show elevated activity while searching for pups in distress. Optogenetic activation of BA-AC neurons modifies auditory cortical activity in an experience-dependent manner, switching from suppression to enhancement of auditory responses in maternally experienced females. BA-AC neurons, therefore, constitute a conduit for pup odor to act directly on the primary sensory cortex to alter vocal perception. We propose that the BA may influence goal-directed maternal behavior beyond merging multisensory stimuli by incorporating the animal’s affective state to enhance the salience of pup vocalizations, resulting in adept pup retrieval
Homologous organization of cerebellar pathways to sensory, motor, and associative forebrain.
Get PDFCerebellar outputs take polysynaptic routes to reach the rest of the brain, impeding conventional tracing. Here, we quantify pathways between the cerebellum and forebrain by using transsynaptic tracing viruses and a whole-brain analysis pipeline. With retrograde tracing, we find that most descending paths originate from the somatomotor cortex. Anterograde tracing of ascending paths encompasses most thalamic nuclei, especially ventral posteromedial, lateral posterior, mediodorsal, and reticular nuclei. In the neocortex, sensorimotor regions contain the most labeled neurons, but we find higher densities in associative areas, including orbital, anterior cingulate, prelimbic, and infralimbic cortex. Patterns of ascending expression correlate with c-Fos expression after optogenetic inhibition of Purkinje cells. Our results reveal homologous networks linking single areas of the cerebellar cortex to diverse forebrain targets. We conclude that shared areas of the cerebellum are positioned to provide sensory-motor information to regions implicated in both movement and nonmotor function