RESEARCH USING SUPERCOMPUTER THAT COULD LINK GENES TO TRAITS AND DISEASES

FROM:  NATIONAL SCIENCE FOUNDATION 

"Bottom-up" proteomics

NSF-funded supercomputer helps researchers interpret genomes
Tandem protein mass spectrometry is one of the most widely used methods in proteomics, the large-scale study of proteins, particularly their structures and functions.

Researchers in the Marcotte group at the University of Texas at Austin are using the Stampede supercomputer to develop and test computer algorithms that let them more accurately and efficiently interpret proteomics mass spectrometry data.

The researchers are midway through a project that analyzes the largest animal proteomics dataset ever collected (data equivalent to roughly half of all currently existing shotgun proteomics data in the public domain). These samples span protein extracts from a wide variety of tissues and cell types sampled across the animal tree of life.

The analyses consume considerable computing cycles and require the use of Stampede's large memory nodes, but they allow the group to reconstruct the 'wiring diagrams' of cells by learning how all of the proteins encoded by a genome are associated into functional pathways, systems, and networks. Such models let scientists better define the functions of genes, and link genes to traits and diseases.

"Researchers would usually analyze these sorts of datasets one at a time," Edward Marcotte said. "TACC let us scale this to thousands."

TREATING AIDS WITH SUPERCOMPUTERS

FROM:   NATIONAL SCIENCE FOUNDATION 

Computing a cure for HIV

Nine ways NSF-supported supercomputers help scientists understand and treat the disease

HIV/AIDS has caused an estimated 36 million deaths, according to the World Health Organization, and remains a major menace worldwide. Today, approximately 35 million people are living with the human immunodeficiency virus (HIV), including more than a million individuals in the United States.

The tendency of HIV to mutate and resist drugs has made it particularly difficult to eradicate. Some treatments have shown progress in slowing or even stopping the progress of the virus, but no cure or vaccine has been discovered that can truly stamp out the disease.

In the last decade, scientists have begun using a new weapon in the fight against HIV: supercomputers.

Scientists harness the power of thousands of computer processors simultaneously to better understand how the HIV virus interacts with the cells it infects, to discover or design new drugs that can attack the virus at its weak spots and even to use genetic information about the exact variants of the virus to develop patient-specific treatments.

Among the researchers using supercomputers to study HIV is Klaus Schulten, the keynote speaker at the 2014 International Supercomputing Conference, held earlier this week in Leipzig, Germany. Schulten, a professor of physics at the University of Illinois at Urbana-Champaign, invented the Nanoscale Molecular Dynamics (NAMD) software program, one of the most widely used tools for understanding diseases at a molecular level.

Supported by the National Science Foundation (NSF) and using some of the nation's most powerful supercomputers, teams of researchers are pushing the limits of what we know about HIV, and how we can treat it.

Below are nine examples of how scientists are applying massive computing power and computational know-how to combat the disease.

1) Modeling HIV: from atoms to actions

In order for HIV to infect non-dividing cells, the HIV virus must enter the cell and entice cellular proteins to act as chaperones, ushering the virus towards the cell nucleus and helping it integrate its genes into the cell's genome. This infection process offers opportunities for medical intervention and may suggest new HIV treatments. However the dynamics of the process can only be "observed" through computational modeling and simulation.

The size of the HIV capsid or shell, combined with its irregular shape, had long prevented scientists from simulating the full capsid structure with adequate resolution. But researchers from Klaus Schulten's group at the University of Illinois at Urbana-Champaign, using the NSF-funded Blue Waters supercomputer, observed how the capsid interacts with drugs and host proteins at the atomic level. The model, consisting of about 1,300 proteins and 4 million atoms, is currently the largest entry in the Research Collaboratory for Structural Bioinformatics Protein Data Bank, a repository for the three-dimensional structural data of large biological molecules.

2) Discovery of hidden pocket in HIV protein leads to ideas for new inhibitors

Researchers from the University of California, San Diego; the Salk Institute for Biological Studies and the National Cancer Institute collaborated on an effort to discover new drug candidates to combat HIV.

With the help of the San Diego Supercomputer Center, the scientists ran molecular simulations to capture the movements of a small pocket on the virus's surface that they believed could be targeted by drugs to prevent the replication of the virus. Using the pocket as a target, they virtually screened thousands of compounds and tested 16 for their ability to block HIV infection in human tissue cultures. Ultimately, they discovered two compounds that inhibit HIV replication and block the activity of reverse transcriptase as effectively as a leading FDA-approved drug, nevirapine. The researchers believe these compounds have the potential to develop into future drugs and are exploring them further.

3) Preventing HIV from reaching its mature state

The mature capsid of the HIV virus is comprised of thousands of interlinked proteins that act like a suit of armor around the virus's genetic material. If this armor-like structure does not form, then the virus is unable to infect cells.

Researchers from the University of Chicago used the Kraken supercomputers at the National Institution for Computational Science (NICS) to study how the mature HIV capsid formed. They found that the seemingly complicated behavior of the capsid's self-assembly was relatively simple once they understood the shape and behavior of the proteins that made it up. The work advanced our understanding of the HIV life cycle and is inspiring the development of new drugs to disrupt the virus's growth. Results appeared in the Biophysical Journal in October 2012.

4) Crowdsourcing a cure

After scientists repeatedly failed to piece together the structure of a protein-cutting enzyme that plays an important role in HIV, they called on the players of FoldIt, an online puzzle video game, to find a solution. Using FoldIt, "citizen scientists" were able to determine how the enzyme folded and solved the mystery of its structure. With further help from the game-players, researchers were able to identify target drugs to neutralize the enzyme.

FoldIt is part of an experimental research project supported by NSF and developed by the University of Washington's Center for Game Science in collaboration with the UW Department of Biochemistry. The case of the crowdsourced protein structure serves as a critical example of how games with a purpose can solve real-world problems.

5) Virtual screening of HIV inhibitors

A team of researchers from Pennsylvania used computer modeling and virtual screening, powered by supercomputers, to identify novel inhibitors of HIV and better understand how they react with the HIV virus. They focused on small molecules that block the interaction between the receptors on the surface of human cells and an important protein on the surface of the HIV envelope.

Using the Blacklight system at the Pittsburgh Supercomputing Center, the researchers virtually screened more than 10 million compounds to find small molecules that would be a good molecular fit for the protein that they were targeting. From the 10 million, they identified six, small-molecule, HIV surface protein complexes that display unique modes of binding. Taken together, they constitute what the researchers believe is a potent class of entry inhibitors against HIV.

6) Membrane effects

Some proteins that anchor HIV to cell membranes are thought to promote the development of the virus. Researchers have found that combining experimental methods with computer simulations can reveal much about the cell-binding dynamics.

Hirsh Nanda of the National Institute of Standards and Technology leads a research team that studies the initial stages of the formation of new HIV virus particles in an infected cell. During these first steps, HIV proteins latch onto cell membranes.

Using the Kraken supercomputer at NICS, Nanda's team was able to study the forces that govern protein assemblies on membranes in far greater detail and much faster than if they were using their lab's computers. Kraken also greatly accelerated the analysis of experimental neutron scattering data that they used to compare with simulations.

The simulations revealed that an important HIV surface protein simultaneously binds to the cell membrane and to viral RNA in order to change shape. Also revealed was how another HIV protein transitions between compact and extended structures upon anchoring to the cell membrane. These discoveries are inspiring new treatment approaches that center on membrane interactions.

7) Computing patient-specific treatment methods

Doctors know that there are many different strains of HIV and that drugs for the disease do not have the same effects in all people. Subtle genetic differences between strains and among individuals lead to a range of treatment outcomes. Using the NSF-supported Kraken and Ranger supercomputers, researchers from University College London and Rutgers University determined the shape of a key protein involved in HIV infection in an individual patient, and then ranked the drug molecules most likely to block the activity.

The project demonstrated how researchers might use genetic sequencing techniques and massive computations to design patient-specific treatment protocols in near-real-time. In the future, it is expected that this type of patient-specific drug selection will become routine.

The research was reported at the annual meeting of the American Association for the Advancement of Science and was published in the Journal of Chemical Theory and Computation.

8) Preparing the next generation to continue the fight

At Merrimack College in Massachusetts, students are learning how to conduct virtual screening using the Stampede supercomputer. Virtual screening uses computational methods to identify small molecules that are likely to bind to a known drug target, often a protein. The method has become a valuable tool for many biotechnology and pharmaceutical companies.

The activity exposes students to massive computing resources and shows them a method of conducting science that few previously knew existed. It's one of many ways that educators around the nation are beginning to prepare students for the workforce of the future by incorporating computational techniques into their curriculum.

9) A boy and the BEAST

When Armand Bilge was a 10th-grader at Lexington High School in Massachusetts, he created a map and timeline that identified when HIV arrived in the Americas, and where and when HIV spread across these continents. To do so, Bilge used a combination of molecular sequencing software and NSF-funded high-performance computing resources.

As a member of an after-school computer club, Bilge used a software program called BEAST to create a detailed evolutionary tree, based on similarities and differences in the 3,000 nucleotide subunits of a gene among 400 known HIV strains. The software ran on the CIPRES (CyberInfrastructure for Phylogenetic Research) science gateway, a public resource developed by the San Diego Supercomputer Center and supported by NSF that allows those interested in evolutionary relationships to study virtually every species on Earth.

Bilge's conclusions support previously published results of HIV experts that suggest that "a single introduction of the virus in Haiti in the mid-1900s resulted in its dispersion across the American continent." The project won first place in biology for the 2012 Massachusetts Science and Engineering Fair.

-- Aaron Dubrow, NSF
Investigators
John Towns
Dan Stanzione
Ralph Roskies
Philip Andrews
Gregory Peterson
Patricia Kovatch
Nancy Wilkins-Diehr

SCIENTIST WINS WORLD FOOD PRIZE FOR INCREASING WORLD WHEAT PRODUCTION

FROM:  U.S. STATE DEPARTMENT 

Plant Scientist, Dr. Sanjaya Rajaram, Wins the 2014 Annual World Food Prize

Media Note

Office of the Spokesperson

Washington, DC

June 18, 2014

---

Secretary of State John Kerry delivered the keynote address at a ceremony at the U.S. Department of State on June 18, where eminent plant scientist, Dr. Sanjaya Rajaram of India and Mexico, was named winner of the 2014 World Food Prize for increasing world wheat production by more than 200 million tons in the years following the Green Revolution, which has had a far-reaching impact in alleviating world hunger.

Dr. Rajaram’s breakthrough achievement in successfully cross breeding winter and spring wheat varieties, which were distinct gene pools that had been isolated from one another for hundreds of years, led to his developing plants that have higher yields and a broad genetic base. More than 480 high-yielding wheat varieties bred by Dr. Rajaram have been released in 51 countries on six continents and have been widely adopted by small- and large-scale farmers alike. Dr. Rajaram followed Nobel Peace Prize Laureate Dr. Norman E. Borlaug at the International Maize and Wheat Improvement Center, CIMMYT, leading its Wheat Program from 1976 to 2001.

Assistant Secretary for Economic and Business Affairs Charles Rivkin hosted the event, and World Food Prize Foundation President and former U.S. Ambassador to Cambodia Kenneth M. Quinn announced the winner. This marks the 11th year the State Department has hosted the World Food Prize announcement.

Secretary Kerry said, “When you do the math, when our planet needs to support two billion more people in the next three decades, it’s not hard to figure out: This is the time for a second green revolution. That’s why Dr. Sanjaya Rajaram is being honored with the World Food Prize. We are grateful for the hundreds of new species of wheat Dr. Rajaram developed, which deliver 200 million more tons of grain to global markets each year and feed millions across the world.”
Dr. Rajaram’s work serves as an inspiration to us all to do more, whether in the private or public sector. Through Feed the Future, a presidential global hunger and food security initiative, the United States is establishing a foundation for lasting progress against global hunger. With a focus on smallholder farmers, particularly women, Feed the Future supports partner countries in developing their agriculture sectors to spur economic growth, increase incomes, and reduce hunger, poverty, and undernutrition. Feed the Future supports a research agenda to harness scientific innovation and technology in agriculture.

Ambassador Quinn said, "The 2014 World Food Prize Laureate is an individual who worked closely with Dr. Borlaug in Mexico and who then carried forward and extended his work, breaking new ground with his own achievements. As we celebrate the United Nations International Year of Family Farming, it is most fitting that the 2014 World Food Prize Laureate is an individual who has truly fulfilled Dr. Borlaug’s last words: ’Take it to the farmer.’”
This year marks the 28th anniversary of the $250,000 World Food Prize, which recognizes individuals who have advanced human development by improving the quality, quantity or availability of food in the world.

The World Food Prize was established in 1986 by Dr. Borlaug in order to focus the world’s attention on hunger and on those whose work has significantly helped efforts to end it.
Dr. Borlaug earned the Nobel Peace Prize in 1970 for his work as a plant breeder and for taking new agricultural practices to developing nations around the world. Each year, more than 4,000 institutions and organizations worldwide are invited to nominate candidates for the prize. The award will be formally presented in a ceremony in October at the Iowa State Capitol in Des Moines, Iowa.

The World Food Prize is guided by a distinguished Council of Advisors that includes former Presidents Jimmy Carter and George H. W. Bush.

STEMGenetics CURRICULUM WOKRS TO IMPROVE STUDENTS' UNDERSTANDING OF RELEVANCE OF GENETICS

Hooked on STEMGenetics
Genetics curriculum blends teacher-led discussion, online learning and hands-on activities

The study of genetics may not be typical in a fifth-grade classroom. But fifth-, seventh- and ninth-graders are benefiting from an innovative curriculum that combines teacher-led discussion, online learning and hands-on activities to broaden students' understanding of how genetic information moves from one generation to the next.

STEMGenetics was developed by Michelle Williams, an associate professor of science education at Michigan State University and Angela DeBarger, a senior research scientist at SRI International.

Now in the third year of a five-year National Science Foundation (NSF) grant, STEMGenetics focuses on familiarizing students with grade appropriate genetics concepts, assessing their grasp of the concepts and providing professional development for teachers involved in the program.

Williams says she and DeBarger chose genetics because "it's an important topic to society and is personally relevant to people in their everyday lives, even young children." She adds that when it comes to genetics "many students have an array of ideas that are not scientifically accurate. By starting early on, we have an opportunity to build a more coherent understanding of the subject."

The project currently serves almost 2,000 students in nine schools in East Lansing, Mich., and Cedar Hills, Texas.

Over five weeks, each grade tackles a series of "motivating questions" such as "How do plants in the same species vary?" or "How do we breed rice plants for high nutrition?" As teachers guide students through the material, they introduce hands-on activities such as planting seeds and crossing different parent plants.

"These activities stimulate a lot of great conversation," says veteran teacher Rob Voigt. Much of the discussion grows from students making predictions and drawing conclusions about genetic information.

To support classroom concepts, students also engage in online modules that may include a story related to the topic, short videos and interactive sections in which students examine data, reflect on it and input their responses in drop-down dialog boxes. Animal and plant breeding simulations help students visualize how genetic information combines to produce various types of offspring.

"This project demonstrates the value of bringing tools of scientific research to younger students," said NSF Program Director Julia Clark. "Having the opportunity to engage in scientific thinking builds a great foundation for future study."

Collaborating on a curriculum

Developing the STEMGenetics content and supporting technology took a small village of scientists, teachers, technology developers and assessment experts. DeBarger and Williams co-designed the units with teachers from different schools and across grade levels. "We had content experts and mentor teachers look at the learning goals to decide which ones are learned best through an interactive model and which processes are appropriate to learn," says Williams. The teams then developed storyboards to convey the concepts so that programmers at SRI could build the simulations and other visuals for the units.

To package their material, Williams and DeBarger wanted a tool that would bring content to the classroom in a unique and effective way. They turned to the web-based inquiry science environment (WISE) developed at the University of California, Berkeley by Williams' former doctoral mentor Marcia Linn. Specifically designed to promote critical thinking skills, WISE has software tools to help students make and justify predictions, describe observations and develop conclusions supported with evidence.

"Students gain experience constructing a good argument and supporting it," says Williams. "A skill," she points out, "that is crucial not only in science, but across disciplines."

The reflection and writing opportunities also act as an assessment so that teachers can monitor student progress. Based on the answers students provide, teachers can encourage the class to think more deeply about a concept or adjust a lesson if students are struggling with a concept. Teachers track lesson adjustments and supply that information to Williams and DeBarger.

"We get data back each year from the teachers and refine the units over the summer," says DeBarger.

Supporting teachers

While technology enhances classroom activities, supporting teachers as they present scientific concepts is essential to the program.

"Teaching is a profession like medicine, and teachers like doctors must be constantly learning," says Amal Ibourk, a graduate student researcher with STEMGenetics. To assist teachers, STEMGenetics offers a robust professional development program that includes a summer workshop, after-school meetings to discuss program nuances, faculty mentors and co-teaching.

 "Our goal is to help teachers build scientific practices and model them to the students," says Ibourk, herself a teacher. These practices include thinking deeply about a passage or critically about data. "If you start at a young age, these practices become a skill."

Fostering lifelong science learning

One of STEMGenetics' strengths is its ability to get students to link ideas in the real world with those in science.

"We want to encourage students to continue linking ideas in life with ideas in science," says Linn. "The goal is for everybody to keep learning science." However, achieving this goal is complicated as Linn notes, because "it's fairly common for people to stop learning science."

As the project moves forward, Williams and DeBarger will focus on two key directions: downward and outward. The team wants to apply what they've learned with middle- and high-school students to students in kindergarten through fourth grade.

"So much that goes on in K-4 helps prepare them for the upper grades," Williams says. "We have a nice opportunity to go downward and enhance other areas of biology."

To raise awareness among policymakers, Williams has been meeting with both state and federal legislators, encouraging them to visit classrooms and see how students and teachers are engaging in science.

"Getting people in the classroom really changes their view about science," says Linn. Adds Williams, "I really want policymakers to see kids excited [about science] and to interact with them. It's crucial to invest in children early on, not just in high school."

Williams' enthusiasm is contagious. When U.S. Sen. Debbie Stabenow (D-Mich.) visited Rob Voigt's fifth-grade classroom at Glencairn Elementary in East Lansing, Mich., she didn't want to leave. The students brimmed with exuberance as they engaged her in a genetics lesson. The same energetic scene played out again in Texas when Reps. Eddie Bernice Johnson (D-Texas) and Mark Veasey (D-Texas) visited West Intermediate in the Cedar Hill School District.

-- Maria Zacharias,
-- Susan Reiss
Investigators
Angela DeBarger
LaTonya Williams
Related Institutions/Organizations
SRI International
Michigan State University
University of California, Berkeley

NSF LOOKS AT DIFFERENT WAYS RELATED CORAL SPECIES SURVIVE CLIMATE CHANGE

FROM:  NATIONAL SCIENCE FOUNDATION 
Related coral species differ in how they survive climate change effects
Genetic data reveal a tale of two corals
December 12, 2013

Ocean waters warming from climate change are placing coral reefs in jeopardy, but a new discovery suggests that two similar-looking coral species differ in how they survive.

One withstands warmer ocean temperatures better than the other.

"We've found that a previously unrecognized species was hiding some corals' ability to respond to climate change," says Iliana Baums, a biologist at Penn State University.

Baums led the research team that included Jennifer Boulay of Penn State, Jorge Cortes of the University of Costa Rica and Michael Hellberg of Louisiana State University.

A paper describing the discovery is published today in the journal Proceedings of the Royal Society B.

"These scientists have identified a 'cryptic,' or hidden, species in a common group of corals," says Michael Lesser, program director in the National Science Foundation's Division of Ocean Sciences, which funded the research.

"The two corals have very different responses to their environment," says Lesser, "and different interactions with other organisms on coral reefs."

Coral reefs protect shorelines from battering by hurricanes and generate millions of dollars in recreation revenue each year. They also provide habitat for an abundance of species used by humans as seafood and serve as a discovery ground for new medicines.

The researchers sampled the lobe coral Porites lobata in the Eastern Pacific Ocean.

"The environment for reef growth isn't the best in the Eastern Tropical Pacific," says Baums, "due to seasonally cold waters, water chemistry that makes it difficult for corals to lay down their skeletons [low aragonite for calcification], and recurring warm waters from the El Niño Southern Oscillation."

The scientists found an unexpected pattern: two coral species that look deceivingly similar and sometimes live together in the same location.

The samples were not all Porites lobata, as the researchers initially thought. Instead, some belonged to the species Porites evermanni.

"That surprised us," Baums says. "The two look identical, and we thought they were the same coral species, but Porites evermanni has a very different genetic makeup.

"We knew about Porites evermanni--it's not a new species--but we didn't expect to find it in the Eastern Pacific. Usually it's in the waters off the Hawaiian Islands."

Boulay wondered if the two differed in the way they live. She found that Porites evermanni was less susceptible to bleaching than Porites lobata.

Bleaching happens when the symbiotic relationship corals have with single-celled algae inside them breaks apart as water temperatures go up.

"If water temperatures continue to rise, coral species that succumb to bleaching more easily will die," Baums says. "We're going to see a shift in the relative abundance, for example, of these two Porites species."

Boulay found other important differences: Porites evermanni had many genetically identical clones, which means that the species is reproducing asexually by breaking apart, although Porites lobata did not.

The clonally-reproducing Porites evermanni also, on average, housed many more tiny mussels that lived in its skeletons. The mussels poked through the surface of the corals and formed keyhole-shaped openings.

The researchers then wanted to determine the connection between Porites evermanni's ability to clonally reproduce and its interactions with mussels and with other members of the reef community.

Jorge Cortes remembered that several years ago a scientist had reported finding that some corals are a target of biting triggerfish.

"That was the missing piece," Baums says. "We realized that triggerfish were eating the mussels inside the coral skeletons. To get at the mussels, the fish have to bite the coral.

"They then spit out the fragments, and those fragments land on the ocean floor and grow into new coral colonies.

"No one had realized how important fish might be in helping corals reproduce. Now there's evidence that triggerfish attacks on Porites evermanni result in asexual reproduction--the coral fragments cloning themselves."

The other coral species, Porites lobata, has fewer mussels and reproduces sexually through its larvae.

It takes two to tango, Baums says, so usually you need a partner. "But in areas of the Eastern Pacific Ocean that are so harsh that only a few individuals can survive, it might be easier for the coral to clone itself."

As for the difference in bleaching, there are two possible explanations, the scientists believe.

One is that the symbiotic algae that live in the coral species are different, and one can withstand hotter temperatures. "Just like in your garden: the tomatoes like the heat more than the cauliflower does," says Baums.

Another possibility is that the difference is not in the symbiotic algae, but in the corals themselves.

"There's been a lot of attention given to how different symbiotic algae react to increases in water temperatures and whether, if a coral species could switch to hardier algae, it could survive in hotter waters," Baums says.

But what the researchers found suggests a different scenario. Although the two Porites corals have the same symbiotic algae species, bleaching still differs.

It may be the corals themselves instead of their symbiotic algae that contribute to bleaching.

A tale of two corals, and a tale, perhaps, of more than two factors.

-NSF-

GENES BY THE NUMBERS

Photo:  DNA.  Credit:  NIH/Wikimedia.

FROM:  NATIONAL SCIENCE FOUNDATION 

Genomic and computational tools provide window to distant past

Out of the estimated 23,000 or more genes in the human genome, about 100 of them will differ--they will be present or not--between any two individuals. Genes lost or gained over time result from evolution and adaptation, as species respond through the years to their environment and other influences.

The availability of genomic sequences now allows scientists to study the presence or absence of whole genes among individuals and between species, and the impact of such changes for evolution.

Some individuals, for example, have a sharper sense of smell than others because they have more copies of olfactory receptor genes, which allow them to detect a wider range of odors. Others, especially those who live in societies with starchy diets, have more copies of the gene responsible for producing amylase, an enzyme in saliva that breaks down starch.

"There have been lots of changes, and we want to know which ones might have been involved in human adaptation," says Matthew Hahn, an associate professor of biology and informatics at Indiana University at Bloomington. "The comparison of whole genomes has revealed large and frequent changes in the size of gene families. Comparative genomic analyses allow us to identify large-scale patterns of change in gene families, and to make inferences regarding the role of natural selection in gene gain and loss."

Using computer models and available genomic data, Hahn studies the differences in genes among humans and other species, and compares them, in order to better understand the timeline of genetic changes and adaptation throughout our history. By developing computational and statistical tools to analyze whole genomes, Hahn and his team are learning new things about the evolution of gene regulation and gene families, human genomic history, and the evolution of phenotypically important genes.

"We can't go back in time, but we can use current species to get a pretty good estimate of what the ancestors looked like, and to get some ideas of what changes occurred and the order of these changes," he says.

The scientists are examining all the genes in the genome, and focusing on differences among species, such as chimpanzees and other primates compared to humans. "There's a 6 percent difference between humans and chimps in the genes they have," he says. "In the end, after 6 million years of being separate, we don't have exactly the same set of genes as chimps. How and when did those differences occur?"

Hahn is conducting his research under a National Science Foundation (NSF) Faculty Early Career Development (CAREER) award, which he received in 2009 as part of NSF's American Recovery and Reinvestment Act funding. The award supports junior faculty who exemplify the role of teacher-scholars through outstanding research, excellent education and the integration of education, and research within the context of the mission of their organization. He is receiving about $1 million over five years.

The work could have wide-ranging applications in diagnosing and treating diseases, since many illnesses and conditions arise from genetic mutations, including the duplication or loss of important genes.

"There is a lot of interest in trying to associate these changes to human diseases," Hahn says. "There are diseases that are caused when you lose or even gain a gene, not just affecting smell or the ability to digest starch. A lot of the genes that differ in copy number are genes involved in our immune response, and these are obvious candidates for the genetic changes underlying differences in disease susceptibility among individuals. By understanding normal variation in gene copy-number, we hope to be able to better recognize changes that may be detrimental to human health."

The researchers often start by examining the differences in the number of copies of different genes among individual humans.

"The 1,000 Genomes Project (an international research effort, launched in 2008, to establish the most detailed catalogue of human genetic variation) has allowed us to study the full genetic complement of genes in a wide variety of human populations, from all of the inhabited continents," he says. "We find differences between individuals within populations and among populations, largely recapitulating the known relationships among humans.

"But we also find population-specific changes in genes that have allowed us to adapt to our surroundings," he adds. "These changes have involved both the adaptive gain and adaptive loss of genes, and are associated with important phenotypic differences among individuals."

To understand the differences shared among all humans, and that distinguish us from our ancestors, the researchers then compare the full complement of genes to those of other primates, including chimpanzees, orangutans, macaques and marmosets.

"These comparisons, and similar ones to other new genomes that are being sequenced all the time, allow us to make strong inferences about what our common ancestral genome looked like, and, therefore, the changes that have occurred along the human lineage," he says.

Such genetic changes are highly likely to have been involved in human-specific adaptations, for example, humans' increased cranium size, according to Hahn.

"Having these genomic and computational tools gives us a window into the distant past that we otherwise would not have had," he says.

-- Marlene Cimons, National Science Foundation
Investigators

LOS ALAMOS SCIENTIST TO DISCUSS IF BEHAVIOR IS PRODUCT OF DNA OR ENVIRONMENT

Photo Caption: Cells in the human body contains strands of DNA nearly 10 feet long that look like this and are packed into cellular sacks less than a millionth of an inch in diameter.  Credit:  LANL

FROM:  LOS ALAMOS NATIONAL LABORATORY

Lab’s Frontiers in Science lectures focus on epigenetics

Is behavior hardwired by DNA or a product of environment?

LOS ALAMOS, N.M., August 7, 2013—Los Alamos National Laboratory scientist Karissa Sanbonmatsu, will discuss epigenetics in a series of Frontiers in Science lectures beginning Tuesday, Aug. 13, at the New Mexico Museum of Natural History and Science in Albuquerque.

The 7 p.m. talk, titled “Nature, Nurture or Neither: The New Science of Epigenetics,” focuses on the age-old question of “nature versus nurture,” and also looks at how social interactions and environmental factors play a role in programming your DNA.

“Over the past decade, epigenetics research has and continues to unveil a whole new kind of biological circuitry,” Sanbonmatsu said. “The act of a mother nurturing or not nurturing her baby programs DNA; so literally, nurture directly affects nature in a way that nature and nurture are fused together.”

The new science of epigenetics studies how DNA is reprogrammed at the molecular level. DNA is often considered the blueprint of life, however, environmental factors and social interactions during formative years can affect genes for more than three generations. This heritable switching is called “epigenetics” and has been associated with diet, exercise, mate preference, depression, autism, eating disorders and response to abuse.

Sanbonmatsu, of Los Alamos’ Theoretical Biology and Biophysics Group, will discuss the new science of epigenetics and how it is related to a wide range of biological phenomena. Her research involves how DNA can be reprogrammed throughout life and how the missing link could be RNA molecules.

“We have been lucky enough to land on the cutting edge of this field, in the area of long non-coding RNAs, which has absolutely exploded in the last three years,” Sanbonmatsu said. “With many suggesting that the number of long non-coding RNAs may rival the number of proteins, the landscape of molecular biology may look entirely different ten years from now."

These Frontiers in Science lectures all begin at 7 p.m., at the following locations:

Tuesday, Aug. 13, New Mexico Museum of Natural History and Science, 1801 Mountain Road NW, Albuquerque

Thursday, Aug. 15, Nick L. Salazar Center for the Arts, Northern New Mexico College, 921 Paseo de Oñate, Española

Tuesday, Aug. 20, Duane W. Smith Auditorium, Los Alamos High School, Los Alamos

Thursday, Aug. 22, James A. Little Theater, New Mexico School for the Deaf, 1060 Cerrillos Road, Santa Fe.

Sponsored by the Fellows of Los Alamos National Laboratory, the Frontiers in Science lecture series is intended to increase local public awareness of the diversity of science and engineering research at the Laboratory.

THE MUTANT PIGEON GENE

Victoria Crown Pigeon.  Credit:  Wikimedia Commons.

FROM: NATIONAL SCIENCE FOUNDATION
Mutant Gene Responsible for Pigeons' Head Crests
Decoded genome reveals secrets of pigeon traits and origins
January 31, 2013

Scientists have decoded the genetic blueprint of the rock pigeon, unlocking secrets about pigeons' Middle East origins, feral pigeons' kinship with escaped racing birds and how mutations give pigeons traits like feather head crests.

"Birds are a huge part of life on Earth, but we know surprisingly little about their genetics," says Michael Shapiro, one of the study's two principal authors and a biologist at the University of Utah.

In the new study, "we've shown a way forward to find the genetic basis of traits--the molecular mechanisms controlling animal diversity in pigeons," he says. "Using this approach, we expect to be able to do this for other traits in pigeons, and it can be applied to other birds and many other animals as well."

The findings appear in a paper published this week in the online journal Science Express.

Shapiro conducted the research with Jun Wang of China's BGI-Shenzhen (formerly Beijing Genomics Institute) and other scientists from BGI, the University of Utah, Denmark's University of Copenhagen and the University of Texas M.D. Anderson Cancer Center in Houston.

"The research identified the genes contributing to variation in the avian head crest, using the domesticated pigeons that so fascinated and inspired Charles Darwin in developing his theory of natural selection," says George Gilchrist, program director in the National Science Foundation's (NSF) Division of Environmental Biology, which funded the research. "This finding illustrates the power of comparative genomics."

Pigeons were domesticated some 5,000 years ago in the Mediterranean region. Key results of this study include sequencing of the genome of the rock pigeon Columba livia, which is among the most common bird species.

There are some 350 breeds of rock pigeons--all with different sizes, shapes, colors, color patterns, beaks, bone structure, vocalizations and arrangements of feathers on the feet and head--including head crests in shapes known as hoods, manes, shells and peaks.

The pigeon's genetic blueprint is among the few bird genomes sequenced so far, along with those of the chicken, turkey, zebra finch and a common parakeet known as a budgerigar or budgie. "This will give us new insights into bird evolution," Shapiro says.

Using software developed by paper co-author Mark Yandell, a geneticist at the University of Utah, the scientists revealed that a single mutation in a gene named EphB2 causes head and neck feathers to grow upward instead of downward, creating head crests.

"This same gene in humans has been implicated as a contributor to Alzheimer's disease, as well as prostate cancer and possibly other cancers," Shapiro says, noting that more than 80 of the 350 pigeon breeds have head crests, which play a role in attracting mates in many bird species.

The researchers compared the pigeon genome to those of chickens, turkeys and zebra finches. "Despite 100 million years of evolution since these bird species diverged, their genomes are very similar," Shapiro says.

A genome for the birds, a gene for head crests

The biologists assembled 1.1 billion base pairs of DNA in the rock pigeon genome; the researchers believe there are about 1.3 billion total, compared with 3 billion base pairs in the human genome. The rock pigeon's 17,300 genes compare in number with the approximately 21,000 genes in humans.

The researchers first constructed a "reference genome"--a full genetic blueprint--from a male of the pigeon breed named the Danish tumbler.

Shapiro says the study is the first to pinpoint a gene mutation responsible for a pigeon trait, in this case, head crests.

"A head crest is a series of feathers on the back of the head and neck," Shapiro says. "Some are small and pointed. Others look like a shell behind the head; some people think they look like mullets. They can be as extreme as an Elizabethan collar."

The researchers found strong evidence that the EphB2 (Ephrin receptor B2) gene acts as an on-off switch to create a head crest when mutant, and no head crest when normal.

They also showed that the mutation and related changes in nearby DNA are shared by all crested pigeons, so the trait evolved just once and was spread to numerous pigeon breeds by breeders.

Full or partial genetic sequences were analyzed for 69 crested birds from 22 breeds, and 95 uncrested birds from 57 breeds. The biologists found a perfect association between the mutant gene and the presence of head crests.

They also showed that while the head crest trait becomes apparent in juvenile pigeons, the mutant gene affects pigeon embryos by reversing the direction of feather buds--from which feathers later grow--at a molecular level.

Other genetic factors determine what kind of head crest each pigeon develops: shell, peak, mane or hood.

Tracking the origins of pigeons

A 2012 study by Shapiro provided limited evidence of pigeons' origins in the Middle East and some breeds' origins in India and indicated kinship between common feral or free-living, city pigeons and escaped racing pigeons.

In the new study, "we included some different breeds that we didn't include in the last analysis," Shapiro says. "Some of those breeds only left the Middle East in the last few decades. They've probably been there for hundreds if not thousands of years. If we find that other breeds are closely related to them, then we can infer those other breeds probably also came from the Middle East."

The scientists found that the owl breeds--pigeon breeds with very short beaks that are popular with breeders--likely came from the Middle East. They're closely related to breeds from Syria, Lebanon and Egypt.

The research also uncovered a shared genetic heritage between breeds from Iran and breeds likely from India, consistent with historical records of trade routes between those regions. People were not only sharing goods along those routes, but probably also interbreeding their pigeons.

As for the idea that free-living pigeons descended from escaped racing pigeons, Shapiro says his 2012 study was based on "relatively few genetic markers scattered throughout the genome. We now have stronger evidence based on 1.5 million markers, confirming the previous result with much better data."

The scientists analyzed partial genomes of two feral pigeons: one from a U.S. Interstate-15 overpass in Utah's Salt Lake Valley, the other from Lake Anna in Virginia.

"Despite being separated by 1,000 miles, they are genetically very similar to each other and to the racing homer breed," Shapiro says.

"Darwin used this striking example to communicate how natural selection works," he says. "Now we can get to the DNA-level changes that are responsible for some of the diversity that intrigued Darwin 150 years ago."

The study's co-authors from the University of Utah include Yandell, Eric Domyan, Zev Kronenberg, Michael Campbell, Anna Vickery and Sydney Stringham; Chad Huff is a co-author from the University of Texas.

The study was also funded by the Burroughs Wellcome Fund, the University of Utah Research Foundation, the National Institutes of Health and the Danish National Research Foundation.

-NSF-