The Human Family Tree is a Bush

More evidence of branching off and reconnecting in the early history of humans

It has been an exciting week week for human ancestry. First, a new species of hominid was identified in the Philippines, Homo luzonensis, and now there’s evidence of the formerly elusive Denisovans in the ancient ancestry of Papuans. Adding to the excitement, this group found evidence of at least three distinct Denisovan lineages, and that humans likely interbred with Denisovan cousins somewhere around New Guinea. This is all pretty amazing, considering we first became aware of Denisovans from a single DNA sample from a finger, found in a cave, in Siberia.

Multiple Deeply Divergent Denisovan Ancestries in Papuans

The Human Family Tree is a Bush

Jacobs et.al, Cell (Research Article)

Highlights

•A new dataset of 161 genomes covering the understudied Indonesia-New Guinea region

•Introgressing Denisovans comprise at least three genetically divergent groups

•Papuans carry haplotypes from two Denisovan groups, with one unique to Oceania

•Some Denisovan introgression was recent and likely occurred in New Guinea or Wallacea

Summary—Genome sequences are known for two archaic hominins—Neanderthals and Denisovans—which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Spatial and temporal structure among these lineages suggest that introgression from one of these Denisovan groups predominantly took place east of the Wallace line and continued until near the end of the Pleistocene. A third Denisovan lineage occurs in modern East Asians. This regional mosaic suggests considerable complexity in archaic contact, with modern humans interbreeding with multiple Denisovan groups that were geographically isolated from each other over deep evolutionary time.


Read the original article HERE … and other summaries here and here.

Promising result in Cancer Vaccine Clinical Trial

Mount Sinai Researchers Develop Treatment That Turns Tumors Into Cancer Vaccine Factories

Promising result in Cancer Vaccine Clinical Trial

Researchers at Mount Sinai have developed a novel approach to cancer immunotherapy, injecting immune stimulants directly into a tumor to teach the immune system to destroy it and other tumor cells throughout the body. 

The “in situ vaccination” worked so well in patients with advanced-stage lymphoma that it is also undergoing trials in breast and head and neck cancer patients, according to a study published in Nature Medicine in April.

The treatment consists of administering a series of immune stimulants directly into one tumor site.  The first stimulant recruits important immune cells called dendritic cells that act like generals of the immune army. The second stimulant activates the dendritic cells, which then instruct T cells, the immune system’s soldiers, to kill cancer cells and spare non-cancer cells. This immune army learns to recognize features of the tumor cells so it can seek them out and destroy them throughout the body, essentially turning the tumor into a cancer vaccine factory.

“The in situ vaccine approach has broad implications for multiple types of cancer,” said lead author Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. “This method could also increase the success of other immunotherapies such as checkpoint blockade.”

After testing the lymphoma vaccine in the lab, it was tested in 11 patients in a clinical trial. Some patients had full remission from months to years. In lab tests in mice, the vaccine drastically increased the success of checkpoint blockade immunotherapy, the type of immunotherapy responsible for the complete remission of former President Jimmy Carter’s cancer and the focus of the 2018 Nobel Prize in Medicine.


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Jumping genes are the exciting part of the Poison Frog Genome

The genome of the strawberry poison frog, Oophaga pumilio, has just been sequenced and the results show that it hosts a wide array of transposable elements, “jumping genes,” virus-like, repetitive sequences that copy themselves inside of genomes. The poison frog has a genome that is twice the size of the human genome, and two-thirds of it is composed of transposable elements. In addition, there is evidence that many of these transposable elements have recently horizontally transferred into the genome.


Genomic Takeover by Transposable Elements in the Strawberry Poison Frog

Rogers RL, Zhou L, Chu C, Márquez R, Corl A, Linderoth T, Freeborn L, MacManes MD, Xiong Z, Zheng J, Guo C, Xun X, Kronforst MR, Summers K, Wu Y, Yang H, Richards-Zawacki CL, Zhang G2, & Nielsen R

Jumping genes are the exciting part of the Poison Frog Genome

Abstract—We sequenced the genome of the strawberry poison frog, Oophaga pumilio, at a depth of 127.5× using variable insert size libraries. The total genome size is estimated to be 6.76 Gb, of which 4.76 Gb are from high copy number repetitive elements with low differentiation across copies. These repeats encompass DNA transposons, RNA transposons, and LTR retrotransposons, including at least 0.4 and 1.0 Gb of Mariner/Tc1 and Gypsy elements, respectively. Expression data indicate high levels of gypsy and Mariner/Tc1 expression in ova of O. pumilio compared with Xenopus laevis. We further observe phylogenetic evidence for horizontal transfer (HT) of Mariner elements, possibly between fish and frogs. The elements affected by HT are present in high copy number and are highly expressed, suggesting ongoing proliferation after HT. Our results suggest that the large amphibian genome sizes, at least partially, can be explained by a process of repeated invasion of new transposable elements that are not yet suppressed in the germline. We also find changes in the spliceosome that we hypothesize are related to permissiveness of O. pumilio to increases in intron length due to transposon proliferation. Finally, we identify the complement of ion channels in the first genomic sequenced poison frog and discuss its relation to the evolution of autoresistance to toxins sequestered in the skin.

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The first step towards a "Cancer Dependency Map"

That most cancers use the same set of molecular tools is a very powerful idea, but it has been hard to figure out what these tools are and how to target them. Follow the link below for a quick, and enthusiastic, summary of genome-scale CRISPR–Cas9 screens of 324 human cancer cell lines from 30 cancer types with the goal of developing a new, diverse and more effective portfolio of cancer drug targets.

'Dismantling cancer' reveals weak spots

The first step towards a "Cancer Dependency Map"

James Gallagher, BBC News

Scientists have taken cancer apart piece-by-piece to reveal its weaknesses, and come up with new ideas for treatment. A team at the Wellcome Sanger Institute disabled every genetic instruction, one at a time, inside 30 types of cancer. It has thrown up 600 new cancer vulnerabilities and each could be the target of a drug.Cancer Research UK praised the sheer scale of the study.

The study heralds the future of personalised cancer medicine. At the moment drugs like chemotherapy cause damage throughout the body. One of the researchers is Dr Fiona Behan, whose mother died after getting cancer for the second time.


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Another helpful summary of the recent paper linking jumping genes to cancer

A recent post discussed an important paper that demonstrated an association between transposable elements, aka ‘jumping genes’, and cancer. Transposable elements are an important but often forgotten class of mutagen that can contribute to genome instability and may disrupt genes and their expression. The original article has an outstanding abundance of data and is not easy reading. The article below provides an accessible summary that’s worth reading if you aren’t an expert in genomics.


Cancer: Scientists find 129 'jumping genes' that drive tumor growth

Catharine Paddock, Medical News Today

Another helpful summary of the recent paper linking jumping genes to cancer

In cancer research, scientists usually look for cancer genes by scouring the genome for altered sequences — or mutations — in DNA. But a new study has now revealed that jumping genes, which customary sequencing overlooks, are also important drivers of tumor growth.

Scientists at the Washington University School of Medicine in St. Louis, MO, found that jumping genes are widespread in cancer and promote tumor growth by forcing cancer genes to remain switched on.

They analyzed 7,769 tumor samples from 15 different types of cancer and found 129 jumping genes that can drive tumor growth through their influence on 106 different cancer genes.

The jumping genes were functioning as "stealthy on-switches" in 3,864 of the tumors that the team analyzed. These tumors came from breast, colon, lung, skin, prostate, brain, and other types of cancer.

A recent Nature Genetics paper gives a full account of the study.


CRISPR gene drive vs CRISPR allelic drive

CRISP-based genome modifying technologies are offer a power and precision people only dreamed of not that long ago. CRISPR gene drives use guide RNAs (gDNAs) to insert gene-drive sequences, and the CRISPR allele drives do the same while also modifying undesired variants at a second position. Gene and allele drives are likely to be central to how humans modify the living environment in the future, in addition to being the starting point for endless unchecked-tech sci-fi nightmare scenarios . The following article provides a clear and helpful explanation of these technologies and some of their applications.

CRISPR-based 'allelic drive' allows genetic editing with selective precision and broad implications

Difference between gene drive and allelic drive explained

Scientists developed a new version of a gene drive that allows the spread of specific, favorable genetic variants, also known as 'alleles,' throughout a population. The new 'allelic drive' is equipped with a guide RNA that directs CRISPR to cut undesired variants of a gene and replace it with a preferred version. Using a word processing analogy, CRISPR-based gene drives allow scientists to edit sentences of genetic information, while the new allelic drive offers letter-by-letter editing.


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Cancer signaling studies take a page from Genetics methods

The following article provides insights into the promise of applying quantitative approaches in the context of tumor tissues and clinical environments. Genetics approaches have dominated cancer research because they generate such an abundance of data ( and because the methodology is so widely and readily generalizable). While genetic variations clearly play an important role in cancer, deviant signaling drives cancer progression and signaling molecules are the targets of most chemotherapeutics. This highlights the importance of understanding cancer signaling pathways with data-rich and quantitatively rigorous methods, similar to those used in genetics. The following article in Science Signaling discusses this topic and is both thorough and accessible. —RPR


Why geneticists stole cancer research even though cancer is primarily a signaling disease

Michael B. Yaffe, Science Signaling

Cancer signaling studies take a page from Genetics methods

Abstract—Genetic approaches to cancer research have dramatically advanced our understanding of the pathophysiology of this disease, leading to similar genetics-based approaches for precision therapy, which have been less successful. Reconfiguring and adapting the types of technologies that underlie genetic research to dissect tumor cell signaling in clinical samples may offer an alternative road forward.


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Population Structure: A Key Concept for Understanding Genetic Variation

It is common for articles to claim that “the gene for” some trait or disease has been identified. Usually they actually mean that an association has been found between an uncommon genetic variant found in, or near, a gene and some trait or disease. These kinds of articles are becoming increasingly common because Genome-Wide Association Studies (GWAS) are becoming cheaper and more common. Though GWAS yield important insights their results can be misleading because ancestral relationships between individuals in the study can create signals that can be misinterpreted as association with the trait being studied. This phenomenon is very powerful and one reason why it is important to have a diverse group of individuals in any genetic study. Underlying ancestral relationships are known as “population structure” and serious thought is required to ensure that it doesn’t skew GWAS results. The paper below is a scientific review article (in an excellent journal with exceptional authors) and not exactly easy reading, but it was written for a broad audience and worth considering the next time you see an article discussing the identification of “the genes for” something or other, even if it appears in Genome-Media.

-RPR


Population Genetics: Why structure matters

Abstract

Population Structure: A Key Concept for Understanding Genetic Variation

Great care is needed when interpreting claims about the genetic basis of human variation based on data from genome-wide association studies.

Main text

Human height is the classic example of a quantitative trait: its distribution is continuous, presumably because it is influenced by variation at a very large number of genes, most with a small effect (Fisher, 1918). Yet height is also strongly affected by the environment: average height in many countries increased during the last century and the children of immigrants are often taller than relatives in their country of origin – in both cases presumably due to changing diet and other environmental factors (Cavalli-Sforza and Bodmer, 1971Grasgruber et al., 2016NCD Risk Factor Collaboration, 2016). This makes it very difficult to determine the cause of geographic patterns for height, such as the ‘latitudinal cline’ seen in Europe (Figure 1).


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Advances in Single Cell RNA-Sequencing

Single cell transcriptomics: A new sequencing approach

Advances in Single Cell RNA-Sequencing

“Researchers from University of Southern Denmark, Wellcome Sanger Institute and BGI, today published a study in the journal Genome Biology comparing the library preparation and sequencing platforms for single-cell RNA-sequencing (scRNA-seq).

Single cell transcriptomics (i.e. scRNA-seq) is a next-generation sequencing approach that simultaneously measures the messenger RNA concentrations (encoded by DNA/genome/genetic blueprint) of thousands of genes, in individual cells. This enables researchers to gain a high-resolution view of cells to unravel heterogenous cell populations and better understand individual cell functions in the body. Although several single-cell protocols exist, the sequencing has traditionally been performed using Illumina technology and sequencing platforms.”


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If all the talk about P-values has you concerned, learn Estimation Stats

P-values got you down? Move past them.

Below are the first couple of paragraphs from an exceptionally clear and helpful webpage that provides an introduction to estimation statistics. P-values are a simple, useful metric from a time when computation was labor intensive but we live in a more data-rich world now and it’s now possible to do statistics in a way that captures the parts we care about—like effect size.


ESTIMATION STATS / WHAT IS ESTIMATION STATS?

This site provides you with a web application to plot experimental data from an estimation statistics perspective. You may have found significance testing and P-values problematic; you may be asking what comes next.

Introducing Estimation Statistics

If all the talk about P-values has you concerned, learn Estimation Stats

Estimation statistics is a simple framework that—while avoiding the pitfalls of significance testing—uses familiar statistical concepts: means, mean differences, and error bars. More importantly, it focuses on the effect size of one's experiment/intervention, as opposed to significance testing.

Significance testing calculates the probability (the P value) that the experimental data would be observed, if the intervention did not produce a change in the metric measured (i.e. the null hypothesis). This leads analysts to apply a false dichotomy on the experimental intervention.

Estimation statistics, on the other hand, focuses on the magnitude of the effect (the effect size) and its precision. This encourages analysts to gain a deeper understanding of the metrics used, and how they relate to the natural processes being studied.


https://www.estimationstats.com/#/background

What your genome won't tolerate

This is one of those projects that’s so clearly interesting and important that it’s surprising nobody has done it already: specifically, this is a very thorough and well-executed analysis of all the places in the human genome that do not appear to tolerate being mutated. If you have access, it’s worth reading. —RPR

Measuring intolerance to mutation in human genetics

Zachary L. Fuller, Jeremy J. Berg, Hakhamanesh Mostafavi, Guy Sella & Molly Przeworski

What your genome won't tolerate?

Nature Genetics (Research Article)

Abstract—In numerous applications, from working with animal models to mapping the genetic basis of human disease susceptibility, knowing whether a single disrupting mutation in a gene is likely to be deleterious is useful. With this goal in mind, a number of measures have been developed to identify genes in which protein-truncating variants (PTVs), or other types of mutations, are absent or kept at very low frequency in large population samples—genes that appear ‘intolerant’ to mutation. One measure in particular, the probability of being loss-of-function intolerant (pLI), has been widely adopted. This measure was designed to classify genes into three categories, null, recessive and haploinsufficient, on the basis of the contrast between observed and expected numbers of PTVs. Such population-genetic approaches can be useful in many applications. As we clarify, however, they reflect the strength of selection acting on heterozygotes and not dominance or haploinsufficiency.


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Finding Ancient Ancestors in Modern DNA

Digging ancient signals out of modern human genomes

Finding Ancient Ancestors in Modern DNA

With new genome analysis tools, scientists have made significant advances in our understanding of modern humans' origins and ancient migrations.

But trying to find ancient DNA, let alone prove that the ancient DNA is ancestral to a population living today is extremely challenging.

A new study in Molecular Biology and Evolution (MBE) adds to this understanding by reconstructing artificial genomes with the analyses of the genome of 565 contemporary South Asian individuals to extract ancient signals that recapitulate the long history of human migration and admixture in the region.

"All in all, our results provide a proof-of-principle for the feasibility of retrieving ancient genetic signals from contemporary human subjects, as if they were genomes from the past embedded in amber," said Luca Pagani, the research coordinator of the study.

The study was led by Burak Yelmen and Mayukh Mondal from the Institute of Genomics of the University of Tartu, Estonia and coordinated by Luca Pagani from the same institution and from the University of Padova, Italy.

"The genetic components we managed to extract from modern genomes are invaluable, given the shortage of ancient DNA available from South Asian human remains, and allow us to elucidate the genetic composition of the ancient populations that inhabited the area," said Burak Yelmen, co-first author of the study.


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Durham Wheat Genome Sequenced, Protecting Pasta's Future

International team decodes the durum wheat genome

“An international consortium has sequenced the entire genome of durum wheat--the source of semolina for pasta, a food staple for the world's population, according to an article published today in Nature Genetics.

Durham Wheat Genome Sequenced, Protecting Pasta's Future

The team has also discovered how to significantly reduce cadmium levels in durum grain, ensuring the safety and nutritional value of the grain through selective breeding.

"This ground-breaking work will lead to new standards for durum breeding and safety of durum-derived products, paving the way for production of durum wheat varieties better adapted to climate challenges, with higher yields, enhanced nutritional quality, and improved sustainability," said Luigi Cattivelli of Italy's Council for Agricultural Research and Economics (CREA).”


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Positive coverage of a study linking genetics to beauty, will be savagely critiqued soon

Researchers identify 'beauty spots' in the genome

Genome-wide association study suggests variants underlying facial beauty varies by sex and claims to detect meaningful signal for these variants. This is an interesting study, but expect it to be attacked soon given recent work that highlights how population stratification can be misinterpreted as significant variant effects (e.g. Sohail, eLIFE, 2019). —RPR

Positive coverage of a study linking genetics to beauty, will be savagely critiqued soon

“Genes play a role in determining the beauty of a person's face, but that role varies with the person's sex, according to a new study by Qiongshi Lu and colleagues at the University of Wisconsin-Madison, published 4th April in PLOS Genetics.

Humans tend to be preoccupied with beauty -- a person's attractiveness is associated with academic performance, career success and economic mobility. But despite its importance, scientists know little about the genetic basis for having a pretty face. In the current work, researchers performed a genome-wide association study using genetic information from 4,383 individuals to pinpoint parts of the genome linked to facial beauty. They had volunteers score yearbook photos based on attractiveness from participants with European ancestry and compared the scores to each person's genetic information. The researchers identified several genes related to facial attractiveness, but their roles and relatedness to other human traits varied by sex. In women, certain genetic variations linked to beauty also appeared to be related to genes impacting body mass, while in males, variants were linked to genes affecting blood cholesterol levels.”



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CRISPR DNA "shredder"

New DNA 'shredder' technique goes beyond CRISPR's scissors

CRISPR DNA "shredder"

An international team has unveiled a new CRISPR-based tool that acts more like a shredder than the usual scissor-like action of CRISPR-Cas9. The new approach, based on Type I CRISPR-Cas3, is able to wipe out long stretches of DNA in human cells with programmable targeting, and has been shown to work in human cells for the first time.


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New Database of Dog Genomes

Researchers create the largest global catalog of variations in the dog genome

By Prabarna Ganguly, Ph.D.
Science Writer/Editor, NHGRI

New Database of Dog Genomes

In 2019, 'King' the Wire Fox Terrier won the Westminster Dog Show in Madison Square Garden, having competed against 2,800 dogs from 203 breeds. The sheer number of dog breeds points toward the major role played by genetics in shaping such variation in dogs.

In a new study, researchers at the National Human Genome Research Institute (NHGRI) have generated the largest catalog of genetic variants associated with physical traits for domesticated dog breeds. The findings, published in Nature Communication, will help researchers assess if variants associated with dog body structure, behavior and life span could also be implicated in related human diseases.

"This study included data from more than 722 dogs and 144 modern breeds," says Dr. Ostrander, NIH Distinguished Investigator and senior author of the paper. "Through the results, we've learned some of the fascinating genetics behind the variability observed in the world's 450 dog breeds."

After humans initially selected for specific traits during dog breeding centuries ago, dogs have since formed traits and characteristics spontaneously over time. Jocelyn Plassais, a postdoctoral researcher in Dr. Ostrander's laboratory and lead author of the study explained that dogs naturally develop disorders that are common to humans, such as various forms cancers, infections and even diabetes. In addition, a vast number of regions within the dog genome remain similar to the human genome. Thus, dog genomes can provide insight into the biological mechanisms of human health and disease.

The researchers used whole genome sequencing and genome-wide association studies to identify genomic variants associated with sixteen observable characteristics. Most of the blood samples from dogs were taken via The Dog Genome Project, a citizen science initiative that relies on donations from motivated dog owners.


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Gene-Expression Profiling to Understand Cancers of Unknown Origins

Phase 2 Trial Examines Gene-Expression Profiling for Cancer of Unknown Primary Site

A randomized phase 2 trial examining the assignment of treatment based on gene-expression profiling compared with standard chemotherapy for patients with cancer of unknown primary site showed no improvement in the 1-year survival rate with the more tailored approach. However, several caveats may limit the relevance of the findings. A report of this study was published in the Journal of Clinical Oncology.1

Gene-Expression Profiling to Understand Cancers of Unknown Origins

Cancer of unknown primary site (CUP) refers to malignancies in which the originating tumor type cannot be identified. As a result, determining the best treatment for this cancer, diagnosed in approximately 31,000 people in the US each year, is extremely difficult.2 In recent years, oncologists have looked to genetic testing to identify the cancer type as a way to improve care.

In the current study, a molecular analysis of biopsied tissue predicted the originating cancer site for all of the 101 patients treated. The analysis identified a total of 16 sites; cancers of the pancreas (21% of participants), gastric system (21% of participants), and malignant lymphomas (20% of patients) were the 3 most common sites to be predicted as the primary site of malignancy. The Japan-based researchers then randomized the patients to receive therapy appropriate to the predicted site of origin (50 patients) or the standard, empiric treatment of paclitaxel plus carboplatin (51 patients).


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Catastrophic loss of amphibian biodiversity

Scientists Uncover the Most Devastating Disease-Afflicted Biodiversity Loss Known to Science


A recent paper published in Science revealed the shocking results of a global disease transmission assessment: A fungal disease affecting amphibians has been identified as the most devastating recorded example of biodiversity loss attributable to a single disease. The analysis was made possible by an extensive collaboration involving experts from 36 institutions.

Over the past half century, the amphibian chytridiomycosis panzootic, an infectious disease that affects amphibians worldwide, has resulted in 90 presumed extinctions as well as the decline of at least 501 amphibian species.

This fungus was identified in amphibian populations about 20 years ago as the cause of death and species extinction at a global scale. The last similar analysis that assessed global amphibian decline was published in 2007 but was mainly focused on the regions that suffered the most decline.

Catastrophic loss of amphibian biodiversity

One of the two Cornell affiliates in the study, Prof. Kelly Zamudio, ecology and evolutionary biology, has worked in Panama, Brazil and the United States studying the effect of frog-killing chytrid fungus Batrachochytrium dendrobatidis using population genetics.

Zamudio said the idea for the global epidemiological analysis started from a conversation going around the amphibians researcher community: “How bad is this? How much have we really lost?”


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Genome of Extreme-Tolerant Fungus from Portugal Church Sequenced

High-Quality Draft Genome Sequence of the Microcolonial Black Fungus Aeminium ludgeri DSM 106916

João Trovão, Igor Tiago, Fabiana Soares, Diana Sofia Paiva, Nuno Mesquita, Catarina Coelho, Lídia Catarino, Francisco Gil, and António Portugal

Christina Cuomo, Microbiology Resource Announcements

Genome of Extreme-Tolerant Fungus from Portugal Church Sequenced

ABSTRACTAeminium ludgeri is an extremotolerant microcolonial black fungus isolated from a biodeteriorated limestone art piece in the Old Cathedral of Coimbra, Portugal (a UNESCO World Heritage Site). The high-quality draft genome sequence of Aeminium ludgeri presented here represents the first sequenced genome for both the recently described fungal family Aeminiaceae and the genus Aeminium.


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Bacteria deploy viruses to trick the immune system

Viruses act as decoys, study finds, helping bacteria evade the immune system

Eric Boodman, Stat News

Bacteria deploy viruses to trick the immune system

These viruses weren’t supposed to affect humans. They were supposed to ride along inside bacteria — unobtrusive hitchhikers taking advantage of another microbe’s machinery. But that wasn’t what Dr. Paul Bollyky and his colleagues saw in their lab dishes three or four years ago. The viruses seemed to be changing the behavior of human immune cells. Instead of gobbling up bacteria as they normally did, white blood cells just sat there.

“They basically don’t eat anything. They don’t move around much either,” said Bollyky, an immunologist and infectious disease specialist at Stanford University. “They would just ignore … the bacteria that were in the dish with them.”

Now, with a paper published Thursday in Science, what began as a chance observation has yielded a startling window into the inner lives of infections — one in which viruses tag-team with bacteria to trick the immune system by providing a decoy. Bollyky describes it as having someone trip the fire alarm so that the rest of the team can pull off a robbery in the chaos that ensues.


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