Walnut genome to be sequenced by UC Davis and USDA

Deciphering the Walnut Genome

“In a new study, a team of scientists at the University of California, Davis, and USDA’s Agricultural Research Service (ARS) used a unique approach to sequence the genomes of the English walnut and its wild North American relative by tapping into the capabilities of two state-of-the-art technologies: long-read DNA sequencing and optical genome mapping. The resulting genome sequences are believed to be of the highest quality ever assembled of any woody perennial.”

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microRNA and cancer therapy

Scientists home in on microRNA processing for novel cancer therapies

“More than a decade of research on the mda-7/IL-24 gene has shown that it helps to suppress a majority of cancer types, and now scientists are focusing on how the gene drives this process by influencing microRNAs. Published this week in the journal Proceedings of the National Academy of Sciences, the findings could potentially have implications beyond cancer for a variety of cardiovascular and neurodegenerative diseases caused by the same microRNA-driven processes.”

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Great story about the application of evolutionary principles to fight cancer

A CLEVER NEW STRATEGY FOR TREATING CANCER, THANKS TO DARWIN

ROXANNE KHAMSI (WIRED)

“Even if cancer therapies kill most of the cells they target, a small subset can survive, largely thanks to genetic changes that render them resistant. In advanced-stage cancer, it’s generally a matter of when, not if, the pugnacious surviving cells will become an unstoppable force. Gatenby thought this deadly outcome might be prevented. His idea was to expose a tumor to medication intermittently, rather than in a constant assault, thereby reducing the pressure on its cells to evolve resistance.“

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How transcription shapes the genome

The role of transcription in shaping the spatial organization of the genome

Bas van Steensel & Eileen E. M. Furlong

Nature Reviews Molecular Cell Biology (Review Article)

Abstract—The spatial organization of the genome into compartments and topologically associated domains can have an important role in the regulation of gene expression. But could gene expression conversely regulate genome organization? Here, we review recent studies that assessed the requirement of transcription and/or the transcription machinery for the establishment or maintenance of genome topology. The results reveal different requirements at different genomic scales. Transcription is generally not required for higher-level genome compartmentalization, has only moderate effects on domain organization and is not sufficient to create new domain boundaries. However, on a finer scale, transcripts or transcription does seem to have a role in the formation of subcompartments and subdomains and in stabilizing enhancer–promoter interactions. Recent evidence suggests a dynamic, reciprocal interplay between fine-scale genome organization and transcription, in which each is able to modulate or reinforce the activity of the other.

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George Smith on what's to gain from looking into the genomes of extinct furry elephants

Decoding a Mammoth with George Church

Join Harvard DNA pioneer George Church and Chris Smith in conversation as they discuss gene cloning, DNA sequencing, decoding the mammoth genome, the risks posed by fossil viruses lurking in extinct genomes, the prospects of xenotransplantation, and safety of gene therapy, and the risks of human CRISPR. The discussion was recorded on March 15th, live in front of a studio audience at the Hello Tomorrow Summit, in Paris, 2019...

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Microbiome may predict preterm births

Spontaneous Preterm Birth Clues Identified in Cervicovaginal Microbiome

NEW YORK (GenomeWeb) – A University of Pennsylvania and University of Maryland team has identified microbial community features and host immune features in the cervix and vagina that appear to coincide with spontaneous preterm birth risk.

Based on targeted sequence data and enzyme-linked immunosorbent assay (ELISA) data that provided a look at cervicovaginal microbial community members and immune protein levels, respectively, in hundreds of women with or without preterm birth, the researchers pinned down half a dozen microbial community types and identified seven taxa with apparent ties to spontaneous preterm birth.

Together with host immune protein levels, the microbiome data provided clues to preterm birth biology, the authors noted in its study, out in Nature Communications today. Moreover, they suggested that it may eventually be possible to develop therapeutic approaches that tap into microbiome or immune features associated with the condition.

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The Possibility of Computational DNA

Reprogrammable DNA

“Researchers from the California Institute of Technology and Harvard University have shown that it is possible to reprogram a DNA-based computer, Wired reports.

The team, led by Caltech's Erik Winfree, reports in Nature that it developed and validated a set of 355 DNA tiles that they could then reprogram into a range of six-bit algorithms. In particular, the team says it constructed 21 circuits that perform algorithms that copy, sort, elect a leader, and generate random patterns, among other tasks, with an error rate of less than 1 in 3,000. This, they add, suggests "molecular self-assembly could be a reliable algorithmic component within programmable chemical systems.“

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Genome vs Exome sequencing in reference to cancer

Q&A With Mark B. Gerstein, PhD, on Diagnostic Genomic vs Exomic Sequencing

“Mark Gerstein, PhD, is Albert L Williams Professor of Biomedical Informatics and professor of molecular biophysics and biochemistry, and of computer science at the Yale School of Medicine in New Haven, Connecticut. He is also codirector of the Yale Program in Computational Biology & Bioinformatics.

Dr Gerstein spoke with Cancer Therapy Advisor about the diagnostic use of whole-genome compared with whole-exome next-generation sequencing to search for gene mutations that are thought to contribute to the risk of cancer and other diseases.1-3“

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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.”

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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.

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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.

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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“

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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. “

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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.”

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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.”

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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.

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Linking development and disease

Putting developmental diseases on the map

Most people use a map to understand the physical world around them. Now, genetic researchers have a map of their own to understand how developmental diseases work at the genetic level.  

In a recent study, UW graduate student Junyue Cao and Dr. Malte Spielmann from the Max Planck Institute profiled approximately 2 million cells from 61 mice embryos between 9 and 14 days old, resulting in a digital representation of how each cell type develops and its gene expression changes.

When a gene is between 9 and 14 days old, most cells that underlie major developmental diseases can be studied, according to Cao. With further application, Cao believes his study can be used as a reference to help other researchers understand how genetic diseases like autism, breast cancer, and parkinson’s disease develop in humans.

“If we can use this to comprehensively categorize the different cell states and their composition in disease or [the] aging process, then potentially, we can fully understand how they are generated in development and why there are different diseases and aging,” Cao said.

Cao and his team collected the largest single-cell dataset, Mouse Organogenesis Cell Atlas (MOCA), which consists of distinctions between individual cells. This dataset has recently been published and in this publication, the team created a genetic map of organ development.

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Cancer cells switch to fast food

Researchers find epigenetic loss that changes how cells obtain energy from cancer

It has been known for decades that cancer cells have an altered metabolism, and it is seen in several biochemical pathways and in particular, in the way they get energy for their survival.

If healthy cells use the mitochondrial respiratory chain, tumors use aerobic glycolysis, a process that allows them to take energy quickly but depending on glucose. This phenomenon - known as the Warburg effect - is caused by several changes that take place during cell transformation.

Now, a new article describes an epigenetic injury found in human tumours which creates this altered path to take energy from the cancer. The study, published in Journal of Clinical Investigation Insight, is a new research carried out by the group led by Manel Esteller, professor of Genetics of the Faculty of Medicine and Health Sciences of the University of Barcelona (UB), ICREA researcher, coordinator of the Cancer Epigenetics and Biology Program at IDIBELL, and director of the Josep Carreras Institute.

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