Dog breeds tend to have signature traits: Border collies love to herd, greyhounds love to chase, and German shepherds make good guard dogs.

Thereā€™s a reason for that: Traits like these are highly heritable, according to a study of 101 dog breeds that identifies genetic differences in behavior.

The , published Oct. 2 in the Proceedings of the Royal Society B, points to 131 genetic variants, and offers new evidence to support what scientists have long suspected: that some of the behaviors that help characterize breeds ā€” a drive to chase, for example, or aggression toward strangers ā€” are associated with distinct genetic differences among them.

ā€œDogs present a good model for understanding what portion of the variation in their behavior is attributable to differences in genetics, and how much to their environment and experiences,ā€ said , an assistant professor of psychology at the 91±¬ĮĻ and a co-author of the study.

Most dog breed diversity has arisen in the last few centuries. People have bred dogs for their looks, but the bulk of breeding efforts have taken aim at eliciting particular behaviors, said James A. Serpell, a professor at the University of Pennsylvaniaā€™s School of Veterinary Medicine.

ā€œIf you look at the evolution of the dog, selection has been primarily for behaviors: hunting behaviors, guarding behaviors, or giving companionship to humans,ā€ said Serpell, the studyā€™s senior author.

What seems obvious ā€” that genes can influence an individualā€™s behaviors ā€” has not always been easy to support with evidence, in large part because behaviors are complex traits, the researchers said.Tendencies such as aggression, anxiety, or a compulsion to chase anything that moves are governed by many genes, not just one.

But dog breeds, being highly inbred, have allowed researchers to make progress in this area. Snyder-Mackler and the research team recognized that, if a dog breed is associated with a particular behavior that distinguishes it from other breeds, it might be easier to detect the genetic variants contributing to that behavior if that breedā€™s genome was compared to a host of others.

The team used data from C-BARQ, short for Canine Behavioral Assessment and Research Questionnaire, a survey that more than 50,000 dog owners have filled out about their pets. C-BARQ returned a result on 14 behavioral ā€œfactorsā€ about each dog surveyed, giving a measure of traits such as stranger-directed aggression, excitability, energy level, and predatory chasing drive.

For this study, the researchers pulled 14,020 of those entries that included information about purebred dogs. To look for associations with genetics, they borrowed data from two earlier studies, together representing 5,697 dogs, for which 172,000 points in the genome had been sequenced.

They found that about half of the variation in the 14 measured behaviors across breeds could be attributed to genetics ā€” a greater proportion than previous studies have found.

The traits with the highest rates of heritability ā€” in other words, those that seemed to be most influenced by genetic factors rather than environmental ones ā€” were behaviors such as trainability, predatory chasing, stranger-directed aggression and attention seeking. For these traits, genetics explained 60 to 70 percent of variation across breeds.

ā€œThese are exactly the types of traits that have been selected for in particular breeds of dogs,ā€ said Serpell. ā€œSo for trainability, youā€™re thinking of breeds like border collies that have to respond to human signals to accomplish complicated tasks; for chasing behavior you can think of something like a greyhound, which is innately predisposed to chase anything that runs; and for stranger-directed aggression you might focus on some of the guard dog breeds that are highly protective and tend to respond in a hostile way to unfamiliar people.ā€

When the researchers looked for genetic variants associated with breed differences in the 14 C-BARQ traits, they found 131 variants tightly linked to these behaviors. Some were located in genes that have been implicated in influencing behavior, including in humans. But many were unknown and provide fodder for future study.

ā€œThis gives us an encouraging start and places to look,ā€ said lead author Evan MacLean of the University of Arizona. ā€œWe have ongoing projects where weā€™ve obtained genetic and behavioral data from the same individuals, so weā€™ll be able to dive deeper into some of these traits and variants to see if the patterns we found here hold up.ā€

As a final step, the team looked to see where the genes in which key variants appeared were expressed in the body. Their analysis showed the genes were much more likely to be expressed in the brain than in other tissues.

The researchersā€™ results also leave plenty of room for individual differences and an animalā€™s environment in influencing behavior.

ā€œItā€™s important to keep in mind that we looked at breed averages for behavior,ā€ Snyder-Mackler said. ā€œWeā€™re not at a point yet where we can look at an individualā€™s genome and predict behavior. Environment and training still has a very, very strong effect.ā€

Bridgett vonHoldt of Princeton University was a co-author. The study was supported with a grant to Snyder-Mackler from the National Institute on Aging.

For more information, contact Snyder-Mackler at nsmack@uw.edu.

Adapted from a University of Pennsylvania news release.

Included with most of these services is the ability for users to download their ā€œrawā€ genetic data, which can be further analyzed using third-party apps. But little is known about how and why consumers are using these apps, or about a variety of potential risks associated with these apps ā€” such as false positives about health information or unknowingly linking a family history to an unsolved crime.

ā€œItā€™s the proverbial ā€˜wild Westā€™ of genetic interpretation,ā€ said , a 91±¬ĮĻ research scientist in the Department of Biostatistics who recently completed her doctorate in the School of Public Health. Sheā€™s the lead author of a new paper, ā€œThird-party genetic interpretation tools: a mixed-methods study of consumer motivation and behavior,ā€ that was published today inĀ .

The team surveyed more than 1,000 people who had paid to obtain their genetic profile through a service like 23andMe or AncestryDNA. Most respondents reported that they downloaded data and went on to use a third-party application like Promethease or GEDmatch.

ā€œWe found that individuals who are initially motivated to learn about ancestry and genealogy frequently end up engaging with health interpretations of their genetic data, too. This has implications for the regulation of such testing and interpretation practices,ā€ said , associate professor of bioethics and humanities, 91±¬ĮĻ School of Medicine, and the senior author of the paper.

The study found that nearly all consumers who took the survey (89%) download their raw data and more than half of those who downloaded also used third-party tools (56%) to research both genealogical and ancestry information on third-party sites.

But third-party interpretation is largely unregulated and there are potential risks for consumers, Nelson said. And there are unanswered questions: What did you consent to? What do you think your data is going to be used for?

Itā€™s often unclear what happens to the consumer data once itā€™s provided to a third-party tool. There are privacy risks, and even the chance that the genetic data may help law enforcement solve crimes. Researchers worry about accuracy, data privacy, reliability and the nationā€™s limited health resources.

False positives for health conditions can also cause emotional strain and put pressure on an already taxed health care system. People may find out about potentially serious diseases without much context or a support system.

On the other hand, third-party tools can also enable crowdsourced research and encourage people to learn about genetics.

Overall, Nelson is pleased that more people are taking an interest in genomics, but more research is needed on how people are using their information.

ā€œWe just had very little data on this,ā€ Nelson said.

, a 91±¬ĮĻ professor of bioethics and humanities, also co-authored the paper.

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For more information, contact Nelson at sarahcn@uw.edu.

Interview transcription was supported by funds from the 91±¬ĮĻ Institute for Public Health Genetics. This work was partially supported by the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI) CSER Consortium, U01 HG006507 and U24 HG007307 (Jarvik, PI). This research used statistical consulting resources provided by the Center for Statistics and the Social Sciences at 91±¬ĮĻ. REDCap and the Participant Portal at ITHS are supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1 TR002319.

In patients with chronic lymphocytic leukemia (CLL), the rate of disease growth varies widely. In a new study from the Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, Massachusetts General Hospital and the 91±¬ĮĻ, scientists report that CLL growth is apt to follow one of three trajectories: relentlessly upward, steadily level or something in between. The particular course the disease takes is tightly linked to the genetic makeup of the cancer cells, particularly the number of growth-spurring ā€œdriverā€ mutations they contain.

The , published online May 29 in the journal , contains a further insight: Genetic changes that occur very early in CLL development exert a powerful influence on the growth pattern the CLL cells will ultimately take. This raises the possibility that physicians may one day be able to predict the course of the disease by its molecular features at the time of diagnosis.

ā€œOur findings provide a framework not only for understanding the differing patterns of CLL growth in patients but also for exploring the basic biological mechanisms that underlie these differences,ā€ said Dr. of Dana-Farber, the Broad Institute and Brigham and Womenā€™s Hospital, who is co-corresponding author with of the Broad Institute and Massachusetts General Hospital. ā€œUltimately, weā€™d like to be able to tie the genotype of the disease ā€” the particular genetic abnormalities in a patientā€™s cancer cells ā€” to its phenotype, or how the cancer actually behaves.ā€

CLL is a useful model for studying the pace of cancer growth because it progresses at widely different rates from one patient to another, said Wu. In many patients, it persists at a low level for many years before advancing to the point where treatment is necessary. In others, it progresses so rapidly that treatment is required shortly after diagnosis.

To see if there were different patterns of CLL growth among patients, researchers drew on data from 107 patients diagnosed with the disease. Beginning at diagnosis, each patient underwent periodic blood tests to track disease progress over the succeeding months and years, and continued until the disease reached a stage where treatment would begin. Each test consisted of a white blood cell count, which served as a proxy measure of CLL: the greater the number of white cells within a blood sample, the greater the burden of the disease. The tests were conducted over a period ranging from two years in one patient to 19 years in another.

The serial testing allowed researchers to calculate growth rates over time for CLL in each patient. They used a statistical model to determine if the rates were consistent with various patterns of cancer growth.

ā€œWe found that some cases of CLL show exponential growth, in which it expands without any apparent limit, while other cases show ā€˜logisticā€™ growth, in which it plateaus at a fairly consistent level,ā€ said co-lead author , a 91±¬ĮĻ assistant professor of applied mathematics.

Cases that didnā€™t fit either category were classified as indeterminate.

To explore whether genetic differences were at the root of these divergent growth patterns, the researchers performed whole-exome sequencing on several CLL samples collected from each patient prior to receiving therapy. Whole-exome sequencing provides a letter-by-letter readout of the regions of DNA that encode for cellular proteins.

They found that exponentially growing CLL typically carried a large number of driver mutations ā€” those that confer a competitive advantage in growth ā€” and quickly reached the stage where treatment was called for. In contrast, logistically growing CLL had fewer genetic alterations and fewer types of alterations and progressed relatively slowly toward the level that requires treatment. Seventy-five percent of patients with exponential growth eventually warranted treatment; by comparison, 21% of those with logistic growth and 67% of those with indeterminate growth eventually required treatment.

By analyzing patientsā€™ serial blood samples collected over a period of time, researchers found that exponential CLL not only grows faster but also evolves faster, spinning off new subtypes of cancer cells, each with a particular set of genetic abnormalities. Whole-exome sequencing revealed that exponential CLL is marked by a great variety of tumor cell types and subtypes, while logistic CLL is marked by a relatively less diverse collection of tumor cells.

The information from whole-exome sequencing further enabled researchers to discover the growth rates of those subpopulations of cells within each patientā€™s leukemia that could be identified on the basis of a subset of mutations, some of them putative driver mutations. These measurements clearly revealed that many of the mutations, which were suspected to be centrally involved in CLL growth, did in fact provide subpopulations with preferential growth acceleration compared to populations lacking these putative drivers. Their results further indicate that the eventual course of CLL growth is inscribed in the genes of tumor cells early in the diseaseā€™s development.

ā€œIf the course of the disease isnā€™t altered by therapeutic treatment, the rate and pattern of CLL growth over time seems to ā€˜play outā€™ according to a predetermined set of genetic instructions,ā€ said Wu.

ā€œThe discovery that CLL growth accelerates in the presence of large numbers of driver mutations is compelling evidence that these mutations do, in fact, confer a growth advantage to cells ā€” that they truly do ā€˜driveā€™ the disease,ā€ said co-lead author Dr. of Dana-Farber, the Broad Institute and the Medical University of Vienna.

Bozic and co-lead authors and at the Broad Institute developed methods to jointly model possible phylogenetic relationships of cancer cell subpopulations ā€” which are a description of each subpopulationā€™s history and relationships to each other during the evolution of the cancer ā€” as well as integrate growth rates with subclone-specific genetic information.

ā€œCombining clinical data with computational and mathematical modeling, we show that the growth of many CLLs seems to follow specific mathematical equations ā€” exponential and logistic ā€” each associated with distinct underlying genetics and clinical outcomes,ā€ said Bozic. ā€œIntegrating tumor burden and whole-exome sequencing data allowed us to quantify the growth rates of different tumor subpopulations in individual CLLs, methodology that could potentially inform personalized therapy in the future.ā€

Co-authors of the study are: Kristen Stevenson, Oriol Olive, Reaha Goyetche, Stacey M. Fernandes, Jing Sun, Wandi Zhang and Donna Neuberg of Dana-Farber; Dr. Jennifer R. Brown of Dana-Farber and Brigham and Womenā€™s Hospital; Laura Rassenti and Dr. Thomas J. Kipps of the Moores Cancer Center at the University of California, San Diego; Daniel Rosebrock, Amaro Taylor-Weiner, Chip Stewart, Alicia Wong and Carrie Cibulskis of the Broad Institute; Johannes G. Reiter, Jeffrey M. Gerold and Martin A. Nowak of Harvard University; Dr. John G. Gribben of the Barts Cancer Institute at the University of London; Dr. Kanti R. Rai of Hofstra North Shore-LIJ School of Medicine; and Michael J. Keating of the MD Anderson Cancer Center.

The study funded by the National Cancer Institute; the CLL Global Research Foundation; the National Heart, Lung, and Blood Institute; the European Union; and the Leukemia and Lymphoma Society.

###

For more information, contact Bozic at ibozic@uw.edu.

Grant numbers: 5P01CA081534-14, 1R01CA155010-01A1, P01CA206978, U10CA180861, 1RO1HL103532-0, PIOF-2013-624924

Adapted from a by the Dana-Farber Cancer Institute.

“Thinking of arsenic as not just a bad guy, but also as beneficial, has reshaped the way that I view the element,” said first author , who did the research for her doctoral thesis at the 91±¬ĮĻ and is now a postdoctoral fellow at the Woods Hole Oceanographic Institution and the Massachusetts Institute of Technology.

The was published this week in the .

“We’ve known for a long time that there are very low levels of arsenic in the ocean,” said co-author , a 91±¬ĮĻ professor of oceanography. “But the idea that organisms could be using arsenic to make a living ā€” it’s a whole new metabolism for the open ocean.”

The researchers analyzed seawater samples from a region below the surface where oxygen is almost absent, forcing life to seek other strategies. These regions may expand under climate change.

“In some parts of the ocean there’s a sandwich of water where there’s no measurable oxygen,” Rocap said. “The microbes in these regions have to use other elements that act as an electron acceptor to extract energy from food.”

The most common alternatives to oxygen are nitrogen or sulfur. But Saunders’ early investigations suggested arsenic could also work, spurring her to look for the evidence.

The team analyzed samples collected during a 2012 research cruise to the tropical Pacific, off the coast of Mexico. Genetic analyses on DNA extracted from the seawater found two genetic pathways known to convert arsenic-based molecules as a way to gain energy. The genetic material was targeting two different forms of arsenic, and authors believe that the pathways occur in two organisms that cycle arsenic back and forth between different forms.

Results suggest that arsenic-breathing microbes make up less than 1% of the microbe population in these waters. The microbes discovered in the water are probably distantly related to the arsenic-breathing microbes found in hot springs or contaminated sites on land.

“What I think is the coolest thing about these arsenic-respiring microbes existing today in the ocean is that they are expressing the genes for it in an environment that is fairly low in arsenic,” Saunders said. “It opens up the boundaries for where we could look for organisms that are respiring arsenic, in other arsenic-poor environments.”

Biologists believe the strategy is a holdover from Earth’s early history. During the period when life arose on Earth, oxygen was scarce in both the air and in the ocean. Oxygen became abundant in Earth’s atmosphere only after photosynthesis became widespread and converted carbon dioxide gas into oxygen.

Early lifeforms had to gain energy using other elements, such as arsenic, which was likely more common in the oceans at that time.

“We found the genetic signatures of pathways that are still there, remnants of the past ocean that have been maintained until today,” Saunders said.

Arsenic-breathing populations may grow again under climate change. Low-oxygen regions are projected to expand, and dissolved oxygen is predicted to drop throughout the marine environment.

“For me, it just shows how much is still out there in the ocean that we don’t know,” Rocap said.

Saunders recently collected more water samples from the same region and is now trying to grow the arsenic-breathing marine microbes in a lab in order to study them more closely.

“Right now we’ve got bits and pieces of their genomes, just enough to say that yes, they’re doing this arsenic transformation,” Rocap said. “The next step would be to put together a whole genome and find out what else they can do, and how that organism fits into the environment.”

Co-author collected the samples and led the DNA sequencing effort as a 91±¬ĮĻ postdoctoral research scientist and now holds a faculty position at the University of Maryland. The other co-author is , a research scientist in the 91±¬ĮĻ School of Oceanography. The study was funded by a graduate fellowship from NASA and a research grant from the National Science Foundation.

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For more information, contact Saunders at jaci@whoi.edu or Rocap at 206-685-9994 or rocap@uw.edu.

For over a century, speciation ā€” where one species splits into two ā€” has been a central focus of evolutionary research. But a new study almost 20 years in the making suggests ā€œspeciation reversalā€ ā€” where two distinct lineages hybridize and eventually merge into one ā€” can also be extremely important. The , appearing March 2 in Nature Communications, provides some of the strongest evidence yet of the phenomenon, in two lineages of common ravens.

ā€œThe bottom line is [speciation reversal] is a natural evolutionary process, and itā€™s probably happened in hundreds or almost certainly thousands of lineages all over the planet,ā€ said , professor of biological sciences at University of Maryland, Baltimore County (UMBC) and co-author on the new study. ā€œOne of our biggest goals is to just have people aware of this process, so when they see interesting patterns in their data, they wonā€™t say, ā€˜That must be a mistake,ā€™ or, ā€˜Thatā€™s too complicated to be correct.ā€™ā€

ā€œWe examined genomic data from hundreds of ravens collected across North America,ā€ said , the studyā€™s first author and a former postdoctoral fellow at UMBC, who is now a postdoc at the Smithsonian Center for Conservation Genomics. “Integrating all of the results across so many individuals, and from such diverse datasets, has been one of the most challenging aspects of this study. Next-generation genomic techniques are revealing more and more examples of species with hybrid genomes.”

When Omland initially began work on this project in 1999, common ravens were considered a single species worldwide. He thought further research might uncover two distinct species ā€” perhaps an ā€œOld Worldā€ and ā€œNew Worldā€ raven ā€” but the real story is much more complicated. Omland reported the existence of two common raven lineages in 2000, one concentrated in the southwestern United States dubbed ā€œCalifornia,ā€ and another found everywhere else (including Maine, Alaska, Norway and Russia) called ā€œHolarctic.ā€

Since then, the plot has thickened. Two undergraduates in Omlandā€™s lab, Jin Kim and Hayley Richardson, analyzed mitochondrial DNA from throughout the western United States and found the two lineages are extensively intermixed. In 2012, the Norwegian Research Council provided major funding for the project and Kearns spent a year at the University of Oslo analyzing nuclear genome data.

The best explanation based on the teamā€™s analysis is that the California and Holarctic lineages diverged for between one and two million years, but now have come back together and have been hybridizing for at least tens of thousands of years.

ā€œIt is fascinating to me that this complex history of raven speciation has been revealed. For decades my students and I held and studied ravens throughout the West and never once suspected they carried evidence of a complex past,ā€ said co-author , professor of wildlife science at the 91±¬ĮĻ. ā€œThanks to collaborations among field workers and geneticists, we now understand that the raven is anything but common.ā€

How does this relate to people? Humans are also a product of speciation reversal, Omland notes, with the present-day human genome including significant chunks of genetic material from Neanderthals and Denisovans, another less well-known hominid lineage. Recent genetic studies have even indicated a mysterious fourth group of early humans who also left some DNA in our genomes.

ā€œBecause speciation reversal is a big part of our own history,ā€ Omland said, ā€œgetting a better understanding of how that happens should give us a better sense of who we are and where we came from. These are existential questions, but they are also medically relevant as well.ā€

Next steps in the current avian research include analyzing genetic data from ravens who lived in the early 1900s to investigate the potential role of humans in the speciation reversal process. ā€œGetting genomic data out of such old, degraded specimens is challenging,ā€ Kearns said, ā€œand all work must be done in a special ā€˜ancient DNAā€™ lab at the Smithsonian’s Center for Conservation Genomics.ā€

If those ravens have a similar distribution of genes from the Holarctic and California lineages as the ravens living today, itā€™s unlikely changes in human civilization over the last century played a role.

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For more information, contact Kearns at kearnsa@si.edu; Johnsen at arild.johnsen@nhm.uio.no; Omland at omland@umbc.edu or 410-455-2243; and Marzluff at corvid@uw.edu or 206-616-6883.

These are , a diverse group of organisms that includes microalgae, viruses, bacteria and archaea. They serve as the base of the marine food chain and are responsible for controlling much of the ocean’s nutrient flow and health.

But given their prevalence, very little is known about how they interact and carry out fundamental processes in the ocean, particularly in deep, low-oxygen waters where the impacts of climate change are becoming significant. In these areas, up to half of all available nitrogen ā€” a nutrient that is essential for all ocean life ā€” is lost due to microbial processes on overdrive because of warmer ocean water and less circulation.

Now, a 91±¬ĮĻ team has on a common but poorly understood bacteria known to live in these areas. By culturing and sequencing the microbe’s entire genome, the oceanographers found that it significantly contributes to the removal of life-supporting nitrogen from the water in new and surprising ways.

“If we want to understand how the oceans are working and be able to model them in any sort of predictive way, we need to more accurately understand what the inputs and outputs are,” said senior author , a 91±¬ĮĻ associate professor of oceanography. “This is an important organism that fixes carbon, is involved in nitrogen loss and is in parts of the ocean that are shifting due to climate change. We now have the first-ever culture in the laboratory and we can study its physiology.”

The were publishedĀ July 19 in the , a Nature publication.

This organism, given the name Candidatus Thioglobus autotrophicus, is present in low-oxygen waters around the world and is one of the dominant organisms in these areas ā€” between 40 and 60 percent of all cells in some regions.

Living things use oxygen for their metabolic activities, but in low-oxygen areas, bacteria and archaea have evolved to “breathe” other elements available in seawater. One of those is a chemical called nitrate which, when respired, produces gaseous nitrogen. That gas escapes to the atmosphere, effectively leaving the ocean and removing valuable nitrogen from the water.

The bacteria grown and sequenced by the 91±¬ĮĻ oceanographers have been pegged as playing a big role in removing nitrogen from the ocean, but until now scientists didn’t have a complete picture of how it happened.

“We are filling in the gaps by providing a full genome,” said lead author , a 91±¬ĮĻ doctoral student in oceanography. “Now we can talk about both what these organisms can and can’t do.”

The research team confirmed the bacteria are contributing to nitrogen loss, but in a different way than expected. More specifically, they are responsible for a key step ā€” converting nitrate to a similar chemical called nitrite ā€” which then goes on to fuel other nitrogen-removal processes. Earlier research had hypothesized that these microbes also produce ammonia, another nitrogen-containing chemical. Instead, the 91±¬ĮĻ team found that the microbes consume ammonia, essentially competing with other organisms for this nitrogen compound that is also important for growth and development.

At a global scale, the areas of the ocean where these bacteria live are getting bigger as climate change creates conditions that produce low-oxygen zones, including warmer ocean temperatures and less water circulation.

“In the very big picture, we know that different types of oxygen minimum zones that house these organisms are getting bigger and more persistent,” Shah said. “So, whatever influence these bugs have on water chemistry and the atmosphere is going to get more and more important ā€” basically, their habitat is expanding.”

Growing this organism in the lab was no easy task. The 91±¬ĮĻ oceanographers combined several techniques to culture the bacteria in as close as possible to their native ocean environment. It took almost a year to stabilize them to the point where researchers could start doing physiological experiments.

Even the experiments, however, took more time than usual, because these organisms grow much slower than most cultures grown in the lab.

“Most experiments lasted 10 to 15 days because they were growing so slowly. But the advantage is they are actually behaving very similarly to how they do in the ocean environment,” Morris said.

Shah collected the organism from a low-oxygen fjord off the coast of British Columbia from the R/V Thomas G. Thompson during a . She then used these organisms to grow identical offspring in the lab.

The researchers will look next at the role this bacteria play in the ocean’s carbon and sulfur cycles. They also recently received National Science Foundation funding to study this organism and its relatives in other low-oxygen areas around the world, including off the coast of Mexico.

of the 91±¬ĮĻ’s Joint Institute for the Study of the Atmosphere and Ocean is a co-author on this study. The work was funded by the National Science Foundation, the 91±¬ĮĻ Royalty Research Fund and the .

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For more information, contact Morris at morrisrm@uw.edu or 206-221-7228 and Shah at vs1@uw.edu or 206-685-4118.

Grant numbers: OCE-1232840, DGE-1068839

But until recently, scientists interested in these single-celled creatures knew next to nothing about their genes.

91±¬ĮĻ scientists have sequenced the complete genetic makeup of one of these algae. As they recently reported , it is only the second time that researchers have sequenced the genome of one of these ecologically important and plentiful algae, known as . Researchers hope to better understand haptophytes and perhaps transform them into an important new tool for aquaculture, biofuel production and nutrition.

“Haptophytes are really important in carbon dioxide management and they form a critical link in the aquatic foodchain,” said senior author and 91±¬ĮĻ biology professor . “This new genome shows us so much about this group.”

The haptophyte Cattolico and her team studied is Chrysochromulina tobin, and it thrives in oceans across the globe. The researchers spent years on a series of experiments to sequence all of Chrysochromulina‘s genes and understand how this creature turns different genes on and off throughout the day. In the process, they discovered that Chrysochromulina would make an ideal subject for investigating how algae make fat, a process important for nutrition, ecology and biofuel production.

“It turns out that their fat content gets high during the day and goes down during the night,” said Cattolico. “A very simple pattern, and ideal for follow-up.”

She believes that that these extreme changes in fat content ā€” even within the span of a single day ā€” may help ecologists understand when microscopic animals in the water column choose to feast upon these algae. But knowledge of how the algal species regulates its fat stores could also help humans.

“Algae recently became more familiar to the general populace because of biofuel production,” said Cattolico. “We needed a simple alga for looking at fat production and fat regulation.”

This led Cattolico to team up with , then a graduate student in the 91±¬ĮĻ Department of Genome Sciences, to sequence the complete genome of this species. Hovde wanted to work on algae in biofuel production, and Chrysochromulina was ideally suited for the task because, unlike most other haptophytes, it has no protective cell wall.

Hovde and Cattolico uncovered other surprises in the Chrysochromulina genome. Like other algae and plants, Chrysochromulina uses light to make food, through the process of photosynthesis. But they also found another gene, called xanthorhodopsin, that may let the alga harvest light and do work outside of the traditional photosynthesis pathway. Cattolico does not know how the alga uses this gene, but would like to investigate this in the future.

In addition, they identified numerous genes that appear to harbor antibiotic activity, which may be useful as the need for new antibiotics continues to rise. But Chrysochromulina is not universally against bacteria. Through this project, Cattolico and her team discovered that there are at least 10 bacterial species that appear to enjoy living near Chrysochromulina.

“That leads to some interesting questions,” said Cattolico. “Is Chrysochromulina selectively using its antimicrobials? Is it ‘farming’ beneficial bacteria in its neighborhood?”

Cattolico would like to understand how these bacteria affect which genes Chrysochromulina switches on and off. That information may pave the way for new studies of the ecology of haptophytes, which could be critical in the face of a changing global climate.

“Haptophytes are very important to our ocean health, especially with these massive ā€”sometimes toxic ā€” blooms they make,” said Cattolico. “We need to understand this issue because ecosystems are only going to get more compromised with climate change.”

The research was published Sept. 23 in the online, open-access journal PLOS Genetics. First author Hovde is now a postdoctoral researcher at the Los Alamos National Laboratory. Other 91±¬ĮĻ co-authors are , Heather Hunsperger, Scott Ryken, Will Yost, Johnathan Patterson and . and were co-authors from Los Alamos National Laboratory, as well as from San Diego State University. The research was funded by the U.S. Department of Energy, Washington Sea Grant, the National Science Foundation, the National Institutes of Health, Los Alamos National Laboratory and the Defense Threat Reduction Agency.

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For more information, contact Cattolico at 206-543-1627 or racat@u.washington.edu.

Grant numbers: U.S. Department of Energy (DE-EE0003046), Sea Grant (NA07OAR-4170007), Los Alamos (WSYN_BIO), Defense Threat Reduction Agency (CBCALL 12-LS6-1-0622), NIH (1RL1CA133831, T32 HG00035), NSF (DGE-0718124, DGE-1256082).

A substantial fraction of the Neanderthal genome persists in modern human populations. A new approach applied to analyzing whole-genome sequencing data from 665 people from Europe and East Asia shows that more than 20 percent of the Neanderthal genome survives in the DNA of this contemporary group, whose genetic information is part of the 1,000 Genomes Project.

Previous research proposes that someone of non-African descent may have inherited approximately 1 percent to 3 percent of his or her genome from Neanderthal ancestors. These archaic DNA sequences can vary from one person to another and were aggregated in the present study to determine the extent of the Neanderthal genome remaining in the study group as a whole. The findings are a start to identifying the location of specific pieces of Neanderthal DNA in modern humans and a beginning to creating a collection of Neanderthal lineages surviving in present-day human populations.

91±¬ĮĻ scientists Benjamin Vernot and Joshua M. Akey, both population geneticists from the Department of Genome Sciences, report their results Jan. 29 in Science Express. Vernot is a graduate student and Akey is an associate professor. Their paper is titled,

To check the accuracy of their approach, Vernot ran their analysis before comparing the suspected Neanderthal sequences they found in modern humans to the recently mapped Neanderthal genome obtained from DNA recovered from bone. This genome came from the paleogenetics laboratory of Svante Paabo of the Max Planck Institute for Evolutionary Anthropology in Germany.

“We wanted to know how well our predictions matched the Neanderthal reference genome,” Akey said. “The analysis showed that, after more refinement of these methods, scientists might not need a reference genome from an archaic species to do this type of study.”

The results suggest that significant amounts of population-level DNA sequences might be obtained from extinct groups even in the absence of fossilized remains, because these ancient sequences might have been inherited by other individuals from whom scientists can gather genomic data, according to Akey. Therein lies the potential to discover and characterize previously unknown archaic humans that bred with early humans.

“In the future, I think scientists will be able to identify DNA from other extinct hominin, just by analyzing modern human genomes,” Vernot said.

“From our end, this was an entirely computational project,” he added, “I think it’s really interesting how careful application of the correct statistical and computational tools can uncover important aspects of health, biology and human history. Of course, you need good data, too.”

Neanderthals became extinct about 30,000 years ago. Their time on the earth, and some of their geographic range, overlapped with humans who anatomically resembled us.

The two closely related groups mated and produced some fertile offspring, such that portions of Neanderthal DNA were passed along to the next generations. In a proposed model, this mixing of DNA could have occurred both before and after the evolutionary divergence of non-African modern humans from a common ancestral population.

It didn’t necessarily take a lot of individual hybrid offspring to introduce Neanderthal genes into early human populations. Still, Akey said that it isn’t known how many Neanderthal ancestors present-day humans have.

But past interactions between the groups, Akey noted, is probably more complicated than previously thought.

“In addition, the analysis of surviving archaic lineages points to the possibility that there were fitness costs to the hybridization of Neanderthal and humans,” Akey said.

“I think what was most surprising to me,” Vernot noted, “is that we found evidence of selection. Last year, I would have bet that a Neanderthal/human hybrid would have been as fit as a fully modern human. This was mostly because we haven’t been separated from them that long, on an evolutionary scale.”

Nevertheless, the Neanderthals were also a probable source for at least a few genetic variations that were adaptive for their human descendants. Neanderthal DNA sequences are found in regions of the genome that have been linked to the regulation of skin pigmentation. The acquisition of these variants by mating with the Neanderthals may have proven to be a rapid way for humans to adapt to local conditions.

“We found evidence that Neanderthal skin genes made Europeans and East Asians more evolutionarily fit,” Vernot said, “and that other Neanderthal genes were apparently incompatible with the rest of the modern human genome, and thus did not survive to present day human populations.”

The researchers observed that certain chromosomes arms in humans are tellingly devoid of Neanderthal DNA sequences, perhaps due to mismatches between the two species along certain portions of their genetic materials. For example, they noticed a strong depletion of Neanderthal DNA in a region of human genomes that contains a gene for a factor thought to play an important role in human speech and language.

According to the scientists, the “fossil free” method of sequencing archaic genomes not only holds promise in revealing aspects of the evolution of now-extinct archaic humans and their characteristic population genetics, it also might provide insights into how interbreeding influenced current patterns of human diversity.

Additionally, such studies might also help researchers hone in on genetic changes not found in any other species, and learn if these changes helped endow early people with uniquely human attributes.

Scientists have discovered a second code hiding within DNA. This second code contains information that changes how scientists read the instructions contained in DNA and interpret mutations to make sense of health and disease.

A research team led by Dr. John Stamatoyannopoulos, 91±¬ĮĻ associate professor of genome sciences and of medicine, made the discovery. The findings are reported in the Dec. 13 issue of Science.

Read the Ā  Also see commentary in Science, ”

The work is part of the Encyclopedia of DNA Elements Project, also known as ENCODE. The National Human Genome Research Institute funded the multi-year, international effort. ENCODE aims to discover where and how the directions for biological functions are stored in the human genome.

Since the genetic code was deciphered in the 1960s, scientists have assumed that it was used exclusively to write information about proteins. 91±¬ĮĻ scientists were stunned to discover that genomes use the genetic code to write two separate languages. One describes how proteins are made, and the other instructs the cell on how genes are controlled. One language is written on top of the other, which is why the second language remained hidden for so long.

“For over 40 years we have assumed that DNA changes affecting the genetic code solely impact how proteins are made,” said Stamatoyannopoulos. “Now we know that this basic assumption about reading the human genome missed half of the picture. These new findings highlight that DNA is an incredibly powerful information storage device, which nature has fully exploited in unexpected ways.”

The genetic code uses a 64-letter alphabet called codons. The 91±¬ĮĻ team discovered that some codons, which they called duons, can have two meanings, one related to protein sequence, and one related to gene control. These two meanings seem to have evolved in concert with each other. The gene control instructions appear to help stabilize certain beneficial features of proteins and how they are made.

The discovery of duons has major implications for how scientists and physicians interpret a patient’s genome and will open new doors to the diagnosis and treatment of disease.

“The fact that the genetic code can simultaneously write two kinds of information means that many DNA changes that appear to alter protein sequences may actually cause disease by disrupting gene control programs or even both mechanisms simultaneously,” said Stamatoyannopoulos.

Grants from the National Institutes of Health U54HG004592, U54HG007010, and UO1E51156 and National Institute of Diabetes and Digestive and Kidney Diseases FDK095678A funded the research.

In addition to Stamatoyannopoulos, the research team included Andrew B. Stergachis, Eric Haugen, Anthony Shafer, Wenqing Fu, Benjamin Vernot, Alex Reynolds, and Joshua M. Akey, all from the 91±¬ĮĻ Department of Genome Sciences, Anthony Raubitschek of the 91±¬ĮĻ Department of Immunology and Benaroya Research Institute, Steven Ziegler of Benaroya Research Institute, and Emily M. LeProust, formerly of Agilent Technologists and now with Twist Bioscience.

Stephanie H. Seiler heads the communications agency .

The Lacksā€™ family has never been compensated for the use of the cells that created a multimillion-dollar industry. And they have never had a say in how the information is used — until now.

ā€œThe generated whole-genome sequence of the HeLa cell line is a valuable resource that may lead to new biomedical insights based on research that use these cells,ā€ said Eric D. Green, director of the National Human Genome Research Institute within the NIH. ā€œWe are grateful to the Lacksā€™ family for agreeing to a framework that makes these valuable data available to researchers.ā€

The 91±¬ĮĻ study, published in the Aug. 8 issue of Nature, pieced together the complicated insertion of the human papillomavirus, or HPV, genome, which contains its own set of cancer genes, into Lacksā€™ genome near an ā€œoncogene,ā€ a naturally occurring gene that can cause cancer when altered. The researchers showed that the proximity of the scrambled HPV genome and the oncogene resulted in its activation, potentially explaining the aggressiveness of both Lacksā€™ cancer and the HeLa cell line.

ā€œThis was in a sense a perfect storm of what can go wrong in a cell,ā€ said Andrew Adey, a PhD student in genome sciences at 91±¬ĮĻ and a co-first author on the study.Ā  ā€œThe HPV virus inserted into her genome in what might be the worst possible way.ā€

Scientists had long tried to reproduce cells in a culture, but they eventually died. The HeLa cells ā€“ taken from Lacks in 1951 — however, reproduced an entire generation every 24 hours and never stopped.

HeLa cells have since been named in nearly 76,000 PubMed abstracts and are considered one of the biggest medical miracles in the last century. The cells allowed scientists to perform experiments without using a living human and led to major medical breakthroughs, including the polio vaccine, cloning and helping develop drugs for treating major illnesses such as herpes, leukemia, influenza, hemophilia and Parkinsonā€™s disease.

Just why Lacksā€™ cells replicated in a culture where others never could has been a mystery.

The authors said their study might explain ā€“ at least in part ā€“ why HeLa is unique. In addition, they discovered that the genome of the HeLa cell line, which has been replicated millions, if not billions of times, has remained relatively stable. They also said their results can help other researchers investigating cancer by studying immortalized cell lines.

ā€œWe demonstrated the value of comprehensive analysis ā€“ through what are called haplotypes ā€“ in characterizing cancer genomes and epigenomes,ā€ said researcher Jay Shendure, a 91±¬ĮĻ associate professor of genome sciences and senior author of the paper in Nature, ā€œThe haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line.ā€

Haplotypes, in short, provide a more complete description and interpretation of genomes, genetic diversity and genetic ancestry, by separating out which genetic variations are present on each copy of each chromosome. Ā Although individual human genome sequencing is increasingly routine, nearly all such genomes are unresolved with respect to haplotype. In this study, haplotypes were crucial for revealing the initial events that drove Lacksā€™ cancer.

To publish their study in Nature, the 91±¬ĮĻ team needed to make their data available to other researchers. Ā And this is where the NIH, the funder of the study, intervened and initiated discussions with Lacksā€™ family.

The genome ā€“ a string of billions of letters that detail the genetic information that makes up a HeLa cell ā€“ can be translated into personal genetic information, such as a personā€™s propensity to develop a disease, including alcoholism, Alzheimerā€™s and bipolar disorder.

In March, a team from Europe sequenced the genome of a different HeLa strain, publishing the results and depositing the data in a publically accessible website. This lead to scientific outcry sparked by an op-ed in The New York Times by the bookā€™s author Rebecca Skloot.

ā€œImagine if someone secretly sent your DNA to one of many companies that promise to tell you what your genes say about you,ā€ Skloot wrote in the March 23 editorial, The Immortal Life of Henrietta Lacks, the Sequel. ā€œNow imagine they posted your genetic information online with your name on it.ā€

Skloot noted that life insurance, disability coverage and long-term care can discriminate against people for certain conditions.

The European group later apologized and took down the data.

The controversy pushed the NIH into setting standards, which will be announced Aug. 8 as well. Ā The NIH met with members of the Lacksā€™ family and two members will now be sitting on an advisory committee within the NIH to grant approval, said Larry Thompson, chief of communications at the National Human Genome Research Institute within the NIH.

He said the younger generation of the Lacksā€™ family realizes that the technology has advanced so much that anyone can now sequence the cells to get genetic data.

ā€œThereā€™s no way to put the genie back in the bottle,ā€ Thompson said.

Wylie Burke, a renowned bioethicist and chair of 91±¬ĮĻā€™s Department of Bioethics and Humanities, said the NIH has done a great thing to reach out to the Lacksā€™ family and understand their concerns. She said many people probably donā€™t understand what it means that their genetic data will be available in a federal repository.

ā€œWe canā€™t do research without participants giving their materials,ā€ she said. ā€œWeā€™ve done focus groups and people want to understand how data is going to be used. They value that opportunity to contribute but want to be respected.ā€

Other researchers who contributed to this work include co-first authors Jacob Kitzman and Joshua Burton, and Joseph Hiatt, Alexandra Lewis, Beth Martin, Ruolan Qiu and Choli Lee.

This project was made possible through support from the National Institutes of Health and the Washington Research Foundation.

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