Daily Archives: February 24, 2017

Neanderthals went extinct 30,000 years ago, taking their precious genetic material with them. But their DNA lives on in their hybrid ancestors: modern-day humans.

smithsonian.com February 24, 2017 11:06AM

Neanderthals may have gone extinct 30,000 years ago, but they still live on inside us. Ever since scientists discovered that Neanderthal DNA comprises roughly 2 percent of the genomes of modern humans of European and Asian heritage, theyve speculated about how exactly those lingering genes affect us today. Now weve found that even though most humans hardly resemble Neanderthals in appearance, their DNA still influences how our genes work today.

Humans and Neanderthals began splitting on the evolutionary tree about 700,000 years ago, but continued to interbreed up until at least 50,000 years ago. Despite a genetic incompatibility that may have made reproduction difficult, enough hybrid human-Neanderthals were born to enshrine bits of their DNA throughout the human genome. Previous research has found that the Neanderthal DNA sequences and genes found in modern humans are linked to depression, fat metabolism and a host of other traits and conditions.

However, just because we can see a gene doesn't mean we know how it works. Genes can be expressed at different strengths, and sometimes not at all. It all comes down to how that DNA is used by the RNA in our cells, which follows DNA's instructions to make proteins. Cells can "regulate" various genes by choosing to use them, ignore them or modify them to make RNA. Unfortunately, unlike relatively permanent DNA, RNA is unstable and thus rarely found in fossils, making it difficult to analyze how the cells of extinct organisms actually utilized their DNA.

In a study published yesterday in the journal Cell, University of Washington genetics researcher Rajiv McCoy and co-authors got around the lack of ancient Neanderthal data by instead looking in their living descendants: today's hybrid humans. "[We set out to use] gene expression from modern humans to get an idea of how gene flow from Neanderthals is impacting human gene expression," says McCoy.

Using a dataset of the genomes of more than 400 deceased people, the researchers looked for instances of heterozygous genes: genes that are the result of a person inheriting a human gene from one parent and a Neanderthal gene from another. The dataset included samples of tissues from 52 different parts of the body, McCoys says, allowing the researchers to compare how human and Neanderthal genes were expressed in these different areas by comparing how much of each gene was transcribed into RNA.

Through analyzing these individuals with human and Neanderthal alleles, or gene variations, McCoy and his team found differences in human and Neanderthal gene expression in 25 percent of the areas they tested. Those differences had potential effects in traits ranging from height to likelihood of contracting lupus. "It really spans the whole spectrum of human genes," says McCoy.

The researchers were also able to compare how strongly or weakly the human and Neanderthal genes were expressed in different body parts.

Interestingly, McCoy says, they found that Neanderthal genes in the brains and testes of the people tested were expressed more weakly than genes in other areas. The reason for this is likely unequal evolution: As humans continued to evolve away from Neanderthals, McCoy says, it's likely that those body parts have evolved faster than others. Thus, they diverged further from the Neanderthal genes, and are less likely to be expressed by cells there.

For Vanderbilt University geneticist Tony Capra, who was not involved in this study, the reduced gene expression in the testes may be a sign of how mutations from Neanderthals might have reduced the fertility of early human-Neanderthal hybrids. "It further illustrates that Neanderthal DNA that remains in modern humans has the potential to influence diverse traits," says Capra, who has done work scanning electronic medical recordsto look for the effects of Neanderthal DNA on our health.

"This is a very comprehensive study of the impact of Neanderthal introgression on gene expression in modern humans," adds Fernando Racimo, a researcher at New York Genome Center who also wasn't involved in the study. Racimo says he would like to see research into other cases of human hybridization, specificallyancient Denovisans and Australian aboriginals, whose genes live on in the inhabitants of Australias Melanesian islands.

McCoy says studying the genetic legacies of Melanesian people is on his wish list, but that will have to wait until RNA samples are collected. "I mooch off of other people's data," he jokes.

The technique used in this study could be applied within the human species too, McCoy adds. Comparing allele expression in different areas of the body and among different people could help scientists pin down more of the intricacies of gene expression, he says. But even by just probingthe role of Neanderthal DNA in our genomes, we can still better understand how our disparate genes work together to make us.

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How Ancient Neanderthal DNA Still Influences Our Genes Today - Smithsonian

Police believe this man killed Liberty German and Abigail Williams on Feb. 13. German took this photo from her phone before the two were forced to a remote area along Deer Creek, where the girls were killed.(Photo: Provided)

DELPHI, Ind. Carroll County SheriffTobe Leazenby clarified his on-air comments from aFriday interviewduring a Fox59 report,notinghe didn't intendto confirm or denythat investigators collected DNA evidence in thedouble homicide investigation ofAbby Williams and Liberty German.

The TV station's report said investigators acquired DNA evidence critical to the investigation of the case. However, Leazenby said he was speaking about physicalevidence in general and not about DNA evidence in particular.

"We can't say that we have evidence or that we don't,"Leazenby said. "At this point all facets of physical evidence are being considered."

Williams and German disappeared Feb. 13 while hiking the historic trails near the Monon High Bridge. Family members reported the girls missing when they failed to return to their pick-up point.

Volunteer searchers found the girls' bodies about 12:15 p.m. Feb. 14. They were about 50 feet north of Deer Creek about a half-mile east of the bridge, police said.

Police released a grainy photo of a man walking the trails about the same time as German and Williams and days later said the man was a suspected in the killings. Investigators announced this week that the photo was taken by German, who also recorded the voice of the man suspected of killing the girls.

Other than the photo and the audio recording, police have released very little of the evidence they have collected.

Police said Feb. 15 that the manner of death was homicide, based on the autopsy that day. But they refused to discuss the cause of death or the injuries the girls endured based on the autopsy.

Leazenby said the department is expediting the analysis of all physical evidence, fairly common in a case such as this. WhileLeazenby said he can't speak to specifically what evidence was acquired at the scene, every crime scene has physical evidence.

"There is an old rule in our business that any time there is an exchange involvinghumans there is take and leave. You take something and you leave something ... whether it's hair shed, skin or even a gum wrapper."

Leazenby said he felt the need to clarify the Fox59 report because "we don't want to have mass confusion."

A reward fund set up for information leading to an arrest topped $50,000 on Thursday.

By early afternoon Friday, police have received more than 5,000 tips in the last 11 days, Leazenby said. Investigators are following up on these tips.

Email tips now outnumber phone tips by 2 to 1,he said.

Tips may be phoned in at844-459-5786 or emailed toabbyandlibbytips@cacoshrf.com. Tipsters may remain anonymous.

Call J&C reporter Emma Ea Ambrose at 765-431-1192. Follow her on Twitter: @emma_ea_ambrose.

J&C breaking news reporter Ron Wilkins can be reached at 765-420-5231; follow on Twitter@RonWilkins2

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Sheriff clarifies reports of DNA evidence - Journal and Courier

February 24, 2017 Artistic rendering of RNA-DNA interactions. A 3-D structure of tightly coiled DNA is depicted as the body of a dragon in Chinese myth. Interacting RNAs are depicted as hairs, whiskers and claws, which are essential for the dragon to function. Credit: Victor O. Leshyk

Bioengineers at the University of California San Diego have developed a new tool to identify interactions between RNA and DNA molecules. The tool, called MARGI (Mapping RNA Genome Interactions), is the first technology that's capable of providing a full account of all the RNA molecules that interact with a segment of DNA, as well as the locations of all these interactionsin just a single experiment.

RNA molecules can attach to particular DNA sequences to help control how much protein these particular genes produce within a given time, and within a given cell. And by knowing what genes produce these regulatory RNAs, researchers can start to identify new functions and instructions encoded in the genome.

"Most of the human genome sequence is now known, but we still don't know what most of these sequences mean," said Sheng Zhong, bioengineering professor at the UC San Diego Jacobs School of Engineering and the study's lead author. "To better understand the functions of the genome, it would be useful to have the entire catalog of all the RNA molecules that interact with DNA, and what sequences they interact with. We've developed a tool that can give us that information."

Zhong and his team published their findings in the Feb. issue of Current Biology.

Existing methods to study RNA-DNA interactions are only capable of analyzing one RNA molecule at a time, making it impossible to analyze an entire set of RNA-DNA interactions involving hundreds of RNA molecules.

"It could take years to analyze all these interactions," said Tri Nguyen, a bioengineering Ph.D. student at UC San Diego and a co-first author of the study.

Using MARGI, an entire set of RNA-DNA interactions could be analyzed in a single experiment that takes one to two weeks.

The MARGI technique starts out with a mixture containing DNA that's been cut into short pieces and RNA. In this mixture, a subset of RNA molecules are interacting with particular DNA pieces. A specially designed linker is then added to connect the interacting RNA-DNA pairs. Linked RNA-DNA pairs are selectively fished out, then converted into chimeric sequences that can all be read at once using high-throughput sequencing.

Zhong and his team tested the method's accuracy by seeing if it produced false positive results. First, the researchers mixed RNA and DNA from both fruit fly and human cells, creating both "true" RNA-DNA pairs, meaning they're either fully human or fully fruit fly, and "false" RNA-DNA pairs, meaning they're half human and half fruit flythese are the ones that shouldn't be detected. The team then screened the entire mixture using MARGI. The method detected a large set of true RNA-DNA interactions, but it also detected approximately 2 percent of the false ones.

"This method is not perfect, but it's an important step toward creating a full functional annotation of the genome," said co-first author Bharat Sridhar, a visiting bioengineering researcher in Zhong's group.

Explore further: Size matters... and structure too: New tool predicts the interaction of proteins with long non-coding RNAs

More information: Bharat Sridhar et al, Systematic Mapping of RNA-Chromatin Interactions InVivo, Current Biology (2017). DOI: 10.1016/j.cub.2017.01.011

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DELPHI, Ind. - Investigators say they discovered DNA evidence at the crime scene where two Indiana teenagers were found murdered last week.

That evidence now has top priority for processing by investigators, Fox 59 reports.

Its a strong lead, in a case where authorities have been clamoring for any clue about the suspect who murdered 13-year-old Abby Williams and 14-year-old Libby German.

In an attempt to identify the possible murder suspect, investigators previously released a grainy suspect photo, a chilling audio of a man's voice saying "down the hill," and now a DNA sample.

Photos of the man police want to speak with.

We asked for a fast-track as far as that piece information, said Carroll County Sheriff Tobe Leazenby. "So I cant go into specifics because of the ongoing [investigation].

Police havent said specifically what kind of evidence they recovered

Investigators believe the girls met the suspect in a chance encounter or the person knew they were going to be there. Liberty German's decision to make a recording provided police with their best information.

The bodies were discovered along the edge of Deer Creek in Delphi which is about a half-mile away from the Monon High Bridge, an abandoned rail bridge over Deer Creekthat was the last place the two girls were seen. They were supposed to meet with family members later Monday evening, but when the teens didnt show up, their families called police.

Officials are asking anyonewho may have taken pictures in the area or was just on the trail to contact authoritiesimmediately.

Anyone with information about this case is encouraged to call the Delphi Homicide Investigation Tip Line at (844) 459-5786. Information can also be reported by calling the Indiana State Police at (800) 382-7537, or the Carroll County Sheriffs Department at (765) 564-2413. Information can also be emailed to Abbyandlibbytip@cacoshrf.com.Information can be reported anonymously

The Indiana State Police, the FBI, and the Carroll County Sheriffs Department have announced a reward ofup to $41,000 in the case, depending upon the value of the information provided.

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DNA evidence discovered at scene where two Indiana teens were found murdered now top priority - kfor.com

February 24, 2017 by Whitney Clavin A protein called DNA primase (tan) begins to replicate DNA when an iron-sulfur cluster within it is oxidized, or loses an electron (blue and purple). Once this primase has made an RNA primer, a protein signaling partner, presumably DNA polymerase alpha (blue), sends an electron fromits reduced cluster, which has an extra electron (yellow and red). The electron travels through the DNA/RNA helix to primase, which comes off the DNA.Thiselectron transfer signalsthe next steps in replication. Credit: Caltech

In the early 1990s, Jacqueline Barton, the John G. Kirkwood and Arthur A. Noyes Professor of Chemistry at Caltech, discovered an unexpected property of DNAthat it can act like an electrical wire to transfer electrons quickly across long distances. Later, she and her colleagues showed that cells take advantage of this trait to help locate and repair potentially harmful mutations to DNA.

Now, Barton's lab has shown that this wire-like property of DNA is also involved in a different critical cellular function: replicating DNA. When cells divide and replicate themselves in our bodiesfor example in the brain, heart, bone marrow, and fingernailsthe double-stranded helix of DNA is copied. DNA also copies itself in reproductive cells that are passed on to progeny.

The new Caltech-led study, based on work by graduate student Elizabeth O'Brien in collaboration with Walter Chazin's group at Vanderbilt University, shows that a key protein required for replicating DNA depends on electrons traveling through DNA.

"Nature is the best chemist and knows exactly how to take advantage of DNA electron-transport chemistry," says Barton, who is also the Norman Davidson Leadership Chair of Caltech's Division of Chemistry and Chemical Engineering.

"The electron transfer process in DNA occurs very quickly," says O'Brien, lead author of the study, appearing in the February 24 issue of Science. "It makes sense that the cell would utilize this quick-acting pathway to regulate DNA replication, which necessarily is a very rapid process."

The researchers found their first clue that DNA replication might involve the transport of electrons through the double helix by taking a closer look at the proteins involved. Two of the main players in DNA replication, critical at the start of the process, are the proteins DNA primase and DNA polymerase alpha. DNA primase typically binds to single-stranded, uncoiled DNA to begin the replication process. It creates a "primer" made of RNA to help DNA polymerase alpha start its job of copying the single strand of DNA to create a new segment of double-helical DNA.

DNA primase and DNA polymerase alpha molecules both contain iron-sulfur clusters. Barton and her colleagues previously discovered that these metal clusters are crucial for DNA electron transport in DNA repair. In DNA repair, specific proteins send electrons down the double helix to other DNA-bound repair proteins as a way to "test the line," so to speak, and make sure there are no mutations in the DNA. If there are mutations, the line is essentially broken, alerting the cell that mutations are in need of repair. The iron-sulfur clusters in the DNA repair proteins are responsible for donating and accepting traveling electrons.

Barton and her group wanted to know if the iron-sulfur clusters were doing something similar in the DNA-replication proteins.

"We knew the iron-sulfur clusters must be doing something in the DNA-replication proteins, otherwise why would they be there? Iron can damage the DNA, so nature would not have wanted the iron there were it not for a good reason," says Barton.

Through a series of tests in which mutations were introduced into the DNA primase protein, the researchers showed that this protein needs to be in an oxidized statewhich means it has lost electronsto bind tightly to DNA and participate in DNA electron transport. When the protein is reducedmeaning it has gained electronsit does not bind tightly to DNA.

"The electronic state of the iron-sulfur cluster in DNA primase acts like an on/off switch to initiate DNA replication," says O'Brien.

What's more, the researchers demonstrated that electron transport through DNA plays a role in signaling DNA primase to leave the DNA strand. (Though DNA primase must bind to single-stranded DNA to kick off replication, the process cannot begin in earnest until the protein pops back off the strand).

The scientists propose that the DNA polymerase alpha protein, which sits on the double helix strand, sends electrons down the strand to DNA primase. DNA primase accepts the electrons, becomes reduced, and lets go of the DNA. This donation and acceptance of electrons is done with the help of the iron-sulfur clusters.

"You have to get the DNA primase off the DNA quicklythat really starts the whole replication process," says Barton. "It's a hand off of electrons from one cluster to the other through the DNA double helix."

Many proteins involved in DNA reactions also contain iron-sulfur clusters and may also play roles in DNA electron transport chemistry, Barton says. What began as a fundamental question 25 years ago about whether DNA could support migration of electrons continues to lead to new questions about the chemical workings of cells. "That's the wonder of basic research," she says. "You start with one question and the answer leads you to new questions and new areas."

Explore further: Structure of key DNA replication protein solved

More information: Elizabeth O'Brien et al. The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport, Science (2017). DOI: 10.1126/science.aag1789

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Electrons use DNA like a wire for signaling DNA replication - Phys.org - Phys.Org

When folks talk about the gene-editing tool CRISPR, theyre usually talking about CRISPR-Cas9, a combination of DNA and enzymes that together act like scissors to cut and paste genes. CRISPR-Cas9 has already been hailed a potential game changer in the fight against cancer, crop pathogens, and environmental problems. But some researchers think a lesser-known flavor of the technology might be the answer to the worlds growing superbug problem. Ladies and gentlemen, meet CRISPR-Cas3.

Cas9 is in vogue for good reason: Its a small enzyme that is really good at precisely targeting specific sequences of DNA, making engineering a genome much easier than ever before. Cas3 is terrible at those things. It shreds up the DNA it targets to a point far beyond repair, causing the cell to die. If CRISPR-Cas9 is a genetic scalpel, Cas3 is a chainsaw. Which is exactly why researchers think it might be just the thing to attack the sort of super-tough bacteria that can resist antibiotics.

What were trying to do is kill bacteria, Rodolphe Barrangou, a molecular biologist at North Carolina State University, told Gizmodo. Its like a Pac-Man thats going to chew up DNA rather than make a clean cut. It chews it up beyond repair. Its lethal.

Barrangou first encountered CRISPR while working for Danisco sequencing Streptococcus thermophilus, a bacteria commonly used in yogurt and cheese production. His early CRISPR work helped lead to the discovery of CRISPR gene editing. Like most scientists in the field, much of his work focused on Cas9. But the clunky, cumbersome Cas3 is a CRISPR enzyme much more common in nature. Barrangou began to wonder whether its boorish nature might be an asset in applications beyond genetic engineering.

In 2015, he co-founded Locus Biosciences, a university spin-off company devoted to reprogramming CRISPR-Cas3 to develop antimicrobials to tackle infectious diseases increasingly resistant to antibiotics, such as C.difficile, E.coli and MRSA. Recently, the company made its public debut after years in stealth mode.

Like Cas9, the Cas3 enzyme can be programmed to target specific DNA, meaning scientists could train it on an unwanted invader. But Cas9 precisely cuts DNA, leaving a double-stranded break that allows the cell to repair itself once the desired edits have been made. Cas3, Barrangou said, is like Pac-Man, chewing up the cell in such a way that leaves it no hope of repair.

Its a very promising idea, this had a lot of potential, Erik Sontheimer, a molecular biologist at University of Massachusetts, told Gizmodo. Though, I want to caution that when it comes to superbugs, there is no magic bullet.

Hard-to-kill bacteria, often dubbed superbugs, have become a major problem, developing resistance to antibiotics more quickly than we can discover new ones. In a rush to find a solution besides just simply more antibiotics, researchers are experimenting with alternatives, like using predatory bacteria to attack deadly human pathogens.

Another company, Eligo Biosciences in France, is also focused on using CRISPR to produce antimicrobials. The hope is that not only would it succeed in killing the desired superbugs, but stave off the creation of future superbugs by only targeting one type of bacteria in the body, rather than indiscriminately wiping out many helpful bacteria along the way.

Antibiotics are indiscriminatethey target all bacteria in the body, Barrangou said. If we can use CRISPR to selectively target a particular bacterial genotype and eradicate it, we can leave the rest of the microbiome in tact. Its like a smart antibiotic.

Barrangous work is in its early stages, but it may be among the most promising alternatives to new antibiotics.

The company has not yet begun clinical trials, but has had success using CRISPR-Cas3 to fight mice infected with two different strains of E.coli, work Barrangou told Gizmodo it plans to publish later this year. Many challenges remain, including figuring out the best way to actually get CRISPR-Cas3 into the bacteria, with their thick cell walls. Theres also the possibility that pathogens could evolve immunity to CRISPR.

One of the reasons there is such a crying need for new therapies is that bacteria are very good at evolving ways around whatever we throw at them, Sontheimer said.

The company will also have to gain FDA approval for any therapy it develops. It hopes that process will be less fraught than it has been for CRISPR-Cas9, since Cas3's destructive properties mean you cant make designer babies, superhumans or any other genetically engineered sci-fi catastrophe.

We dont edit a cell and we dont add anything, said Barrangou. But we could kill some bad bacteria.

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Scientists Are Creating a Genetic Chainsaw to Hack Superbug DNA to Bits - Gizmodo