Cell population mapping from bulk single-cell RNA data

Cell composition analysis of bulk genomics using single-cell data

Amit Frishberg, Naama Peshes-Yaloz, Ofir Cohn, Diana Rosentul, Yael Steuerman, Liran Valadarsky, Gal Yankovitz, Michal Mandelboim, Fuad A. Iraqi, Ido Amit, Lior Mayo, Eran Bacharach, & Irit Gat-Viks

Nature Methods (Research Article)

Abstract—Single-cell RNA sequencing (scRNA-seq) is a rich resource of cellular heterogeneity, opening new avenues in the study of complex tissues. We introduce Cell Population Mapping (CPM), a deconvolution algorithm in which reference scRNA-seq profiles are leveraged to infer the composition of cell types and states from bulk transcriptome data (‘scBio’ CRAN R-package). Analysis of individual variations in lungs of influenza-virus-infected mice reveals that the relationship between cell abundance and clinical symptoms is a cell-state-specific property that varies gradually along the continuum of cell-activation states. The gradual change is confirmed in subsequent experiments and is further explained by a mathematical model in which clinical outcomes relate to cell-state dynamics along the activation process. Our results demonstrate the power of CPM in reconstructing the continuous spectrum of cell states within heterogeneous tissues.

Applying genomic meta-analyses to understand disease

Wanted: More Data, the Dirtier the Better

by Esther Landhuis, Quanta Magazine 

“To distill a clear message from growing piles of unruly genomics data, researchers often turn to meta-analysis — a tried-and-true statistical procedure for combining data from multiple studies. But the studies that a meta-analysis might mine for answers can diverge endlessly. Some enroll only men, others only children. Some are done in one country, others across a region like Europe. Some focus on milder forms of a disease, others on more advanced cases. Even if statistical methods can compensate for these kinds of variations, studies rarely use the same protocols and instruments to collect the data, or the same software to analyze it. Researchers performing meta-analyses go to untold lengths trying to clean up the hodgepodge of data to control for these confounding factors.”

READ MORE …

Strata Oncology using NGS for advanced cancer

Strata Oncology Launches Expanded StrataNGS for Patients with Advanced Cancer

ANN ARBOR, Mich., March 19, 2019 /PRNewswire/ -- Strata OncologyTM, a leading precision oncology company, today announced the launch of version 3.0 of StrataNGSTM, its pan-cancer assay for solid tumors. The updated 500-gene assay utilizes DNA and RNA from tumor samples to detect all clinically actionable biomarkers — including microsatellite instability (MSI), tumor mutational burden (TMB), and PD-L1 — recommended by leading guidelines, in a single test. Test results are provided in a streamlined report that facilitates rapid, confident interpretation and identification of potential treatment options and clinical trials.

READ MORE …

Somatic histone mutations occur in >4% of diverse tumour types and in crucial regions of histone proteins

The expanding landscape of ‘oncohistone’ mutations in human cancers

Benjamin A. Nacev, Lijuan Feng, John D. Bagert, Agata E. Lemiesz, JianJiong Gao, Alexey A. Soshnev, Ritika Kundra, Nikolaus Schultz, Tom W. Muir, & C. David Allis

Nature (Research Article)

Abstract

Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrates for chromatin-modifying and remodelling enzymes, are mutated in tumours including gliomas, sarcomas, head and neck cancers, and carcinosarcomas. Classical ‘oncohistone’ mutations occur in the N-terminal tail of histone H3 and affect the function of polycomb repressor complexes 1 and 2 (PRC1 and PRC2). However, the prevalence and function of histone mutations in other tumour contexts is unknown. Here we show that somatic histone mutations occur in approximately 4% (at a conservative estimate) of diverse tumour types and in crucial regions of histone proteins. Mutations occur in all four core histones, in both the N-terminal tails and globular histone fold domains, and at or near residues that contain important post-translational modifications. Many globular domain mutations are homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory ‘acidic patch’ of histones H2A and H2B, or are predicted to disrupt the H2B–H4 interface. The histone mutation dataset and the hypotheses presented here on the effect of the mutations on important chromatin functions should serve as a resource and starting point for the chromatin and cancer biology fields in exploring an expanding role of histone mutations in cancer.

READ MORE …

Immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion

Neoantigen-directed immune escape in lung cancer evolution

Rachel Rosenthal, Elizabeth Larose Cadieux, Roberto Salgado, Maise Al Bakir, David A. Moore, Crispin T. Hiley, Tom Lund, Miljana Tanić, James L. Reading, Kroopa Joshi, Jake Y. Henry, Ehsan Ghorani, Gareth A. Wilson, Nicolai J. Birkbak, Mariam Jamal-Hanjani, Selvaraju Veeriah, Zoltan Szallasi, Sherene Loi, Matthew D. Hellmann, Andrew Feber, Benny Chain, Javier Herrero, Sergio A. Quezada, Jonas Demeulemeester, Peter Van Loo, Stephan Beck, Nicholas McGranahan, Charles Swanton & The TRACERx consortium

Nature (Research Article)

Abstract

The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.

READ MORE …

New CRISPR Diagnostics Firm

Broad, Wyss Institute Researchers Launch CRISPR Dx Firm Sherlock Biosciences

NEW YORK (GenomeWeb) – Engineering biology startup Sherlock Biosciences announced today that it has launched with initial financing of $35 million and licenses to foundational CRISPR and synthetic biology technology from the Broad Institute and Harvard's Office of Technology Development…

Sherlock will use engineering biology tools, including CRISPR and synthetic biology, to develop a new generation of molecular diagnostics that can rapidly deliver accurate results for a vast range of needs in virtually any setting and at low cost, the company said.

The financing includes a $17.5 million non-dilutive grant and an investment from the Open Philanthropy Project, as well as funds from additional undisclosed investors.

READ MORE …

Combination therapy for cancer therapy

Functional Genomics Approach To Identify New Combination Therapies For Cancer Treatment

“In our recent publication in Science Advances, we describe the use of an in vivo-based functional genomics screen to identify genes whose inhibition potentiates a response to anti-PD-1 immunotherapy. Specifically, we define a novel mechanism whereby targeting the collagen receptor, discoidin domain receptor 2 (DDR2), elicits a significantly enhanced response to immune checkpoint blockade with PD-1 inhibitors. Of specific note is the observation this combination is robust across multiple tumor models including melanoma, sarcoma, breast, bladder and colon cancer indicating that DDR2 expression is an important and broadly used mechanism by cancer cells to escape checkpoint blockade therapy“

READ MORE …

Setback for myeloma therapy Venclexta

Roche, AbbVie forced to slam brakes on myeloma studies of star drug Venclexta after researchers flag higher risk of death

“Two heavyweight pharma players today said they’ve been forced to stop recruiting patients for all ongoing studies involving Venclexta (venetoclax) for multiple myeloma. Roche and AbbVie say the drug arm has been linked to a higher rate of death than the control group, prompting the FDA to issue a partial hold ordering them to suspend any new patient recruitment for the blood cancer trials until they can sort out what is happening.“

READ MORE …

CRISP documentary reviewed in Ars Technica

New documentary has a good time asking how gene editing might change the world

Here's a poorly kept secret: the internal chatter at a given research and scientific institution is typically more interesting than what emerges on the public record. Published papers and newspaper interviews don't come with the banter, pop-culture references, or sheer wit that pumps through most nerds' veins.

I thought back to all that nerd humor when I reflected on Human Nature, a documentary about gene editing and CRISPR that had its world premiere at South by Southwest 2019. There's a lot of ground to cover on such a topic, and the film, co-produced by Dan Rather, does quite well by identifying existing research and studies, then grounding them with context and equal parts optimism and pessimism. But Human Nature is also the rare science film that isn't afraid to let its smart talking heads be funny, dorky, or just plain sharp.

Distinguishing amplification artifacts from biologically derived somatic mutations in single-cell sequencing data

Linked-read analysis identifies mutations in single-cell DNA-sequencing data

Craig L. Bohrson, Alison R. Barton, Michael A. Lodato, Rachel E. Rodin, Lovelace J. Luquette, Vinay V. Viswanadham, Doga C. Gulhan, Isidro Cortés-Ciriano, Maxwell A. Sherman, Minseok Kwon,  Michael E. Coulter, Alon Galor, Christopher A. Walsh & Peter J. Park

Nature Genetics (Research Article)

Whole-genome sequencing of DNA from single cells has the potential to reshape our understanding of mutational heterogeneity in normal and diseased tissues. However, a major difficulty is distinguishing amplification artifacts from biologically derived somatic mutations. Here, we describe linked-read analysis (LiRA), a method that accurately identifies somatic single-nucleotide variants (sSNVs) by using read-level phasing with nearby germline heterozygous polymorphisms, thereby enabling the characterization of mutational signatures and estimation of somatic mutation rates in single cells.

Space-Herpes, just what the world needs now

Space Travel Causes Viruses To 'Resurrect' Inside Astronauts

“It seems space travel has a very unexpected side effect – herpes.

NASA scientists discovered that dormant herpes viruses lurking inside more than half of astronauts aboard the International Space Station (ISS) and Space Shuttle "resurrected" after time spent in space. The results have been published in Frontiers in Microbiology.

Fortunately, very few went on to develop symptoms. However, the study authors warn, virus reactivation rates appear to increase as time goes on – an observation that could pose a major challenge to missions to Mars and further into deep space. “

READ MORE …

Google AI variant caller goes deep on rice genomes

Analyzing 3024 rice genomes characterized by DeepVariant

“Rice is an ideal candidate for study in genomics, not only because it’s one of the world’s most important food crops, but also because centuries of agricultural cross-breeding have created unique, geographically-induced differences. With the potential for global population growth and climate change to impact crop yields, the study of this genome has important social considerations.

This post explores how to identify and analyze different rice genome mutations with a tool called DeepVariant. To do this, we performed a re-analysis of the Rice 3Kdataset and have made the data publicly available as part of the Google Cloud Public Dataset Program pre-publication and under the terms of the Toronto Statement.

We aim to show how AI can improve food security by accelerating genetic enhancement to increase rice crop yield. According to the Food and Agriculture Organization of the United Nations, crop improvements will reduce the negative impact of climate change and loss of arable land on rice yields, as well as support an estimated 25% increase in rice demand by 2030.”

READ MORE …

ALS Awards for target discovery and therapy development

TARGET ALS AWARDS SIX INNOVATIVE RESEARCH TEAMS WITH ADDITIONAL TARGET DISCOVERY FUNDS

New York City – Target ALS is pleased to announce that it has awarded target discovery and development funding to six research consortia that are working toward the development of ground-breaking therapeutic approaches to treating ALS.

In 2016 – 2017, Target ALS provided multi-year grants to a number of unique research consortia to encourage ALS research ideation and active involvement from both the pharma/biotech industry as well as the most talented new investigators in the field. In a historic first, either a pharma/biotech researcher or a new investigator led each team. These teams were awarded funding for a range of novel projects from early stage target discovery to the development of new therapeutic approaches.

A wave of creative thinking and collaboration followed. Indeed, many projects have led to the development of new, ground-breaking therapeutic approaches while others are advancing our understanding of pathophysiology of ALS.  In response to this growing momentum, the Target ALS Independent Review Committee (IRC) granted six of the most promising collaborative projects an additional year of funding.

READ MORE …

Standardized Germline Variant Calling Performance Metrics

GA4GH Benchmarking Team Releases Best Practices for Comparing Germline Variant Calls

NEW YORK (GenomeWeb) – Members of the benchmarking team of the Global Alliance for Genomics and Health have developed methods for producing standardized performance metrics for benchmarking small germline variant calls.

The GA4GH Benchmarking team brings together participants from research institutes, technology companies, government agencies, and clinical laboratories. It includes researchers from the National Institute of Standards and Technology (NIST), Illumina, Ontario Institute for Cancer Research, DNAnexus, and others.

As explained in a Nature Biotechnology paper published yesterday, the methods that they have developed address challenges associated with standardizing metrics like recall and precision, comparing different representations of variant calls, and stratifying performance by variant type and genome context. The team has made the code used for the benchmarking available in Github.

READ MORE …

Exome sequencing reveals molecular features of the pediatric variants of follicular lymphoma

Molecular Characterization of Pediatric Follicular Lymphoma

“Pediatric follicular lymphomas involve interactions in MAPK and G-protein protein receptor signaling pathways, according to results of a new study. This study, published online in Haematologica, identified a number of novel mutations and signaling pathways associated with pediatric follicular lymphomas.

Classic follicular lymphoma, an indolent B-cell lymphoma, is very rare in children, whereas pediatric-type nodal follicular lymphoma (PTNFL) and primary follicular lymphoma of the testis (PFLT) occur more frequently in this population compared with adults. While the molecular landscape of classic follicular lymphoma has been more thoroughly studied, comparatively little is known about the molecular features of the pediatric variants of follicular lymphoma.”

READ MORE …

Personalis introduces new universal cancer immunogenomics platform, ImmunoID NeXT™

Personalis, Inc. to Present at ICI-IO Combinations Summit 2019

MENLO PARK, Calif.--(BUSINESS WIRE)--Personalis Inc., a leader in advanced genomics for precision oncology, today announced that they are scheduled to present at ICI-IO Combinations Summit 2019 in Boston on Wednesday, March 20, 2019 at 2:30 PM, EDT.

The presentation, entitled “Challenges and Solutions: Enabling multidimensional tumor immunogenomics for advancing biomarker discovery,” will introduce Personalis’ new universal cancer immunogenomics platform, ImmunoID NeXT™. In addition to an overview, the presentation will also highlight how this platform can be used to overcome the challenges facing immuno-oncology translational and clinical researchers. By deriving new insights through our industry leading NGS analysis platform, ImmunoID NeXT provides solutions to enable the development of safer, more effective precision oncology therapeutics and combinations.

READ MORE …

Improve clinical care for Ovarian cancer using multiple genome sequences

Simultaneous Sequencing of Paired Germline and Somatic Specimens Enhanced Clinical Care in Ovarian Cancer

In a small sample of women with ovarian cancer for whom simultaneous next-generation DNA sequencing was performed on paired germline and tumor specimens, test results influenced clinical decision-making for nearly 25% of patients. This study was presented at the Society of Gynecologic Oncology (SGO)’s 50th Annual Meeting on Women’s Cancer.

Targeted sequencing using the BROCA test, a gene panel designed for patients with a suspected hereditary cancer predisposition, was performed between July 2017 and July 2018 on paired peripheral blood (germline) and ovarian cancer tumor specimens (somatic) for 36 women with newly diagnosed ovarian cancer and 7 women with recurrent disease. Tumor specimens were obtained from surgical specimens, biopsy, or cytology in 72.1%, 25.6%, and 2.3% of cases, respectively.

READ MORE …

Head to Head: CRISPR Therapeutics AG (CRSP)’s and Arrowhead Pharmaceuticals Inc. (NASDAQ:ARWR)

Reviewing CRISPR Therapeutics AG (CRSP)’s and Arrowhead Pharmaceuticals Inc. (NASDAQ:ARWR)’s results

Both CRISPR Therapeutics AG (NASDAQ:CRSP) and Arrowhead Pharmaceuticals Inc. (NASDAQ:ARWR) compete on a level playing field in the Biotechnology industry. We will evaluate their performance with regards to profitability, analyst recommendations, risk, dividends, earnings and valuation, institutional ownership.

READ MORE …

Head to Head: Fate Therapeutics (NASDAQ:FATE) versus Genetic Technologies (GENE)

Head to Head Contrast: Fate Therapeutics (NASDAQ:FATE) and Genetic Technologies (GENE)

Genetic Technologies (NASDAQ:GENE) and Fate Therapeutics (NASDAQ:FATE) are both small-cap medical companies, but which is the superior business? We will compare the two businesses based on the strength of their valuation, earnings, dividends, risk, profitability, analyst recommendations and institutional ownership.

READ MORE …

Chinese gene editing therapies are developing

China’s race to test ‘mutation-free’ gene-editing technology on cancer patients

BEIJING — China could be just over a year away from clinical trials of a new gene-editing therapy with an unprecedented high level of safety, according to a team of Chinese scientists involved in the research programme.

The scientists said the research, based on groundbreaking work published in the journal Science earlier this month, could help save the lives of many patients battling deadly diseases including cancer.

The existing genome-editing method works like a shotgun, breaking up a large numbers of genome strands and sometimes missing its intended target, causing unnecessary damage to cells.

The new tool under development in China targets and swaps individual “letters” in the DNA with extreme precision, avoiding cuts to the strands and significantly reducing the risk of unexpected mutations.

READ MORE …