Human Genome Still Chock-Full of Mysteries

Posted: 13 Oct 2010 03:10 PM PDT

BOSTON — No one really knows all the genetic parts needed to make a human being.

Exactly how many genes make up the human genome remains a mystery, even though scientists announced the completion of the Human Genome Project a decade ago. The project to decipher the genetic blueprint of humans was supposed to reveal all of the protein-producing genes needed to build a human body.

"Not only do we not know what all the genes are, we don't even know how many there are," Steven Salzberg of the University of Maryland in College Park said October 11 during a keynote address at the Beyond the Genome conference, held in Boston. Most estimates place the human gene count in the neighborhood of 22,000 genes, which falls between the number of genes in a chicken and the number in a grape.

Grape plants have 30,434 genes, by the latest count. Chickens have 16,736 genes, a number Salzberg said will likely grow as scientists put the finishing touches on the chicken genome. As in humans, the gene totals for each species are not as precise as they seem and are subject to revision.

The most accurate estimate of the human gene count is the RefSeq database maintained by the U.S. National Institutes of Health, Salzberg said. He laid out arguments for favoring this estimate, such as its inclusion of all confirmed genes to date, in a paper published in May in Genome Biology. By the RefSeq count, humans have 22,333 genes. But another government database lists 38,621 human genes. And a different project called Gencode currently recognizes 21,671.

Such disparate numbers stem from the fact that genes comprise only about 1 percent of the 3 billion As, Ts, Gs and Cs that make up the human genetic instruction book. And the genes aren't conveniently laid out as single, continuous stretches of genetic code. Instead, human genes are found in protein-encoding pieces called exons, interspersed with stretches of DNA that don't make protein. These spacers are called introns.

To make matters worse, each exon in a gene codes for only a portion of a protein. Cells can mix and match different combinations of exons to make various proteins.

Traditionally, scientists have used computer programs to sift through billions of DNA letters and pinpoint the locations of genes. The programs have improved over the years, but they still aren't as good as people at plucking exons from the sea of introns and figuring out how those protein-encoding segments are spliced together, said Clara Amid, a computational biologist at the Wellcome Trust Sanger Institute in Hinxton, England.

Amid is involved in the Gencode project, an effort to identify all the human genes and the many permutations of those genes that can lead to a dizzying number of proteins. She and her colleagues pick out genes the old-fashioned way — by hand. The researchers get plenty of clues where genes are from computerized gene-finders, studies that sequence RNA produced by genes, and from comparisons of human DNA to the genomes of other animals. Synthesizing all that information allows people to accurately find and mark the locations of genes, a process scientists call annotation. "The best computerized methods could replicate the manual annotation only 40 to 50 percent of the time," Amid said October 12 at the Beyond the Genome conference.

The Gencode team isn't finished with its work; several chromosomes still need the human touch. Gencode's current count is 21,671 human genes. "The number will go up, definitely," Amid said. Already the team has located several new genes on chromosome 4 thanks to data from RNA-sequencing projects, she said.

Exactly how many new genes might be located by sequencing RNA instead of DNA is anyone's guess. Scientists who sequenced RNA from fruit flies discovered 1,938 new genes, Brenton Graveley from the University of Connecticut Health Center in Farmington said at the conference.

The Mammalian Gene Collection, one effort to catalog all of the full-length RNA versions of genes, lists 18,877 human genes. That number is likely to represent the lower boundary of the gene count, Salzberg said.

If new RNA sequencing methods detect the same proportion of new genes in people as were found in fruit flies, the human genome could gain about 3,000 more genes in addition to those already confirmed by RefSeq. "That would be an exciting result," Salzberg said. "I'd be surprised, but we like surprises in science."

Image: Flickr/ ott1mo

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Implants May Help Heroin Addiction

Posted: 13 Oct 2010 02:38 PM PDT

People addicted to heroin or prescription opiates might have a hands-free device for getting through the rigors of drug withdrawal. The medication buprenorphine implanted under the skin and released over 24 weeks can ease drug cravings and helps some patients stay clean, researchers report in the Oct. 13 Journal of the American Medical Association.

Buprenorphine is a semisynthetic opioid compound prescribed for pain relief and for addiction withdrawal. Buprenorphine works something like methadone, a synthetic opioid developed in the 1930s. Both drugs are prescribed for withdrawal from addiction to heroin or prescription pain relievers such oxycodone, Dilaudid, codeine and Vicodin.

But buprenorphine in tablet form can be misused by patients who crush the pills, liquefy them and inject them for a stronger effect.

To get around such abuse and to ensure that a person is getting a standardized dose of the drug, researchers devised the implants — polymer compounds composed of ethylene vinyl acetate and buprenorphine — that slowly release the drug into the body over 24 weeks. They recruited 163 adults diagnosed with opioid dependence and randomly assigned 108 to get the implants and 55 to receive placebo implants. The study's subjects included users of heroin or prescription opioids. All participants received drug counseling during the trial and submitted regular urine samples.

People in either group could request additional doses of buprenorphine as under-the-tongue tablets if they felt their treatment was insufficient to control cravings. Nearly 60 percent of those assigned to buprenorphine requested the extra tablets during the first 16 weeks, as did more than 90 percent of those who had placebo implants. Even so, 37 percent of urine samples from people with buprenorphine implants tested clean for illicit opioids during the trial, compared with only 22 percent of those with placebo implants.

About two-thirds of people with a buprenorphine implant completed the study, compared with less than one-third of those who had a placebo implant.

"In the addiction field, there's a pretty close relationship between sticking around in treatment — what we call retention — and how well you are doing," says study coauthor Walter Ling, a psychiatrist at the UCLA School of Medicine.

Drug dependence is a chronic, relapsing condition, with recovery taking a long time for most people, says Linda Gowing, an addiction researcher at the University of Adelaide in Australia. Motivation to quit is countered by the craving, and there is often stigma associated with attending addiction clinics, she says.

Providing take-home doses of medication is problematic because it allows drugs such as buprenorphine to be used inappropriately or sold on the black market. "The use of implants provides a degree of flexibility for clients, while also maintaining medication with minimal risk of misuse," she says.

The treatment consists of four matchstick-sized implants placed under the skin of the inner arm. Titan Pharmaceuticals of South San Francisco, Calif., which developed the implantable form of the drug and calls it Probuphine, is currently conducting another trial to confirm the findings. Results are due out in 2011.

In the JAMA study, Ling and his colleagues excluded people with chronic diseases or psychiatric conditions. While that limited some factors that might muddy the results, it also left the trial with "the best patients, in a sense," says Douglas Bruce, a physician at Yale University School of Medicine. By screening out people whose addictions are complicated by mental illness, AIDS or hepatitis, he says, "that means it's not necessarily a real-life experience."

Bruce also notes that implants may have a downside: People with them may not show up for regular counseling as reliably as they would if they were receiving weekly supplies of buprenorphine tablets. "Most people become drug users because of sexual trauma as kids or other violence. Bad things happen to people, and drugs make them feel better." To break the addiction cycle, Bruce says, medication must be complemented with counseling. "They will always have to take the meds if they never deal with the root issue."

Nevertheless, Bruce says, the study shows promise. "It's a great start. One of the things we want to know is what sort of therapy will people need to stay engaged [in a drug program] and how long do people need this treatment — is three to six months really sufficient?"

Image: Flickr/coaxeus

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The Year’s Best Fossil Finds

Posted: 13 Oct 2010 02:18 PM PDT

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Fossils provide unparalleled peeks into Earth's living history in the form of mineralized bones and shells, body imprints and even piles of poop. There always seems to be another twist and turn in evolution's creations awaiting trowel-wielding scientists.

From dinosaur-eating snakes to shark-bitten piles of crocodile poop (seriously), dig up some of this year's best finds with us in celebration of National Fossil Day.

Squashed Jurassic Spider

This almost perfectly preserved spider fossil from China dates back 165 million years ago, to the middle Jurassic era.

Known as Eoplectreurys gertschi, the spiders are older than the only two other specimens known by around 120 million years and rival their detail, paleontologists said in February.

Spider fossils are tough to find because their soft bodies don't preserve well. Thanks to fine volcanic ash, however, this spider was squashed without breaking up its delicate exoskeleton.

Image: Paul Selden

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Monster Galaxy Cluster Found in the Distant Universe

Posted: 13 Oct 2010 10:15 AM PDT

A monstrously huge cluster of galaxies lurks 7 billion light-years away. The cluster weighs in around 800 trillion suns and holds hundreds of galaxies, making it the most massive galaxy cluster ever found at such a great distance.

Despite its tremendous bulk, the cluster was hidden until astronomers looked for the distortions it created in the cosmic microwave background, the oldest light in the universe. This light was emitted when ions and electrons first combined to form atoms just after the Big Bang, and has been traveling through the rest of the matter in the universe for the last 13.7 billion years or so to reach telescopes on Earth. As the light passes through massive galaxy clusters, it can get distorted in a phenomenon called the Sunyaev-Zel'dovich effect.

Astronomers using the South Pole Telescope at (where else?) the South Pole have found several galaxy clusters by searching for this effect. But this newest cluster, named SPT-CL J0546-5345, is the heavyweight champion.

Because the cluster is so far away, astronomers see it as it appeared 7 billion years ago, when the universe was half its current age and before the solar system even existed. Even then, the cluster was almost as massive as the nearby Coma Cluster of galaxies, which is one of the densest known. Since then, the cluster should have quadrupled in size, astronomers inferred, making it one of the most massive clusters in the universe. Details on the cluster are published in the Astrophysical Journal.

The cluster also appears full of "old" galaxies that are not forming many stars at a rapid rate, which means the galaxies must have come together to form the cluster within the first 2 billion years of the universe's history. In the image above, a follow-up with the infrared Spitzer Space Telescope and an optical camera on the Blanco 4-meter telescope at the Cerro Tololo Inter-American Observatory in Chile, galaxies with "old" stellar populations are circled in yellow, and galaxies with "young" stellar populations are circled in blue.

Galaxy clusters this massive and distant can be used to study how dark matter and dark energy influenced the growth of cosmic structures.

Image: Infrared: NASA/JPL-Caltech/M. Brodwin (Harvard-Smithsonian CfA) Optical: CTIO Blanco 4-m telescope/J. Mohr (LMU Munich)

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X-Shaped Space Thing Is Smashed-Up Asteroid

Posted: 13 Oct 2010 10:05 AM PDT

Astronomers are now almost certain an x-shaped object discovered in the asteroid belt earlier this year is the first documented asteroid-to-asteroid collision.

There's a small chance a space rock may have instead spun itself into pieces, but two independent teams of scientists think it's a matter of time before that explanation is snuffed out. Whatever happened to create the trail, it's a big clue to what's littering the solar system with fine particles.

"This is the first time we've seen anything like this," said David Jewitt, an astronomer at the University of California Los Angeles and author of one of two studies of the object, P/2010 A2, published Oct. 13 in the journal Nature. "It's a door-opener to the study of disintegrating asteroids."

Jewitt, who used new Hubble Space Telescope images to chart P/2010 A2's progress from January through May, said asteroid belt objects die either by colliding with one another or by rotating so quickly they fly apart.

"What we don't know is which is more frequent or important," Jewitt said, adding that such smash-ups contribute to a persistent cloud of dust in the solar system known as the Zodiacal cloud.

The U.S. Air Force's near-Earth asteroid program discovered the dust trail on January 6 and reported it as a comet. But astronomers later determined the 30,000-mile-long trail is made of rocky dust, signaling the remains of an asteroid. If a collision did spew out the dust, Jewitt said a small asteroid traveling more than 3 miles per second careened into a 75-mile-wide asteroid, blasting off 100,000 tons of rocky dust.

"The energy would have been comparable to a small atomic bomb, maybe a kiloton of TNT," he said.

Despite the finding, Jewitt thinks such events are less likely than previously thought to contribute to the Zodiacal cloud of dust littering the solar system.

"The dust just doesn't come from asteroids, it comes from comets," he said, noting that P/2010 A2's cloud expanded more slowly than anyone expected. "Our best guess now is that comets are the bigger source."

Colin Snodgrass, an astronomer at the Max-Planck Institute for Solar System Research in Germany who worked with a different team of scientists, agrees.

"It's about 1,000 to 10,000 times less than what you would expect if asteroid collisions were the major contributors," Snodgrass said.

Snodgrass said big new telescopes, such as the Large Synoptic Survey Telescope, should pick more asteroid collisions out of the sky in the coming years.

"This size we'll see every 1 to 10 years," he said, referring to P/2010 A2. "The smaller collisions are more common, so we'll see those once a year, maybe every month or so."

Video: NASA, ESA and D. Jewitt. Images: 1) NASA, ESA and D. Jewitt, 2) Colin Snodgrass.

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Culture Evolves Slowly, Falls Apart Quickly

Posted: 13 Oct 2010 10:00 AM PDT

Societies come together slowly, but can fall apart quickly, say researchers who applied the tools of evolutionary biologists to an anthropological debate.

Using archaeological records and linguistic analyses rather than fossils and genes, they created an evolutionary tree of political forms once found in Pacific islands.

The study, published October 13 in Nature, was intended to illuminate an issue of contention among archaeologists, anthropologists and historians: whether societies become more complex in incremental steps or sudden bursts, and whether they dissolve in similar fashion.

"The evolution of complex societies since the end of the last ice age has long been a major topic of investigation and debate," wrote researchers led by anthropologists Thomas Currie and Ruth Mace of University College, London. "These debates have continued largely in the absence of rigorous, quantitative tests."

According to the classic academic narrative of political evolution, post-ice age complexity — defined as increasing levels of social hierarchy — evolved slowly but surely, with mechanical predictability. First came egalitarian bands of closely-related people; then came larger but still-egalitarian tribes, with only informal leadership; these clustered into chiefdoms, with hereditary leaders; chiefdoms united into states, with bureaucracies and administrative offices.

To some scholars, however, this narrative is deterministic. They say that political evolution doesn't proceed neatly from lower to higher complexity, but proceeds in bursts. To them, tribes, chiefdoms and states all represent distinct evolutionary trajectories rather than stages of a single progression. The critics also say that the tendency of societies to move from higher to lower complexity has been underestimated.

Making it all the more difficult to settle the debate is its basis in an incomplete archaeological record. But "just as evolutionary biologists use phylogenetic trees constructed using genetic data to test evolutionary hypotheses, anthropologists have recently begun to use cultural phylogenetics to test hypotheses about human social and cultural evolution," wrote Currie and Mace.

The researchers focused their attention on Austronesia, a general name for Pacific islands inhabited by the descendants of people who left Taiwan 5,200 years ago and eventually settled much of southeast Asia and Oceania, from Madagascar in the west to Easter Island in the east.

As Austronesian settlers moved from island to island, their language bifurcated again and again, taking unique local forms that in many cases persist to this day. By comparing the languages, other researchers had been able to reconstruct a chronological narrative of the islands' settlement.

Over 84 societies in this tree, Currie and Mace overlaid what's known from archaeological records of their social structure, which underwent "spectacular political differentiation to give rise to examples of the entire range of political organization," wrote Collapse author Jared Diamond in an accompanying commentary.

When they compared the resulting tree to trees generated by computational models of different anthropological narratives — linear and stepwise, varied and lurching — the researchers found a close match to the linear. Political complexity indeed grew slowly, bit by bit, with no sudden jumps from bands to chiefdoms or tribes to states.

"Political evolution, like biological evolution, tends to proceed through small steps rather than through major jumps in 'design space,'" wrote Mace and Currie.

However, purely forward-marching models didn't fit the data. There was evidence of societies marching backwards as well, and this didn't follow the same step-by-step path. Societies could collapse.

The study will undoubtedly be criticized, especially for its rough categorization of subtle political differences into four hierarchical categories, wrote Diamond. But what's most important is that the techniques of evolutionary biologists can be applied to anthropology.

Most anthropologists interpret the past "by narrative accounts of individual cases, less often by narrative comparisons of selected cases, and infrequently by comprehensive narrative surveys," Diamond wrote. "My first reaction to Currie and colleagues' paper was one of surprise: why hadn't we used their method before, because it is so obviously superior?"

According to Diamond, cultural phylogenies might be devised for societies in southern and central Africa, which have highly diverse languages and rich political histories.

Analyzing political evolution in Europe and central Asia, where most languages have gone extinct and cultures have long intermingled, is "the grand challenge," he said.

Image: 1) Easter Island moai, 13th-16th century./Flickr, Robert Nyman. 2) Gateway to the royal compound of the 11th Paramount Chief of Tonga, circa 13th century./Thomas Currie.

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Citations: "Rise and fall of political complexity in island South-East Asia and the Pacific." By Thomas E. Currie,, Simon J. Greenhill, Russell D. Gray, Toshikazu Hasegawa & Ruth Mace. Nature, Nature, Vol. 467 No. 7317, September 9, 2010.

"Political evolution." By Jared Diamond. Nature, Nature, Vol. 467 No. 7318, September 9, 2010.

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Bloody Gourd May Contain Beheaded King’s DNA

Posted: 13 Oct 2010 04:00 AM PDT

Sick of taxes, a lack of rights and living in poverty, French revolutionists condemned Louis XVI to the guillotine on the morning of January 21, 1793. After a short but defiant speech and a menacing drum roll, one of the last kings of France lost his head as a crowd rushed the scaffold to dip handkerchiefs into his blood as mementos.

Or so the story goes.

Lending new life to the demise of Louis XVI, scientists performed a battery of DNA tests on dried blood inside a decorative gunpowder gourd that purportedly contained one such handkerchief. The results, described Oct. 12 in the journal Forensic Science International: Genetics, show the blood belongs to a blue-eyed male from that time period: a possible dead-ringer for the executed king.

"The next step is find a descendant either of the king or his mother," said Davide Pettener, a population geneticist at the University of Bologna in Italy who helped with the analysis. "Otherwise we'll have to try to get a sample of the dried heart of Louis XVI's son."

The son was Louis-Charles, known as the Dauphin (heir to the French throne) or Louis XVII, and he died from illness or poisoning at age 10 more than two years after his father was executed. His heart is kept in a crystal vase in the Cathedral Basilica of St. Denis on the outskirts of Paris.

"It's going to be very difficult to obtain permission from the French authorities, but we may try," Pettener said.

An anonymous Italian family who've owned the gourd since at least 1900, possibly the late 1800s, approached one of Pettener's colleagues to do the genetic analysis. Before the family obtained the gourd, it allegedly was a gift to Napoleon Bonaparte, who became First Consul of France in 1799 and Emperor in 1804.

"It's a very strange story," Pettener said. "We thought it was a joke at first because we work on population genetics. But we realized it's very important from a historic point of view."

The gourd, presently valued at about 500,000 euro ($700,000), is emblazoned with key figures of the French Revolution and bears an inscription that reads, as translated from French into English by the researchers, "Maximilien Bourdaloue on January 21st, dipped his handkerchief in the blood of the king after his beheading."

There was no handkerchief in the gourd when the scientific team received it, but there was plenty of dried blood inside to scrape out five small samples. Two laboratories performed three kinds of DNA analysis: One probed the Y chromosome (inherited from the father), another scrutinized the HERC2 gene (associated with blue eyes) and the last examined the DNA in mitochondria (the powerhouses of cells, which are inherited from the mother).

The tests showed the blood belonged to a blue-eyed man with a rare genetic makeup and not to an animal, nor to anyone in the laboratories, nor the gourd-owning family nor or any one of tens of thousands of people in genetic databases. Pettener added that the blood is also "quite old," making a forgery more unlikely.

"A match on the Y chromosome of the Dauphin will immediately authenticate the blood as belonging to the king Louis XVI," Carles Lalueza-Fox, a biologist at Universitat Pompeu Fabra in Barcelona and lead scientist of the analysis team, wrote in an e-mail to Wired.com. "In any case, even with this information, we have historical evidence that this gourd could in fact contain the blood of the king."

Images: Paolo Garagnani/Davide Pettener/Elsevier

Citation: Lalueza-Fox, C. et al. "Genetic analysis of the presumptive blood from Louis XVI, king of France." Forensic Science International: Genetics, Oct. 12, 2010.

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Top 20 Microscope Photos of the Year

Posted: 13 Oct 2010 03:00 AM PDT

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The subject of this year's top microscope photo in the 36th annual Nikon Small World competition looks more like neon suspension bridges or sailboats than what it really is: mosquito heart muscle magnified 100 times.

The image, which used flourescence technology to highlight different parts of the specimen, stood out as one of the most beautiful of the entries. And it also had scientific merit as part of the photographer's research on how mosquitoes carry and spread disease.

"Mosquitoes remain one of the greatest scourges of mankind," said winner Jonas King of Vanderbilt University in a press release Oct. 13. "And this image of the mosquito heart helps us understand how they transport nutrients, hormones, and even pathogens such as malaria throughout their bodies."

Having been one of the judges of the Nikon Small World competition this year, I know how many truly stunning contenders there were. Selecting the best 20 was quite a challenge. The judges, which included both journalists and scientists, spent an entire day slowly whittling the record 2,200 images down to the best. I am definitely biased, but I think the group we ended up with is the best the contest has ever seen.

The other winning photomicrographs we chose included subjects such as a wasp's nest, the olfactory bulbs of zebra fish, seaweed, soy sauce, cancer cells, sulfur and a rat retina. As you look through them here, see if you can guess what they are before you read the captions.

The top photos were displayed online prior to the announcement today of how they placed so that the public could vote on them. Your top choice was the 40 times magnified image of a female black bean aphid with babies on board (below) by Tomas Cabello of the Universidad of Almería in Spain.