Category Archives: Genome

Homo naledi may have lived at the same time as the first modern humans. Left: Neo skull of Homo naledi. Right: Omo 2 skull, one of the earliest modern humans. Photo credit: Wits University/ John Hawks Photograph: Wits University

Despite what many people believe, paradigm-shifting moments in science - where our understanding of a particular explanation is challenged by a single finding - are actually quite rare. But one happened in paleoanthropology on 9 May with the publication of three linked papers describing new fossils belonging to the enigmatic hominin Homo naledi.

Many people tend to think of human evolution as a very linear path: from primitive creatures more or less directly to ourselves. But for most of the history of evolution, there were multiple species of hominins running (or climbing) around the African landscape, each with their own unique physical adaptations to the challenges of survival. As with all evolutionary experiments, some of these adaptations proved more successful than others. Based on careful study of fossils spanning millions of years in Africa, paleoanthropologists thought they had a good understanding of how the experiments results unfolded. Human evolution wasnt a straight progression by any means, but more like a complicated bush, with branches leading off in many directions. Still, there were definite trends that made their way into our textbooks. Hominin lineages with some trait combinations died off without leaving any descendants. In the lineages that persisted, brains got bigger, legs longer, arms shorter, fingers less curved, teeth smaller.

It mostly made sense, and the new species discovered in a South African cave in 2015 seemed initially to fit within this paradigm. Homo naledi, as it was called, had some very primitive morphological features that meant it was likely very ancient indeed - possibly 2 million years ago, close to the root of our genus Homo.

But the recent discovery of a new set of H. naledi remains, in a separate chamber of the same cave system, and the first direct dates of the earlier H. naledi skeletons, has challenged this tidy story. Shockingly, the remains dated to just 236-335,000 years ago. This makes H. naledi very young: contemporaneous with early modern H. sapiens elsewhere in Africa. Yet, as the new fossils confirmed, H. naledi possessed a weird mosaic of primitive (ancient) and derived (more human-like) traits, such as small brain sizes (roughly a third of the size as ours: you can see the difference in the picture above) but human-like hands and limbs.

One reason this has paleoanthropologists in an uproar is that it means some features, such as small brain sizes, persisted long after they thought it possible. Berger et al. suggests that in light of this, we perhaps should be concerned about fossils which we have assigned to species on the basis of morphology rather than direct dates. If some remains have been misclassified, we may need to change our ideas about how different hominin lineages evolved. Another implication of these dates is that these hominins were around South Africa when stone tools began to be made. While they havent been found in association with any tools in the cave, we must still be open to the possibility that these small brained hominins could have made them. Finally, whether or not the H. naledi remains were deliberately buried inside the cave remains an extremely contentious issue among paleoanthropologists. These possibilities - both still unverified - pose a robust challenge for archaeologists to grapple with.

Notably, there are some things that these fossils wont change: 1) We are indeed the product of evolution (Im anticipating some of the comments on this post inevitably challenging evolution. Sorry guys, the evidence is incontrovertible and the fact that scientists change their minds as to the details when new discoveries are made speaks to the strength of the scientific process, not the weakness of the theory). 2) Humans originated in Africa, 3) There were multiple kinds of hominins co-existing for much of human evolution, 4) Humans are likely descended from H. erectus, with subsequent ancestry from some of the other kinds of hominins (Denisovans, Neanderthals, and probably others).

So where does H. naledi fit within the overall picture of human evolution in Africa? Its still unresolved. Berger et al. suggested three scenarios: First, H. naledi belongs to one of the lineages leading to H. habilis, H. rudolfensis, H. floresiensis, and A. sediba. Alternatively, H. naledi is younger - a sister lineage to the clade that contains H. erectus and the big-brained later hominins (including H. sapiens). The final scenario is that H. naledi is even younger still - a sister lineage to H. sapiens. Another possibility is that H. naledi is the result of hybridisation between two or more lineages, perhaps one related to humans and one related to Australopithecines.

The unusual combination of primitive and derived features of H. naledi make distinguishing between the above scenarios difficult without genetic evidence. If we could get a genome from one or more H. naledi individuals, we could determine the phylogenetic relationship between it and the big-brained hominins: H. sapiens and H. neanderthalensis (we dont yet know the brain size of Denisovans). This would tell us whether or not human populations had ancestry from this group (and perhaps others).

On a bioarchaeological level (assuming we could get DNA from multiple individuals in the cave), we could ask whether H. naledi individuals buried in the cave were close relatives, and whether there was a relationship between burial location and genetic relatedness. The answers to these questions might give us some insights into the social structure of the species, whether the individuals buried within the cave constituted a single population close in time, or whether there is detectable genetic change over time in the individuals within the cave. We could also use the molecular clock to estimate the time of divergence of H. naledi to the other hominins.

Ancient DNA could answer a lot of questions regarding H. naledis ancestry and relationships, but unfortunately were not there yet. While the dates of these fossils fit comfortably within the range at which we can obtain ancient DNA (currently up to ~560780,000 years ago), Berger et al. notes in their paper that attempts to obtain aDNA from H. naledi remains have thus far proven unsuccessful. One of the team members, Dr John Hawks, noted on twitter in a conversation with myself and others that three separate ancient DNA labs have actually made the attempt without any luck (ours at the University of Kansas wasnt one of them, for the record), but that they will keep trying.

This is an important reminder of just how difficult and frustrating ancient DNA research can be, and if theres anything I wish the interested public would know about it, its this: Behind the exciting news that comes out every month about this ancient genome or that lie scores of failed attempts, and the frustrated tears of many graduate students.

Ancient DNA preservation depends on many different variables, such as the temperature(s), UV radiation, and pH the remains have been subjected to, the type of bone, tooth, or tissue being sampled, and the amount of water, salinity, microbes, and oxygen present in the depositional context. This is why some very ancient bones will yield their genetic secrets, while ones just a few hundreds of years old wont no matter how hard you try. Furthermore, morphological preservation of bone doesnt always correspond with biomolecular preservation, and we cant necessarily know in advance whether DNA will be present in a skeleton before we attempt to recover it. Thus ancient DNA researchers must always be mindful about addressing important questions, be responsible about sampling fossils, and not commit too many resources (particularly money and time) to samples which wont work. Knowing when to stop working on a sample that wont yield DNA is almost as important as determining which samples to attempt in the first place.

Will we ever get a H. naledi genome? Based on the hints weve gotten so far, the odds dont look great. Just as with H. floresiensis, the other small-brained hominin that persisted until quite recently (50,000 years ago), their position in our family tree looks to remain unclear for a while - a lesson to us about how much we still have to learn. But if I werent relentlessly optimistic, I wouldnt have lasted long in the world of ancient DNA research. Perhaps it will just take a little more time and luck. Weve certainly seen these two variables in abundance throughout the remarkable story of H. naledis discovery.

Berger et al. Homo naledi and Pleistocene hominin evolution in subequatorial Africa. eLife 2017;6:e24234. DOI: http://dx.doi.org/10.7554/eLife.24234

Dirks PHGM et al. The age of Homo naledi and associated sediments in the Rising Star Cave, South Africa. eLife 2017;6:e24231 DOI: http://dx.doi.org/10.7554/eLife.24231

Hawks J et al. New fossil remains of Homo naledi from the Lesedi Chamber, South Africa. eLife 2017;6:e24232. DOI: http://dx.doi.org/10.7554/eLife.24232

Thompson JC. Human evolution: New opportunities rising. eLife 2017;6:e26775 DOI: http://dx.doi.org/10.7554/eLife.26775

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Homo naledi genome: Will we ever find this elusive key to human evolution? - The Guardian

Plant biologists and biochemists from UCLA, UC Berkeley and UC San Francisco have produced a gold mine of data by sequencing the genome of a green alga called Chromochloris zofingiensis.

Scientists have learned in the past decade that the tiny, single-celled organism could be used as a source of sustainable biofuel and that it produces a substance called astaxanthin, which may be useful for treating certain diseases. The new research could be an important step toward improving production of astaxanthin by algae and engineering its production in plants and other organisms.

The study is published online in the journalProceedings of the National Academy of Sciences.

Chromochloris zofingiensis is one of the most prolific producers of a type of lipids called triacylglycerols, which are used in producing biofuels.

Knowing the genome is like having a dictionary of the algas approximately 15,000 genes, said co-senior author Sabeeha Merchant, a UCLA professor of biochemistry. From there, researchers can learn how to put the words and sentences together, and to target our research on important subsets of genes.

C. zofingiensis provides an abundant natural source for astaxanthin, an antioxidant found in salmon and other types of fish, as well as in some birds feathers. And because of its anti-inflammatory properties, scientists believe astaxanthin may have benefits for human health; it is being tested in treatments for cancer, cardiovascular disease, neurodegenerative diseases, inflammatory diseases, diabetes and obesity. Merchant said the natural version has stronger antioxidant properties than chemically produced ones, and only natural astaxanthin has been approved for human consumption.

The study also revealed that an enzyme called beta-ketolase is a critical component in the production of astaxanthin.

Algae absorb carbon dioxide and derive their energy from sunlight, and C. zofingiensis in particular can be cultivated on non-arable land and in wastewater. Harnessing it as a source for renewable and sustainable biofuels could lead to new ways to produce clean energy, said Krishna Niyogi, co-senior author of the paper and a scientist at the Department of Energys Lawrence Berkeley National Laboratory.

Over the past decade-plus, Merchant said, research with algae, a small plant called rockcress, fruit flies and nematode worms all so-called model organisms has been advanced by other scientists determining their genome sequences.

They are called model organisms because we use what we learn about the operation of their cells and proteins as a model for understanding the workings of more complex systems like humans or crops, she said. Today, we can sequence the genome of virtually any organism in the laboratory, as has been done over the past 10 to 15 years with other model organisms.

Merchant, Niyogi and Matteo Pellegrini, a UCLA professor of molecular, cell and developmental biology and a co-author of the study, maintain a website that shares a wealth of information about the algas genome.

During the study, the scientists also used soft X-ray tomography, a technique similar to a CT scan, to get a 3-D view of the algae cells , which gave them more detailed insights about their biology.

Niyogi is also a UC Berkeley professor of plant and microbial biology and a Howard Hughes Medical Institute Investigator. The studys other authors are researchers Shawn Cokus and Sean Gallaher and postdoctoral scholar David Lopez, all of UCLA; postdoctoral fellow Melissa Roth, and graduate students Erika Erickson, Benjamin Endelman and Daniel Westcott, all of Niyogis laboratory; and Carolyn Larabell, a professor of anatomy, and researcher Andreas Walter, both of UC San Francisco.

The research was funded by the Department of Energys Office of Science, the Department of Agricultures National Institute of Food and Agriculture, the National Institute of General Medical Sciences of the National Institutes of Health, and the Gordon and Betty Moore Foundation.

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Discovery of an alga's 'dictionary of genes' could lead to advances in biofuels, medicine - UCLA Newsroom

Francis Collins, the gregarious 67-year-old who directs the National Institutes of Health, doesn't shy away from a challenge. Collins made a name for himself in the early 2000s when, as director of the Human Genome Project, he oversaw the completion of sequencing 3 billion genes. Now, as the head of the nation's foremost biomedical research engine, Collins faces a new task: finding solutions to the opioid epidemic, which killed more than 33,000 Americans in 2015.

"I'd like all of us, the academics, the government, and the private sector, to think about this the way we thought about HIV/AIDs in the early 1990s, where people were dying all around us in tens of thousands."

At the Prescription Drug Abuse and Heroin Conference last month, Collins announced a public-private partnership, in which the NIH will collaborate with biomedical and pharmaceutical companies to develop solutions to the crisis. President Donald Trump and Health and Human Services Secretary Tom Price "strongly supported" the idea, he said. This isn't Collins' first such partnership: During his tenure as directorBarack Obama appointed him in 2009Collins has developed ongoing collaborations with pharmaceutical companies such as Lilly, Merck, and GlaxoSmithKline for Alzheimer's disease, diabetes, and rheumatoid arthritis. For each partnership, the NIH and the companies pool tens of millions of dollars, with the agreement that the resulting data will be public and the companies will not immediately patent treatments. The jury's still out on resultsthe partnerships are about halfway through their five-year timelines. But Collins, a self-described optimist, remains hopeful. "Traditionally it takes many years to go from an idea about a drug target to an approved drug," said Collins at the conference. "Yet I believea vigorous public private partnership could cut that time maybe even in half."

I talked to Collins about the partnership, potential treatments in the pipeline, and the NIH's role in confronting the ongoing epidemic.

Mother Jones: Why is a public-private partnership needed?

Francis Collins: While NIH can do a lot of the good science, and we can accelerate [it] if we have resources, we aren't going to be the ones making pills. Many of the large-scale clinical trials are not done generally by us but by the drug companies. A successful outcome herein terms of ultimately getting rid of opioids and the deaths that they causewould not happen without full engagement by the private sector.

MJ: Which companies will be involved?

FC: It will be a significant proportion of the largest companies. I can't tell you the total listas I said, the 15 largest were there. Certainly the groups that already have some drugs that are somewhere in the pipeline will be particularly interested in ways to speed that up.

MJ: What do you hope will come out of it in the short term?

FC: I think that we could increase the number of effective options to help people get over addiction, and [the] treatments for overdose, particularly when fentanyl is becoming such a prominent part of this dangerous situation. The current overdose treatments are not necessarily as strong as they need to be. We could make progress there pretty quickly, I thinkin a matter of even a year or twoby coming up with formulations of drugs that we know work but in a fashion that would have new kinds of capabilities. [The drugs would be] stronger, as in the overdose situation, or have the potential of longer-acting effects, as in treating addiction. [It's] not necessarily a different drug, but a different formulation of the drug. And drug companies are pretty good at that.

MJ: And in the long term?

Without pharmaceutical companies, "we'd be completely hopeless as far as new treatment."

FC: The goal really needs to be to find nonaddictive but highly potent pain medicines that can replace the use of opioids given the terrible consequences that surround their use. This will be particularly important for people who have chronic pain, where we really don't have effective treatments now. The good news is that there's a lot of really interesting science pointing us to new alternatives, [like] the idea of coming up with something that interacts with that opioid receptor but only activates the pathway that results in pain reliefnot the somewhat different pathway that results in addiction. That's a pretty new discovery that could actually be workable, and a lot of effort ought to be put into that.

I'd like all of us, the academics, the government, and the private sector, to think about this the way we thought about HIV/AIDs in the early 1990s, where people were dying all around us in tens of thousands. Well, that's what's happening now with opioids. This ought to be all hands on deckwhat could we do to accelerate what otherwise might take a lot longer? It's interesting talking to the drug companies, who have really gotten quite motivated and seem to be determined to make a real contribution here. There are quite a number of new drugs that are in the pipeline somewhere, and they haven't been moving very quickly, because companies haven't been convinced there was enough of a marketopioids are relatively cheap. And also they've been worried that it would be hard to get new pain medicines approved if they had any side effects at all. Now that we've seen opioids have the most terrible side effect of allnamely, deathit would seem that as new analgesics come along, that the ability to approve some that might give you a stomachache now and then would probably be better.

MJ: There's a lot of wariness of big pharmaceutical companies right now, given Big Pharma's role in creating this problem to begin with. How do you make sure that whatever treatments are developed are affordable?

FC: That's a very big concern for everybody right now. It's front and center in these discussions about development of new drugs and pricing of existing drugs. And I don't know the full answer to that. This is just part of a larger discussion about drug pricing which applies across the board, whether we're talking about drugs for cardiovascular disease or cancer or, in this case, alternatives for opioids. But we need them. As much as people might want to say, "Oh, pharmaceutical companies, they're all just out to make money," they also have the scientific capabilities and they spend about twice what the government does on research and development. If they weren't there, we'd be completely hopeless as far as new treatment.

MJ: Trump's latest budget proposes a 20 percent cut to the NIH for 2018. Are you worried about having enough funding?

FC: Of course I am. And not just for this, but for all the other things that NIH is called upon to do as part of our mission. I'm an optimist, and what I have seen in my 24 years at NIH is that opportunity in medical research is not a partisan issueit's not something that's caught up in politics most of the time. And having seen the enthusiasm represented by the Congress in their passage of the 21st Century Cures [Act] just four months ago with incredible positive bipartisan margins, I think when the dust all settles, people will look at these kinds of investments and see them as a high priority for our nation. But of course, that's my optimistic view.

The rest is here:
The Genius Who Helped Unlock the Human Genome Is Taking On the Opioid Crisis - Mother Jones

The Scientist

First In Vivo Human Genome Editing to Be Tested in New Clinical Trial The Scientist Sangamo Therapeutics will use zinc finger nucleases to introduce the gene for a missing clotting factor into the livers of men with hemophilia B. and more »

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First In Vivo Human Genome Editing to Be Tested in New Clinical Trial - The Scientist

Around 4,500 years ago, a mysterious craze for bell-shaped pottery swept across prehistoric Europe. Archaeologists have debated the significance of the potsartefacts that define the Bell Beaker culturefor more than a century. Some argue that they were the Bronze Ages hottest fashion, shared across different groups of people. But others see them as evidence for an immense migration of Beaker folk across the continent.

Now, one of the biggest ever ancient-genome studies suggests both ideas are true. The study,posted on bioRxivon May 9, analysed the genomes of 170 ancient Europeans and compared them to hundreds of other ancient and modern genomes. In Iberia and central Europe, skeletons found near Bell Beaker artefacts share few genetic tiessuggesting that they were not one migrating population. But in Britain, individuals connected to Beaker pots seem to be a distinct, genetically related groupthat almost wholly replaced the islands earlier inhabitants.

If true, this suggests that Britains Neolithic farmers (who left behind massive rock relics, including Stonehenge) were elbowed out by Beaker invaders. To me, thats definitely surprising, says Pontus Skoglund, a population geneticist at Harvard Medical School in Boston, Massachusetts, who was not involved in the research. The people who built Stonehenge probably didnt contribute any ancestry to later people, or if they did, it was very little.

Some archaeologists say that the study does not prove the scale of the British Beaker invasion, but agree that it is a major work that typifies how huge ancient-DNA studies are disrupting archaeology. Its groundbreaking, says Benjamin Roberts, an archaeologist at Durham University, UK.

The variety of Beaker artefacts makes it hard to define them as emerging from one distinctive culture: many researchers prefer to call their spread the Bell Beaker phenomenon, says Marc Vander Linden, an archaeologist at University College London. The distinctive pots, possibly used as drinking vessels, are nearly ubiquitous; flint arrowheads, copper daggers and stone wrist guards are common, too. But there are regional differences in ceramics and burial style. And the immense, yet discontinuous, geographical range of Beaker sitesfrom Scandinavia to Morocco, and Ireland to Hungaryhas sown more confusion. After a few hundred years, the pots vanish from the record.

A 2004 analysis of strontium isotopes, which vary according to regional geochemistry, suggested that some Beaker-associated individuals did migrate in their lifetimes. Past ancient-DNA studies have also hinted at a huge migration, linking Beaker-associated individuals in central Europeto an influx of Steppe peoples from what is now Russia and Ukraine.

The latest work, led by geneticists Iigo Olalde and David Reich at Harvard Medical School, involved 103 researchers at dozens of institutions, including Bronze Age archaeologists. Reichs team analysed more than 1million DNA variants across the genomes of individuals who lived in Europe between 4700 and 1200BC. The team declined to comment because the paper has not yet been published in a peer-reviewed journal.

The analysis seems to dispel the idea of one Beaker people arising from a specific source. Individuals in Iberia (which has been proposed as the wellspring for the culture) shared little ancestry with those in central Europe. Even Beaker-associated people in the same region came from different genetic stock. That pattern contrasts withearlier upheavals in Europe driven by mass migrations, says Skoglund. Bell Beaker is the best example of something that is pots and not people that are spreading, he says.

But in Britain, the arrival of Bell Beaker pots coincided with a shift in the islands genetics. Reichs team analysed the genomes of 19 Beaker individuals across Britain and found that they shared little similarity with those of 35 Neolithic farmers there. The pot-makers were more closely related to 14individuals from the Netherlands, and had lighter-coloured skin and eyes than the people they replaced. By 2000BC, signals of Neolithic ancestry disappear from ancient genomes in Britain, Reichs team findlargely replaced by Beaker-associated DNA. Such turnover is pretty striking, says Garrett Hellenthal, a statistical geneticist at University College Londonwho has studied the peopling of the island through the genomes of living Brits. More data could reveal surprises, but the team makes a good case that Beaker folk replaced the regions early farmers, he says.

Reichs team calculates that Britain saw a greater than 90% shift in its genetic make-up. But Roberts says he doesnt see evidence for such a huge shift in the archaeological record. The rise of cremation in Bronze Age Britain could have biased the finding, he cautions, because it might have eliminated bones that could have been sampled for DNA. Although archaeologists are excited to seeancient DNA yield breakthroughs in problems that have vexed their field for decades, says Linden, he expects some push back against the latest studys conclusions. Its not at all the end of the story.

This article is reproduced with permission and wasfirst publishedon May 17, 2017.

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Bronze-Age "Beaker Culture" Invaded Britain, Ancient-Genome ... - Scientific American

The Scientist

First In Vivo Human Genome Editing Tested in New Clinical Trial The Scientist DEResearchers have edited the human genome before, but always in cells outside the body. Now, biotech company Sangamo Therapeutics is recruiting participants for clinical trials in which patients with hemophilia B, Hurler syndrome, or Hunter syndrome ... and more »

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First In Vivo Human Genome Editing Tested in New Clinical Trial - The Scientist

The discovery of genome-editing enzymes such as CRISPR-Cas9 has resulted in numerous efforts to develop new therapeutics to address genetic disease. Thats because the ability to make modifications to a patients genome holds tremendous potential. Unfortunately, potential might be all it has right now.

There are a few barriers right now to this technology really hitting the mainstream, said Ross Wilson, project scientist and principal investigator at the University of California Berkeley, California Institute for Quantitive Biosciences. One of the main concerns is around safety, and a lot of work and testing is being done when these enzymes modify a genome to make sure they are not making unwanted modifications at the same time. The good news is these enzymes are making precise edits without unwanted effects. Another nice thing is scientists are developing new versions of these enzymes that are even better and even less likely to make unwanted changes to genomes.

[Also:Intermountain makes strides in precision medicine, advanced imaging]

Another barrier to bringing CRISPR to the mainstream is related to the delivery of the therapeutic enzymes, which is the field Wilsons lab is focusing on.

Its pretty easy to take human cells in a petri dish and modify them using these enzymes, because we can use a little electric shock to trick the cells into taking the enzymes inside, Wilson said. But this is the sort of thing that cant really be done in a living patient. Cells are very savvy when it comes to what they let inside because they have to defend against viruses, for example. These genome editing enzymes look like a threat.

Indeed, a major challenge is getting around the cells defenses and carrying out genome editing for efficient modification of cells within a patient. However, one type of therapy moving forward quickly is called autologous transplantation, essentially a patient making a donation to themselves.

Learn more at thePrecision Medicine Summitin Boston, June 12-13, 2017. Register here.

The way this works is you take out some blood cells from a patient and in the laboratory make a modification to those cells and then return these cells to the patient, Wilson said. One gene-based disease that could be cured this way is sickle cell disease. If you take a patients stem cells out, edit the genome in those cells, and transplant them back into the patient, you can cure the gene that is responsible for sickle cell.

Therapies based on autologous transplantation will be the first to really take root, Wilson said.

But this is a narrow window of therapies, Wilson said. If you wanted to reach the broadest number of patients you would need a way to edit the genome inside a living patient. Thats the second big barrier.

[Also:Direct-to-consumer genetic tests: Great for patients, tough on doctors]

Another barrier to this kind of genetic work is the level of understanding of the genetic foundation of different disease states.

There are a lot of things people suffer from, like heart disease, for example, where a lot of genes may be working together to cause a poor outcome in a patient, he said. As medical research advances, we will have a better picture of what sort of things need to be edited to give people better outcomes. Our understanding of the interplay between our genes and our health is one of the things that will give us the most opportunity in putting gene editing therapy to use.

Wilson will discuss precision medicine issues at the HIMSS and Healthcare IT News Precision Medicine Summit, June 12-13, 2017, in Boston, during a session entitled How genome editing might reshape the medical landscape.

Twitter:@SiwickiHealthIT Email the writer: bill.siwicki@himssmedia.com

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Genome editing has a long way to go before widespread buy-in ... - Healthcare IT News

May 17, 2017 Credit: CC0 Public Domain

Harvard Medical School researchers have mapped the interaction partners for proteins encoded by more than 5,800 genes, representing over a quarter of the human genome, according to a new study published online in Nature on May 17.

The network, dubbed BioPlex 2.0, identifies more than 56,000 unique protein-to-protein interactions87 percent of them previously unknownthe largest such network to date.

BioPlex reveals protein communities associated with fundamental cellular processes and diseases such as hypertension and cancer, and highlights new opportunities for efforts to understand human biology and disease.

The work was done in collaboration with Biogen, which also provided partial funding for the study.

"A gene isn't just a sequence of a piece of DNA. A gene is also the protein it encodes, and we will never understand the genome until we understand the proteome," said co-senior author Wade Harper, the Bert and Natalie Vallee Professor of Molecular Pathology and chair of the Department of Cell Biology at Harvard Medical School. "BioPlex provides a framework with the depth and breadth of data needed to address this challenge."

"This project is an atlas of human protein interactions, spanning almost every aspect of biology," said co-senior author Steven Gygi, professor of cell biology and director of the Thermo Fisher Center for Multiplexed Proteomics at Harvard Medical School. "It creates a social network for each protein and allows us to see not only how proteins interact, but also possible functional roles for previously unknown proteins."

Bait and prey

Of the roughly 20,000 protein-coding genes in the human genome, scientists have studied only a fraction in detail. To work toward a description of the entire cast of proteins in a cell and the interactions between themknown as the proteome and interactome, respectivelya team led by Harper and Gygi developed BioPlex, a high-throughput approach for the identification of protein interplay.

BioPlex uses so-called affinity purification, in which a single tagged "bait" protein is expressed in human cells in the laboratory. The bait protein binds with its interaction partners, or "prey" proteins, which are then fished out from the cell and analyzed using mass spectrometry, a technique that identifies and quantifies proteins based on their unique molecular signatures. In 2015, an initial effort (BioPlex 1.0) used approximately 2,600 different bait proteins, drawn from the Human ORFeome database, to identify nearly 24,000 protein interactions.

In the current study, the team expanded the network to include a total of 5,891 bait proteins, which revealed 56,553 interactions involving 10,961 different proteins. An estimated 87 percent of these interactions have not been previously reported.

Guilt by association

y mapping these interactions, BioPlex 2.0 identifies groups of functionally related proteins, which tend to cluster into tightly interconnected communities. Such "guilt-by-association" analyses suggested possible roles for previously unknown proteins, as these communities often commingle proteins with both known and unknown functions.

The team mapped numerous protein clusters associated with basic cellular processes, such as DNA transcription and energy production, and a variety of human diseases. Colorectal cancer, for example, appears to be linked to protein networks that play a role in abnormal cell growth, while hypertension is linked to protein networks for ion channels, transcription factors and metabolic enzymes.

"With the upgraded network, we can make stronger predictions because we have a more complete picture of the interactions within a cell," said first author Edward Huttlin, instructor of cell biology at Harvard Medical School. "We can pick out statistical patterns in the data that might suggest disease susceptibility for certain proteins, or others that might suggest function or localization properties. It makes a significant portion of the human proteome accessible for study."

Launching point

The entire BioPlex network and accompanying data are publicly available, supporting both large-scale studies of protein interaction and targeted studies of the function of specific proteins.

Although the network serves as the largest collection of such data gathered to date, the authors caution it remains an incomplete model. The current pipeline expresses bait proteins in only one cell type (human embryonic kidney cells) grown under one set of conditions, for example, and distinct interactions may occur in different cell types or microenvironments.

As the network increases in size and more human proteins are used as baits, scientists can better judge the accuracy of each individual protein interaction by considering its context in the larger network. Isolating the same protein complex several times, each time using a different member as a bait, can provide multiple independent experimental observations to confirm each protein's membership. Moreover, by using prey proteins as bait, many protein interactions can be observed in the opposite direction as well. Both of these scenarios greatly reduce the likelihood that particular interactions were identified due to chance. The team continues to add to BioPlex, with a target goal of around 10,000 bait proteins, which would cover half of the human genome and would further increase the predictive power of the network.

"We certainly aren't seeing all the interactions, but it's a launching point. We think it's important to continue to build this map, to see how much of it is reproduced in other cell types under different conditions, to see whether the interactions are similar or dynamic," Gygi said. "Because whether you're interested in cancer or neurodegenerative disease, basic development or evolutionary fitnessyou can make new hypotheses and learn something from this network."

Explore further: Facebook for the proteome

More information: Architecture of the human interactome defines protein communities and disease networks, Nature (2017). nature.com/articles/doi:10.1038/nature22366

Journal reference: Nature

Provided by: Harvard Medical School

There are approximately 20,000 human genes that encode proteins, but despite remarkable progress since the human genome was first sequenced more than a decade ago, scientists still understand in detail how only a small fraction ...

Scientists at the Max Planck Institute of Biochemistry in Martinsried near Munich and at the MPI of Molecular Cell Biology and Genetics in Dresden have now drawn a detailed map of human protein interactions. Using a novel ...

How did protein interactions arise and how have they developed? In a new study, researchers have looked at two proteins which began co-evolving between 400 and 600 million years ago. What did they look like? How did they ...

Proteins, those basic components of cells and tissues, carry out many biological functions by working with partners in networks. The dynamic nature of these networks - where proteins interact with different partners at different ...

An international research team has developed the largest database of protein-to-protein interaction networks, a resource that can illuminate how numerous disease-associated genes contribute to disease development and progression. ...

A team of researchers at Sinai Health System's Lunenfeld-Tanenbaum Research Institute (LTRI) and University of Toronto's Donnelly Centre has developed a new technology that can stitch together DNA barcodes inside a cell ...

After decades of research aiming to understand how DNA is organized in human cells, scientists at the Gladstone Institutes have shed new light on this mysterious field by discovering how a key protein helps control gene organization.

Breeding in plants and animals typically involves straightforward addition. As beneficial new traits are discoveredlike resistance to drought or larger fruitsthey are added to existing prized varieties, delivered via ...

(Phys.org)A pair of researchers from Stanford University has studied the energy used by a type of small parrot as it hops from branch to branch during foraging. As they note in their paper uploaded to the open access site ...

Researchers have successfully developed a novel method that allows for increased disease resistance in rice without decreasing yield. A team at Duke University, working in collaboration with scientists at Huazhong Agricultural ...

University of Chicago psychology professor Leslie Kay and her research group set out to resolve a 15-year-old scientific dispute about how rats process odors. What they found not only settles that argument, it suggests an ...

More than 28,000 species of plants around the world have a medical use but poor documentation means people are not making the most of the health benefits, according to a survey released on Thursday.

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Link:
New study maps protein interactions for a quarter of the human ... - Phys.Org

Meaningful public debate seems almost impossible in an era of political bubbles isolating us one from another and facts becoming a matter of opinion. Unfortunately, our political culture is crumbling just as rapid scientific breakthroughs confront us with some of the most serious moral, ethical and policy questions of our age.

And there is a real urgency. Scientific breakthroughs surrounding human gene editing, for instance, have moved medical treatments that seemed science fiction just a few years ago within scientists reach. Today, tools like CRISPR/Cas9 allow making modifications to the human genome in ways that are more efficient and safer than ever before. And the science emerges rapidly, constantly offering new venues for treating what used to be incurable diseases.

The idea of editing the human genome raises questions that science alone cannot answer. What are the ethical and moral boundaries of the human race editing its own genome? Who will have access to many of the potentially expensive medical treatments resulting from this new area of research? And where is the line between treating serious disease and enhancing humans beyond what society considers normal?

None of these questions have simple or obvious answers. What is needed are broad societal discussions, not just about the scientific risks and benefits, but also about the moral, political, and societal complexities surrounding human genome editing.

Even though the scientific community cannot provide definitive answers to some of these moral or political questions, meaningful public debate is impossible if it is not based on the best available science and accurate facts. We in the scientific community therefore have a special obligation to fully engage with a broader publicboth about the science of human gene editing and on the societal concerns that may arise from its applications.

As members of the National Academy of Science and National Academy of Medicine study committee that recently released its final report on human genome editing, we were tasked to offer opinions about the future direction and medical promise of breakthroughs in biology. We looked intensely through public hearings here and abroadas well through a literature reviewfor diverse voices on the moral, regulatory and ethical issues associated with multiple uses of these technologies. Our conclusions point to the hopes and perils these breakthroughs offer.

We all recognized that none of us could or should speak for the larger public. A central theme throughout our report was the need for the key decision makers in scienceboth private and governmentto commit to a robust, systemic, substantive and ongoing public dialog. The Genome Editing report was a step along that road, but it is not the final destination.

Some mechanisms for engagement are already in place, especially including when it comes to the approval of clinical trials within existing regulatory frameworks. But the need for broad public debate will likely emerge from questions that fall outside of the regulatory realm and deal with areas where science raises value-based or moral concerns.

For the scientific community, this will sometimes mean going beyond their comfort zone and engaging with a wide variety of audiences on questions of faith, morality, and values. It also means that the reason for the scientific community to engage in these debates is not to convince people of particular viewpoints or to promote this new technology. Instead, what all public engagement efforts should have in common is a commitment to listening to and respecting the voices of others, including ones from audiences less versed in the details or facts of the subject matter. And listening can start long before the engagement itself, using public opinion surveys, focus groups, and a host of other tools.

The broader scientific community also has a responsibility to engage as educators to offer facts to help inform the debate, particularly if faced with groups who intentionally misrepresent or ignore the best available science and facts that underline it. Scientists need to understand that a majority of citizens who may express concerns about human gene editing or its applications are neither ignorant nor wrong.

Policy choices for most citizens involve weighing different societal, political, moral, and scientific risks and benefits. It is very likely that some will agree with scientists that a technology like human gene editing is safe and still oppose it on moral or religious grounds. The relative weight we as citizens put on any risk or benefit depends on social contexts, including class or economic status, on media portrayals, and on personal value systems, to name just a few. All of those factors shape how we each recalculate our mental algorithms as new information about risks or benefits emerges.

Public engagement on human gene editing is not a box that we need to check before proceeding with potentially controversial applications. It is an ongoing process that will help science and society understand and navigate the societal, political and moral complexities that will emerge as CRISPR and other scientific breakthroughs continue to innovate medicine and many other areas of our lives.

In sum, the time for science policy setting being done exclusively by scientists is over, and when ethical and moral issues (like genome editing) arise the era of full public engagement has begun.

See more here:
Human Genome Editing: Who Gets to Decide? - Scientific American (blog)

An international team of scientists, including a researcher from Berkeley Lab, has characterized the genome of Biomphalaria glabrata, a freshwater snail that transmits a parasitic worm responsible for the infectious disease schistosomiasis, also known as snail fever.

The genome analysis could help researchers disrupt the life cycle of Schistosoma mansoni, a parasitic flatworm transmitted to humans through contact with contaminated freshwater.

The snails carry the worm eggs, which hatch in freshwater and can penetrate the skin of humans. Inside the human host, the worm can lead to anemia, abdominal bleeding, and enlargement of the liver and lungs, among other complications.

The study was led by Coen Adema at the University of New Mexico. Berkeley Labs Monica Munoz-Torres led the biocuration of experimental data and literature related to the structure and localization of the snails genes.

We provided guideposts that helped identify candidates for the genes in this study, said Munoz-Torres, a bioinformatics scientist in the Environmental Genomics and Systems Biology Division.

To do this, she relied upon an open-source genome annotation editor called Apollo. The free, web-based software was first released five years ago by Berkeley Lab scientists to support the community-based curation of genomes, and is now used by thousands of scientists all over the world.

The World Health Organization notes that more than 240 million people worldwide, mainly in tropical and subtropical climates, need preventive treatment for schistosomiasis.

To read the Nature Communications study, click here.

Link:
Scientists Sequence Genome of Snail That Spreads Parasitic Worm - ScienceBlog.com (blog)