Population genomic and evolutionary modeling analyses find QTL relevant to global health (BMC Genomics)

Population genomic and evolutionary modeling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus

Stephen R. Doyle†Email authorView ORCID ID profile, Christopher J. R. Illingworth†, Roz Laing, David J. Bartley, Elizabeth Redman, Axel Martinelli, Nancy Holroyd, Alison A. Morrison, Andrew Rezansoff, Alan Tracey, Eileen Devaney, Matthew Berriman, Neil Sargison, James A. Cotton,and John S. Gilleard

BMC Genomics (Research Article)

Infections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the reduced efficacy in some human-infective helminths. Understanding the mechanisms by which resistance evolves is the focus of increasing interest; robust genetic analysis of helminths is challenging, and although many candidate genes have been proposed, the genetic basis of resistance remains poorly resolved.

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Why don't we make heritable gene editing available to everybody?

We should not fear 'editing' embryos to enhance human intelligence, says leading geneticist George Church

One of the world’s leading geneticists says it will only be a matter of time before the genes of  human embryos are ‘edited’ to enhance their health and intelligence – and it is something we should embrace rather than fear.

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EGFR is required for regeneration

Study uncovers genes that control process of whole-body regeneration

When it comes to regeneration, some animals are capable of amazing feats. If you cut off a salamander’s leg, it will grow back. When threatened, some geckos drop their tails to distract their predator, only to regrow them later.

Other animals take the process even further. Planarian worms, jellyfish, and sea anemones can actually regenerate their bodies after being cut in half.

Led by Assistant Professor of Organismic and Evolutionary Biology Mansi Srivastava, a team of researchers is shedding new light on how animals pull off the feat, along the way uncovering a number of DNA switches that appear to control genes for whole-body regeneration. The study is described in a March 15 paper in Science.

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Next Next Gen Detection of Structural Variants

Accurate detection of complex structural variations using single-molecule sequencing

Fritz J. Sedlazeck, Philipp Rescheneder, Moritz Smolka, Han Fang, Maria Nattestad, Arndt von Haeseler, and Michael C. Schatz

Nature Methods (Research article)

Abstract—Structural variations are the greatest source of genetic variation, but they remain poorly understood because of technological limitations. Single-molecule long-read sequencing has the potential to dramatically advance the field, although high error rates are a challenge with existing methods. Addressing this need, we introduce open-source methods for long-read alignment (NGMLR; https://github.com/philres/ngmlr) and structural variant identification (Sniffles; https://github.com/fritzsedlazeck/Sniffles) that provide unprecedented sensitivity and precision for variant detection, even in repeat-rich regions and for complex nested events that can have substantial effects on human health. In several long-read datasets, including healthy and cancerous human genomes, we discovered thousands of novel variants and categorized systematic errors in short-read approaches. NGMLR and Sniffles can automatically filter false events and operate on low-coverage data, thereby reducing the high costs that have hindered the application of long reads in clinical and research settings.

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Ed Yong gets punny about evolution in the Atlantic

This Is a Truly Lousy Experiment About Evolution

By placing feather-eating lice on white, black, and gray pigeons, researchers showed how the parasites change color to better blend in.

“Believing that it is always best to study some special group, I have, after deliberation, taken up domestic pigeons,” wrote one Charles Darwin in On the Origin of Species. Four years earlier, Darwin had taken to raising pigeons in his own dovecote, hobnobbing with other pigeon fanciers, and carefully measuring the birds. In the diverse breeds, with their fantails, feather-duster feet, and frilly backs, Darwin saw validation for his ideas about evolution. If people could artificially select for such astonishing diversity in just a few generations, nature was surely capable of far more over longer timescales.

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Important reminder that your genome is your property

Your invaluable genome

Genomic data is the currency of a new era of medicine that promises incredible advances. Here, bioinformatician Nana Mensah explains why…

In the race for greatest medical revolution of the 21st century, genomics is undoubtedly a frontrunner. Those outside of the field, however, might still find themselves wondering: 'what's all the fuss about?' There are many reasons why genomics is revolutionary, but data is at the root of it all. As genomics is used more and more in mainstream care, it becomes ever more important to understand the great power and value of this new kind of data, writes Nana Mensah.

From cell to computer

While the word ‘genome’ refers to the entire sequence of DNA of an individual organism, the term ‘genomic data’ refers to its digital representation – a large data file resulting from the sequencing process.

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The true number of human miRNAs

An estimate of the total number of true human miRNAs

Julia Alles, Tobias Fehlmann, Ulrike Fischer, Christina Backes, Valentina Galata, Marie Minet, Martin Hart, Masood Abu-Halima, Friedrich A Grässer,  Hans-Peter Lenhof, Andreas Keller, and Eckart Meese

Nucleic Acids Research (Research Article)

Abstract—While the number of human miRNA candidates continuously increases, only a few of them are completely characterized and experimentally validated. Toward determining the total number of true miRNAs, we employed a combined in silico high- and experimental low-throughput validation strategy. We collected 28 866 human small RNA sequencing data sets containing 363.7 billion sequencing reads and excluded falsely annotated and low quality data. Our high-throughput analysis identified 65% of 24 127 mature miRNA candidates as likely false-positives. Using northern blotting, we experimentally validated miRBase entries and novel miRNA candidates. By exogenous overexpression of 108 precursors that encode 205 mature miRNAs, we confirmed 68.5% of the miRBase entries with the confirmation rate going up to 94.4% for the high-confidence entries and 18.3% of the novel miRNA candidates. Analyzing endogenous miRNAs, we verified the expression of 8 miRNAs in 12 different human cell lines. In total, we extrapolated 2300 true human mature miRNAs, 1115 of which are currently annotated in miRBase V22. The experimentally validated miRNAs will contribute to revising targetomes hypothesized by utilizing falsely annotated miRNAs.

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Connecting chromatin states (Epigenetics) to structural variation in human genomes

Chromatin organization modulates the origin of heritable structural variations in human genome 

Tanmoy Roychowdhury and Alexej Abyzov

Nucleic Acids Research (Article)

Abstract

“Structural variations (SVs) in the human genome originate from different mechanisms related to DNA repair, replication errors, and retrotransposition. Our analyses of 26 927 SVs from the 1000 Genomes Project revealed differential distributions and consequences of SVs of different origin, e.g. deletions from non-allelic homologous recombination (NAHR) are more prone to disrupt chromatin organization while processed pseudogenes can create accessible chromatin. Spontaneous double stranded breaks (DSBs) are the best predictor of enrichment of NAHR deletions in open chromatin. This evidence, along with strong physical interaction of NAHR breakpoints belonging to the same deletion suggests that majority of NAHR deletions are non-meiotic i.e. originate from errors during homology directed repair (HDR) of spontaneous DSBs. In turn, the origin of the spontaneous DSBs is associated with transcription factor binding in accessible chromatin revealing the vulnerability of functional, open chromatin. The chromatin itself is enriched with repeats, particularly fixed Alu elements that provide the homology required to maintain stability via HDR. Through co-localization of fixed Alus and NAHR deletions in open chromatin we hypothesize that old Alu expansion had a stabilizing role on the human genome.”

Pediatric cancer mutation review

The genomic landscape of pediatric cancers: Implications for diagnosis and treatment

E. Alejandro Sweet-Cordero1 and Jaclyn A. Biegel

Science (Review Artice)

Abstract-The past decade has witnessed a major increase in our understanding of the genetic underpinnings of childhood cancer. Genomic sequencing studies have highlighted key differences between pediatric and adult cancers. Whereas many adult cancers are characterized by a high number of somatic mutations, pediatric cancers typically have few somatic mutations but a higher prevalence of germline alterations in cancer predisposition genes. Also noteworthy is the remarkable heterogeneity in the types of genetic alterations that likely drive the growth of pediatric cancers, including copy number alterations, gene fusions, enhancer hijacking events, and chromoplexy. Because most studies have genetically profiled pediatric cancers only at diagnosis, the mechanisms underlying tumor progression, therapy resistance, and metastasis remain poorly understood. We discuss evidence that points to a need for more integrative approaches aimed at identifying driver events in pediatric cancers at both diagnosis and relapse. We also provide an overview of key aspects of germline predisposition for cancer in this age group.

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Cancers are tissue-specific, truly important perspective

Tissue-specificity in cancer: The rule, not the exception

Kevin M. Haigis, Karen Cichowski, and Stephen J. Elledge

Science (article)

“Abstract—We are in the midst of a renaissance in cancer genetics. Over the past several decades, candidate-based targeted sequencing efforts provided a steady stream of information on the genetic drivers for certain cancer types. However, with recent technological advances in DNA sequencing, this stream has become a torrent of unbiased genetic information revealing the frequencies and patterns of point mutations and copy number variations (CNVs) across the entire spectrum of cancers. One of the most important observations from this work is that genetic alterations in bona fide cancer drivers (those genes that, when mutated, promote tumorigenesis) show a remarkable spectrum of tissue specificity”

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We'll need AI to deal with coming wave of genome data

Getting smart about artificial intelligence

By: Alison Cranage, Science writer

“Genomics is set to become the biggest source of data on the planet, overtaking the current leading heavyweights – astronomy, YouTube and Twitter. Genome sequencing currently produces a staggering 25 petabytes of digital information per year. A petabyte is 1015 bytes, or about 1,000 times the average storage on a personal computer. And there is no sign of a slowdown.”

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A boozy view of the human genome project, where it's been and might go

Human Genome Project: new alcohol abuse study could help us finally unlock secrets to beating genetic diseases

“Geneticists tried to exploit the revelations about the genome with studiesthat combed through thousands of tiny genetic changes in hundreds of thousands of patients with different diseases to see how they compared to healthy people. This enabled them to correlate genetic changes in diseased DNA in a manner unimaginable before June 2000. The “genetic architecture” of a wide number of conditions from cancers to schizophrenia to addiction became much better understood as a result.

Yet after the first few thousand studies were published, geneticists were horrified to discover that 98% of the disease-associated changes they’d identified in the genome do not occur in the genes. Instead, the vast majority of changes related to disease occur in the 98% of the genome that is not made up of genes – known as the “junk genome”, since few had the foggiest notion of what it was or how to study it.”

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Insights into the bugs in your guts, their diversity and associations with disease

Novel insights from uncultivated genomes of the global human gut microbiome

“Largely due to challenges cultivating microbes under laboratory conditions, the genome sequence of many species in the human gut microbiome remains unknown. To address this problem, we reconstructed 60,664 prokaryotic draft genomes from 3,810 faecal metagenomes from geographically and phenotypically diverse human subjects. These genomes provide reference points for 2,058 previously unknown species-level operational taxonomic units (OTUs), representing a 50% increase in the phylogenetic diversity of sequenced gut bacteria. On average, new OTUs comprise 33% of richness and 28% of species abundance per individual and are enriched in humans from rural populations. A meta-analysis of clinical gut microbiome studies pinpointed numerous disease associations for new OTUs, which have the potential to improve predictive models. Finally, our analysis revealed that uncultured gut species have undergone genome reduction with loss of certain biosynthetic pathways, which may offer clues for improving cultivation strategies in the future.”

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Gene expression used for leukemia diagnostics

Gene expression patterns identify high-risk chronic lymphocytic leukemia

A 290-gene expression signature and IGHV mutation status stratified patients with chronic lymphocytic leukemia to identify those with high-risk disease who might benefit from prompt initiation of therapy, according to a study published in Frontiers in Oncology.

Although CLL treatment is typically delayed until disease progression, it is uncertain whether patients would benefit from treatment immediately following diagnosis, when they have a smaller tumor mass and are in better physical condition.

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The origins of an important cancer causing virus

Origin and evolution of papillomavirus (onco)genes and genomes

Anouk Willemsen and Ignacio G. Bravo

biorxiv (Research Article)

Abstract—Papillomaviruses (PVs) are ancient viruses infecting vertebrates, from fish to mammals. Although the genomes of PVs are small and show conserved synteny, PVs display large genotypic diversity and ample variation in the phenotypic presentation of the infection. Most PVs genomes contain two small early genes E6 and E7. In a bunch of closely related human PVs, the E6 and E7 proteins provide the viruses with oncogenic potential. The recent discoveries of PVs without E6 and E7 in different fish species place a new root on the PV tree, and suggest that the ancestral PV consisted of the minimal PV backbone E1-E2-L2-L1. Bayesian phylogenetic analyses date the most recent common ancestor of the PV backbone to 424 million years ago (Ma). Common ancestry tests on extant E6 and E7 genes indicate that they share respectively a common ancestor dating back to at least 184 Ma. In AlphaPVs infecting primates, the appearance of the E5 oncogene 53-58 Ma concurred with i) a significant increase in substitution rate, ii) a basal radiation, and iii) key gain of functions in E6 and E7. This series of events was instrumental to build the extant phenotype of oncogenic human PVs. Our results assemble the current knowledge on PV diversity and present an ancient evolutionary timeline punctuated by evolutionary innovations in the history of this successful viral family.

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Viral coinfection increases variation, fitness

Beneficial coinfection can promote within-host viral diversity 

Asher Leeks, Ernesto A. Segredo-Otero, Rafael Sanjuán, and Stuart A. West

Virus Evolution (Research Article)

Abstract—In many viral infections, a large number of different genetic variants can coexist within a host, leading to more virulent infections that are better able to evolve antiviral resistance and adapt to new hosts. But how is this diversity maintained? Why do faster-growing variants not outcompete slower-growing variants, and erode this diversity? One hypothesis is if there are mutually beneficial interactions between variants, with host cells infected by multiple different viral genomes producing more, or more effective, virions. We modelled this hypothesis with both mathematical models and simulations, and found that moderate levels of beneficial coinfection can maintain high levels of coexistence, even when coinfection is relatively rare, and when there are significant fitness differences between competing variants. Rare variants are more likely to be coinfecting with a different variant, and hence beneficial coinfection increases the relative fitness of rare variants through negative frequency dependence, and maintains diversity. We further find that coexisting variants sometimes reach unequal frequencies, depending on the extent to which different variants benefit from coinfection, and the ratio of variants which leads to the most productive infected cells. These factors could help drive the evolution of defective interfering particles, and help to explain why the different segments of multipartite viruses persist at different equilibrium frequencies.

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Paradigm-shifting discovery in virology--multicellular replication!

A multicellular way of life for a multipartite virus

Anne Sicard, Elodie Pirolles, Romain Gallet, Marie-Stéphanie Vernerey, Michel Yvon, Cica Urbino, Michel Peterschmitt, Serafin Gutierrez, Yannis Michalakis, and Stéphane Blanc

eLife (Research Article)

Abstract

A founding paradigm in virology is that the spatial unit of the viral replication cycle is an individual cell. Multipartite viruses have a segmented genome where each segment is encapsidated separately. In this situation the viral genome is not recapitulated in a single virus particle but in the viral population. How multipartite viruses manage to efficiently infect individual cells with all segments, thus with the whole genome information, is a long-standing but perhaps deceptive mystery. By localizing and quantifying the genome segments of a nanovirus in host plant tissues we show that they rarely co-occur within individual cells. We further demonstrate that distinct segments accumulate independently in different cells and that the viral system is functional through complementation across cells. Our observation deviates from the classical conceptual framework in virology and opens an alternative possibility (at least for nanoviruses) where the infection can operate at a level above the individual cell level, defining a viral multicellular way of life.

Coverage of the Genome-wide Off-target analysis by Two-cell embryo Injection

A Tool To Validate The Safety Of Gene Editing Systems

AsianScientist (Mar. 12, 2019) – A team of international scientists has developed a technique to evaluate the safety of genome-editing techniques. The research was published in Science. CRISPR-Cas9 is a new generation of gene-editing tool that has been widely used. However, the risk of off-target effects in vivo, which could lead to diseases such as cancer, remains a serious concern. A variety of off-target detection schemes have been developed, with most relying on the prediction of off-target sites based on sequence similarity or in vitro amplification. However, the latter process may introduce a large amount of noise, thus making it difficult to separate off-target signals from background noise. Whether CRISPR-Cas9 induces off-target effects has been controversial.

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Read the original article at Science

Insights into how cancers escape an important class of treatments

Genome-wide screening identifies novel genes and biological processes implicated in cisplatin resistance

Abstract

Cisplatin-based chemotherapeutic regimens are frequently used for treatments of solid tumors. However, tumor cells may have inherent or acquired cisplatin resistance, and the underlying mechanisms are largely unknown. We performed genome-wide screening of genes implicated in cisplatin resistance in A375 human melanoma cells. A substantial fraction of genes whose disruptions cause cisplatin sensitivity or resistance overlap with those whose disruptions lead to increased or decreased cell growth, respectively. Protein translation, mitochondrial respiratory chain complex assembly, signal recognition particle–dependent cotranslational protein targeting to membrane, and mRNA catabolic processes are the top biologic processes responsible for cisplatin sensitivity. In contrast, proteasome-mediated ubiquitin-dependent protein catabolic process, negative regulations of cellular catabolic process, and regulation of cellular protein localization are the top biologic processes responsible for cisplatin resistance. ZNRF3, a ubiquitin ligase known to be a target and negative feedback regulator of Wnt–β-catenin signaling, enhances cisplatin resistance in normal and melanoma cells independently of β-catenin. Ariadne-1 homolog (ARIH1), another ubiquitin ligase, also enhances cisplatin resistance in normal and melanoma cells. By regulating ARIH1, neurofibromin 2, a tumor suppressor, enhances cisplatin resistance in melanoma but not normal cells. Our results shed new lights on cisplatin resistance mechanisms and may be useful for development of cisplatin-related treatment strategies.—Ko, T., Li, S. Genome-wide screening identifies novel genes and biological processes implicated in cisplatin resistance.

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Epigenetics: Fascinating but under appreciated sources and effects (original article)

Biological Invasion: The Influence of the Hidden Side of the (Epi)Genome

Abstract

1.Understanding the mechanisms underlying biological invasions and rapid adaptation to global change remains a fundamental challenge, particularly in small populations lacking in genetic variation. Two under‐studied mechanisms that could facilitate adaptive evolution and adaptive plasticity are the increased genetic variation due to transposable elements, and associated or independent modification of gene expression through epigenetic changes.

2.Here we focus on the potential role of these genetic and non‐genetic mechanisms for facilitating invasion success. Because novel or stressful environments are known to induce both epigenetic changes and transposable element activity, these mechanisms may play an underappreciated role in generating phenotypic and genetic variation for selection to act on. We review how these mechanisms operate, the evidence for how they respond to novel or stressful environments, and how these mechanisms can contribute to the success of biological invasions by facilitating adaptive evolution and phenotypic plasticity.

3.Because genetic and phenotypic variations due to transposable elements and epigenetic changes are often well regulated or “hidden” in the native environment, the independent and combined contribution of these mechanisms may only become important when populations colonize novel environments. A focus on the mechanisms that generate and control the expression of this variation in new environments may provide insights into biological invasions that would otherwise not be obvious.

4.Global changes and human activities impact on ecosystems and allow new opportunities for biological invasions. Invasive species succeed by adapting rapidly to new environments. The degree to which rapid responses to environmental change could be mediated by the epigenome – the regulatory system that integrates how environmental and genomic variation jointly shape phenotypic variation ‐ requires greater attention if we want to understand the mechanisms by which populations successfully colonize and adapt to new environments.

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