rotating_earth_large, July 16, 2009, by Jeff Akst  —  In a world without natural selection and no vast mountain ranges dividing populations, one might expect biodiversity to remain forever stagnant. But according to a study published this week in Nature, new species can arise arbitrarily and without provocation, challenging the widely held notion that physical isolation and selection are the driving forces behind speciation.

“So much of ecology and evolutionary biology is based on this idea of adaptive divergence leading to speciation,” said evolutionary biology Charles Goodnight of the University of Vermont, who was not involved in the work. “What this [study] is saying is that speciation may just be a result of random processes.”

In 2001, Stephen Hubbell of the University of Georgia proposed the neutral theory of biodiversity, in which the patterns of biodiversity across the globe are explained largely by chance. The idea brought into question the traditional, niche-based view of ecological community structure, which posits that organisms diffuse across a variable environment as a result of competition for resources. Hubbell’s theory, explained physicist Amos Maritan of the University of Padova in Italy, who wrote an accompanying review to the current study, demonstrated that this type of species segregation can happen “in a spontaneous way.”

However, neutral theory described the spatial distribution of species once they form, but not how or why they arise in the first place. Complex systems biologist Yaneer Bar-Yam of the New England Complex Systems Institute in Cambridge, Mass., and colleagues expanded this model to explain the process of speciation. They found that starting with a population of genetically identical individuals in a homogeneous environment, sexual reproduction, mutation, and limited dispersal led to the splitting of species — as defined by a threshold genetic distance — after just 300 generations, in the absence of physical barriers and selection.

“Traditionally, it was believed that most species arise because physical barriers prevent mating for long enough for the populations to diverge,” said Bar-Yam. Similarly, natural selection in a heterogeneous environment can explain species divergence, as spatially divided populations adapt to their local environments. “But what our work shows is that’s not necessary,” he said.

“That doesn’t mean that [geographic barriers and selection] are not playing a role,” Bar-Yam added. It’s like a spontaneous traffic jam, he explained. An accident is not necessary for traffic to back up. “It’s enough just to have heavy traffic, and you’ll have jams forming,” he said. But if there is an accident, there’s no doubt the traffic will slow. Likewise, “if there is a barrier, you expect that species will form,” he said, “[but our results suggest that] the underlying process of spontaneous formation of species is so strong that it’s overwhelming [such local] processes.”

As in previous models of neutral selection, the patterns of biodiversity estimated by this new model accurately reflected the observed patterns in nature, Bar-Yam said. From speciation rates to patterns of species richness and abundance, the model produced spatial dynamics that approximated the empirical data known for a variety of species, including plants, birds, and fish. The universality of these results raises “the possibility that something really simple could be underlying many of the patterns seen,” said physicist Jayanth Banavar of Penn State University, who coauthored the accompanying review with Maritan. Species may arise and coexist simply as a result of spatial and genetic diffusion, he said.

However, “more study is needed to assess whether the assumptions are in fact justified in real field data,” Banavar cautioned, such as how genetically similar individuals must be in order to successfully produce offspring and the distance those offspring disperse after birth. Additionally, the model must be expanded to include how species interact with each other, Maritan added, as “interactions are relevant to understanding biodiversity.”

Still, this simplified model is “a step forward,” Banavar said. It examines “speciation in a more natural way than has been done previously [while] retaining many of the patterns that [are] seen in nature. It’s the next step in considering realistic speciation processes.”


Dutch Doctors Say the Unborn may Have Memories by the 30th Week of Pregnancy,, July 16, 2009, by Lauren Cox  —  Like any prospective mom, as 21-year-old Angela Morton goes through her first pregnancy the family stories of her own baby years begin to emerge — including her mother’s trick of calming her with Aerosmith’s 1988 song “Angel” anytime she was a fussing as an infant.

“That was the song for me I guess,” said Morton. “But I’ve never even heard it since I was a baby.”

Morton’s mother may have discovered a secret infant-soothing property in Steven Tyler’s rock ballads. Or, more likely, she was was playing on an aspect of fetal memory outlined by researchers in Tuesday’s issue of the journal Child Development.

In a study of 100 of pregnant women in the Netherlands, researchers say they found evidence that fetuses have short-term memory of sounds by the 30th week of pregnancy, and develop a long-term memory of sound after that.

The researchers documented the memory by watching fetal movements with ultrasound while they played “vibroacoustic” sound to the growing baby. Five of the fetuses in the study did not move in reaction to the sound and were eliminated from the study.

But among the fetuses who did move, researchers repeated the sound until the fetus “habituated” to it and no longer reacted. Doctors let some time pass and then tested the memory of the fetus by playing the sound in intervals to see if the fetus “remembered” or recognized the sound and did not react.

The study found that by 30 weeks of age, a fetus could “remember” a sound for 10 minutes. By the 34th week a fetus may be able to “remember” the sound for four weeks.

Morton thought that same sort of memory could have been why she was calmed by Steven Tyler as an infant.

“She [Morton’s mother] used to go play it when she pregnant and sing along& then when I was fussy as a baby she used to play it and I calmed down,” she said.

Right now Morton mostly plays Christian rock and The Beatles for her baby boy Christian, who is due in November. She says she’s thinking about expanding the music collection for her baby in case there is more to this research.

Recognizing Memory in the Womb

While researchers have long documented “habituation” of the fetus — an experiment with car horns and pregnant women in the 1920s was the first to do so — child development specialists might not all agree that this is a form of memory as everyday people think of it.

“In this case, they appear to be study a very primitive type of memory called habituation or sensitization which is the tendency of animals to stop responding to a repeated stimulus,” said Mark Strauss, autism researcher and associate professor at the University of Pittsburgh wrote in an e-mail to

“It is already known that a fetus will habituate to a stimulus. Indeed, even just a single muscle cell that is stimulated by an electrical stimulus will stop contracting, indicating a type of memory,” said Strauss.

But Strauss was intrigued that the fetal memory could last that either 10 minutes, or even four weeks, as the researchers suggested.

“What is critically important to recognize, however, is that these memories are not conscious or introspective voluntary memories they way an older child or adult thinks about past experiences,” said Strauss. “They are very different and, indeed, involve lower areas of the brain that are very different from high-level brain area.”

But that difference only piques the interest of some neurologists who are looking at how memories form in the human brain from the first moments in life through the later stages of dementia.

“It’s interesting to say that babies have some memory, some intake of things, even if they’re born premature. There’s a lot of movement towards making intensive care units friendlier, controlling noise for example, for premature babies,” said Dr. Paul Graham Fisher, a professor of neurology at Stanford University.

“Early kids can lie down memories, but what’s going to be the really cool thing is how do they do it,” he said. “How do stem cells, the very early cells in the brain, encrypt memory in the brain?”

Keeping the Peace in the Womb

While researchers strive to figure out the mechanics of memory, child development experts say studies like these may encourage parents to keep the earliest of environments in mind.

“Beyond ensuring healthy nutrition, research of this type, along with the work of others regarding infant memory should help us understand the importance of a safe, relatively low stress environment during this very sensitive period of development,” said Rahil Briggs, a pediatric psychologist at the Montefiore Medical Center in New York City.

“It really is as if there is a recorder going on in there from the beginning, and we’ve got to be careful about what it’s recording,” she said.


Gene Study Shows Earlier Signs of Memory Loss, Hints at Earlier Intervention,, July 16, 2009, by Joseph Brownstein  —  For people with a common genetic variation, researchers have discovered signs of the possible onset of Alzheimer’s before a patient would be clinically diagnosed by a doctor.

In people with the ApoE4 gene variation, one previously implicated as affecting the likelihood of Alzheimer’s, researchers have been able to pinpoint some signs of memory loss beginning in the person’s mid- to late-50s — without the patient having full-blown Alzheimer’s disease or dementia.

“[One could argue] we really captured for the first time the onset of Alzheimer’s disease,” explained Dr. Richard Caselli, a neurologist at the Mayo Clinic in Scottsdale, Ariz.

“What’s passing as normal aging itself correlates with the most common genetic risk factor for Alzheimer’s disease,” he said, adding that the symptoms are noticeable in a clinical setting, but not in everyday life.

“It’s not the sort of thing that you can look at somebody or they can look at themselves and know.”

Researchers caution that when in interpreting the findings, one should keep in mind that people who had shown some memory loss were still functioning normally and having the gene did not impair anyone at an earlier age.

For the study, researchers followed and looked at data for 815 subjects, 317 of whom had the ApoE4 variant. They administered a variety of neuropsychological tests to the patients and found that memory was affected in some patients with the ApoE4 gene as they reached their late 50s and into their 60s.

The study results are published in the most recent issue of the New England Journal of Medicine.

“You can start to see cognitive impairment, memory decline, in ApoE4 carriers early, although they’re not clinically diagnosed with dementia or mild cognitive impairment,” said Rudy Tanzi, director of the genetics and aging unit at Massachusetts General Hospital. “I think it’s important that this study has elegantly confirmed what many of us have been dancing around for years.”

But researchers caution that ApoE4 is not a gene that by itself determines the fate of a person’s brain.

“ApoE4 is not sufficient to give you the disease. It works together with not only your lifestyle and environmental factors&but it works together with other genetic factors, some of which confirm risk&but some of which confirm protection,” said Tanzi.

Dr. Richard Lipton, professor and vice chair of neurology at the Albert Einstein College of Medicine concurred.

“Not everyone who carries the E4 gene develops Alzheimer’s disease,” he wrote in an e-mail to ABC News. “We have 100-year-olds in one of our studies who carry the gene and have no evidence of memory decline. And not everyone who develops Alzheimer’s disease has an E4 gene; only about half of people who develop Alzheimer’s disease carry an E4 gene.”

Genetic Testing for an Alzheimer’s Future?

While another Alzheimer’s study published in the most recent New England Journal issue found patients who underwent testing for the ApoE4 gene and received counseling handled it well, researchers generally advised against getting such a genetic test.

“I do not recommend that people go out and have this test,” said Caselli. “I think it’s an important tool for research right now, but as of this moment there isn’t any routine benefit people would get from this information.

“There’s many different considerations&unless there’s a compelling reason a person should know [such as research], then no, I would not recommend that people go out and get this test.”

Caselli noted that a number of problems could arise from getting the test, in the forms of employer discrimination, insurance discrimination, and children who might learn of an increased risk to themselves.

“I argue that until we have the entire set of genetic risk factors for Alzheimer’s&and look a them as a group, in the end you’re cumulative risk involves hundreds, if not thousands of risk factors,” said Tanzi, whose own research has focused on finding all of the genes connected with Alzheimer’s.

He notes, however, that a study such as this could be easily misinterpreted.

“You don’t want to risk that kind of discrimination when it’s not really warranted. It’s not warranted,” Tanzi said. “Just because you carry an E4, you’re not cognitively different from anyone else. Importantly, there’s no correlation between ApoE4 and intellectual achievement.

“There is no effect on E4 as measure by your occupation or educational success or outcomes. It’s just saying the disease is starting before you see symptoms, but it’s pretty close to when the symptoms occur.”

The Next Step

Caselli said one effect of this study is that it adds to the knowledge that Alzheimer’s might affect the elderly, but does not begin then.

“The age group that we’re talking about is pre-retirement,” he said.

While people may typically think of Alzheiemr’s as an “old person’s disease,” he said, “actually, the earliest stages of it happen where we’re still employed.

“It’s important to keep in mind that this could start to have an effect on people in very intellectually demanding jobs as they age, as they try to remain employed.”

Most research going on, Caselli said, is targeted at people who are much older. He believes that as we move towards experimental trials for prevention, “we really have to shift the spotlight to a younger age.”

But while the disease might have its roots in that age group, he said, it does not generally have its symptoms then.

“I’m hoping that we don’t generate a lot of panic in a lot of people in this age group,” said Caselli.

“The dangerous way to look at it is to say people who carry E4 are cognitively deficient, even earlier in life,” said Tanzi. “You don’t want to invite discrimination when they’re in the prime of their lives, when they’re just fine.”, July 16, 2009, WASHINGTON (Reuters) – President Barack Obama designated $1.825 billion on Thursday for emergency use to fight the new pandemic of H1N1 swine flu.

The money will go to buy vaccine ingredients to help health officials plan for immunization campaigns and to help get the vaccines approved at the U.S. Food and Drug Administration, Obama said in a letter to House of Representatives Speaker Nancy Pelosi.

The money comes from $7.65 billion that Congress already appropriated to the Department of Health and Human Services for the swine flu pandemic.

Google, July 16, 2009, WASHINGTON (Reuters) – The influential American Medical Association on Thursday said it supported the healthcare overhaul legislation moving through committees in the Democratic-led House of Representatives and urged its approval.

“This legislation includes a broad range of provisions that are key to effective, comprehensive health system reform,” AMA executive vice president Michael Maves wrote to the House committee leaders.

In particular, he said, the doctors’ group backs the insurance market reforms that seek to expand healthcare coverage and the proposed health insurance exchange. In this exchange consumers would choose between private insurers and a public plan.

He also cited the ban on exclusion from coverage for pre-existing conditions and an increased reliance on primary care doctors.

On federal healthcare programs, the AMA said it welcomed the changes in Medicare health care for the elderly which would include a repeal of the sustainable growth rate formula and the expansion of Medicaid for the poor.

“This year, the AMA wants the debate in Washington to conclude with real, long overdue results that will improve the health of America’s patients,” he wrote.


Tracking the movement of DNA and the location of structural proteins in the nucleus reveals that DNA placement makes the difference between activity and silence. SUSAN GASSER, director of the Friedrich Miescher Institute for Biomedical Research in Basel, describes her decades-long quest to understand this fundamental process.

Tracking the dance of DNA and structural proteins within the nucleus shows that placement makes the difference between gene activity and silence.

 20090717-1, July 16, 2009, by Susan M. Gasser  —   What’s true of the best architecture is also true of cellular structures: form follows function. We biologists often take this mantra to an extreme, searching for the function of a molecule or gene without much consideration of its structure, its physical location, or its movement within the cell.

One of the things that attracted me to the field of nuclear organization was the need to understand not only how structural proteins interact with DNA, but also where they bind and why. I wasn’t interested in single-gene regulation, but the form that the entire genome takes-not only in metaphase, when chromosomes assume their characteristic X shape, but also during interphase, when the business of cellular function gets done. Over the last 10 years, we turned to quantitative imaging of GFP-tagged chromosomes, genes, and proteins in living cells. By probing the organization and dynamics of the genome within the nucleus, we have been able to discern much about the elegant choreography that links form to function.

In 1983, when I started working in the field, chromatin research was relatively sleepy. It had been a decade since the nucleosome had been shown to be the basic unit of genome organization-a building block containing eight histones around which 147 bp of DNA is coiled. We also knew that the basic nucleosomal fiber persisted throughout the cell cycle, from metaphase through interphase, yet most scientists thought histones were nondescript-identical units without function beyond that of rendering DNA generally less accessible than it is in a bacterium. We proposed that histones served as “general repressors” of DNA-based functions. At the time, only a few scientists pursued the arcane idea that modification of histone proteins, then mostly acetylation, might be functionally significant. In the early 1980s, talks on histone modifications were in late evening sessions; few thought it cutting-edge work.

Yet histone modification eventually captured everyone’s imagination. Once researchers showed that mutations that removed N-terminal tails or changed specific residues could provoke striking phenotypes in yeast, few could contest the importance of these proteins and their modifications. Not only did mutations in histones change the folding of the DNA, but they could affect which genes were being transcribed and when cell division occurred.

Today almost everyone who works on transcription studies chromatin. Researchers have made antibodies to nearly every modification found on histones, both in cores and tails. The field has come to accept that there exists a histone code (although it is more like a series of signposts than a code per se) that influences genome function. But the structure of the genetic material within the nucleus is controlled by much more than histones. I’ve spent much of my career working out the other players that give this essential organelle its form-and, subsequently, its function.


My interest in the structure of the nucleus began when I started as a postdoc in Ulrich Laemmli’s lab at the University of Geneva in 1983. As young college graduates, my husband and I had decided to try something other than the usual hop from the halls of the University of Chicago to another graduate school in the United States. We moved to Switzerland, where my husband had roots, to pursue our PhDs; his was in logic and mine in molecular biology. This took me to Jeff Schatz’s laboratory at the Biozentrum of the University of Basel, a place teeming with excitement and excellent science. After my PhD, I joined Laemmli’s lab, which was known for its work on mammalian metaphase chromosomes, as well as phage assembly and the invention of the SDS polyacrylamide gel. In his lab, I started looking at how the nucleus organizes DNA by seeking proteins, other than histones, that were important in packaging the genome.

The structural proteins of the nucleus are distinctly different from those of the cytoplasm. Neither actin filaments nor microtubules give the nucleus or the genome its shape. For that reason we disliked the term “nucleoskeleton,” which implied a cytoskeleton-like organization. Laemmli was interested in finding proteins that helped package DNA into loops that would be transcribed in interphase nuclei, but then further compacted to form metaphase chromosomes. We looked for factors that might help organize enhancers, promoters, genes, origins of replication and other control elements, indexing the nucleus to facilitate its function. Our goal was to find out how the genome was spatially-and not just linearly-organized.

In Laemmli’s lab, I developed the biochemical skills that I later put to use when I started my own lab 3 years later at the Swiss Institute of Experimental Cancer Research (ISREC) in Lausanne, up the lake from Geneva. To carve out my own niche, I returned to the organism I’d worked on with Schatz-budding yeast-and applied to it the techniques I’d used on Drosophila and HeLa cells as a postdoc. We started by isolating the DNA fragments that were bound to structural proteins after extraction of histones. We reasoned that if we could find the tracts of DNA that were tightly associated with nonhistone proteins, we might get our hands on both proteins and DNA with structural or organizational roles. By working backwards from these sequences to the proteins that bound them, we felt we could identify and then disrupt the genes for nonhistone proteins that might be involved in genome folding.


We tagged one chromosomal locus-not located near telomeres-and used a confocal microscope to watch its movement in 5 second increments within the stained perimeter of the nucleus.

One protein that emerged in large quantities from these searches was the repressor activator protein 1 (Rap1)-a protein that David Shore had just identified in Kim Nasmyth’s laboratory at the Medical Research Council in Cambridge, as a silencer and promoter binding factor. It was unclear how Rap1 worked, but we soon showed that Rap1 could bind the repetitive telomeric DNA, which caps the ends of the chromosome.

David Shore showed that Rap1 interacted with the silent information regulators Sir3 and Sir4, and proposed that the Rap1-Sir interaction rendered tracts of DNA transcriptionally silent. But it was still a confusing picture. We didn’t understand what exactly telomeres had to do with silencing at a non-telomeric loci, but given the interactions of these proteins, it looked as if these relatively inert repeats of DNA might contribute more than simply capping chromosome ends.

In Lausanne I was joined by Thierry Laroche, an outstanding microscopy technician, whom I had met in Geneva. He pioneered our efforts in high-resolution fluorescence microscopy to examine the distribution of Rap1 and of telomeres and silent chromatin in yeast nuclei. At that point, no one really believed that you could see structures within the nucleus of yeast, as the nucleus itself is only 2 microns in diameter. But with affinity-purified antibodies and a lot of patience, we could discern discrete spots of Rap1 staining at the rim of the yeast nucleus. Given the abundance of Rap1 binding sites in the telomeric repeats, we deduced that the Rap1 foci were clusters of telomeres. This was exciting because it suggested to us that the interphase nucleus wasn’t just a jumble of DNA. While it didn’t have membrane-bound organelles, it was beginning to look like the nucleus might have domains that performed very specific functions.


While the Sir4 protein was the first protein we found to tether telomeres to the nuclear envelope, the Ku protein turned out to be an even more critical anchor. Ku tethers telomeres by binding Mps3 which spans the inner nuclear envelope, allowing telomeres to cluster. Ku also recruits Sir4 to the chromosomal ends. Together with Sir2 and Sir3, Sir4 forms a complex that spreads along the proximal chromatin by binding histones and DNA. The condensed chromatin stays at the nuclear envelope through an interaction of Sir4 with Enhancer of silent chromatin 1 (Esc1).
Source: Biochim Biophys Acta, 1677:120-31, 2004

With those results I was able to convince Bernhard Hirt, the director of ISREC, to purchase one of the first confocal microscopes made by Zeiss. Using 3D laser scanning microscopy, our conclusions were irrefutable: telomeres and Rap1 were clustered in foci at the nuclear envelope.1,2 At the same time, we used antibodies that Lorraine Pillus at the University of California Berkeley had raised to the yeast Sir proteins, and found that these formed identical foci. We examined Rap1 spots in a range of mutants, including strains that lacked either SIR3 or SIR4 themselves. The absence of Sir proteins had a profound effect on Rap1 localization, as well as on the distribution of the other components of silent chromatin: when SIR silencing was compromised, we could no longer see telomeric foci, visualized by Rap1 and the remaining Sir proteins, at the nuclear periphery. This meant that silent domains, notably subtelomeric genes, were indeed selectively sequestered at the nuclear envelope. It also implicated Sir proteins in tethering the telomeres to the nuclear membrane (see graphic above).3 It was exciting to see how microscopy could validate concepts we had discussed and tested biochemically for many years: we could see a chromatin domain, decipher its structure, and visualize the location of particular proteins. High-resolution microscopy provided an open door and a powerful tool for analysis-as useful as Laemmli’s gels had been in the 1980s.

To determine whether the telomeres were actually tethered to the nuclear membrane rather than simply excluded from the nuclear center, we combined genetics and biochemistry, and cross-checked results by microscopy. We fished for other proteins that could interact with Rap1, Sir factors, and also to origins of replication, which were also tightly bound to an insoluble fraction of histone-depleted yeast nuclei. Over the years, we have developed a range of assays that allow us to determine accurately the location of proteins and sequences within intact nuclei. Using these, we dissected the pathways that anchor DNA to the membrane and to nuclear pores, which allow proteins and RNA to pass through the double lipid bilayer of the nuclear envelope.

By probing the organization and dynamics of the genome within the nucleus, we have been able to discern much about the elegant choreography that links form to function.

An intriguing picture was beginning to emerge in the early 1990s. Repetitive DNA domains like telomeres seemed to play key roles in genome organization, as well as in setting up local domains of transcriptional repression. We knew that telomeres were capable of silencing genes directly adjacent to their repetitive regions, but we started to think that a spatial proximity to telomeres-and not only linear proximity-might promote repression. Amanda Fisher in London had similar thoughts about the repression of genes in proximity to centromeric repeats-the centers of the X-shaped chromosome-during B-cell development. Her work showed that the developmentally regulated genes were often brought near centromeric repeats when they were repressed. Collectively, our work showed how nontranscribed repetitive DNA-such as that found at telomeres and centromeres-can influence nuclear organization and gene expression.4

To return to the role of histone modifications in this repression, we teamed up with Michael Grunstein’s lab at the University of California, Los Angeles, who had been testing the effect of histone tail mutants on Sir3 and Sir4 binding in vitro. A postdoc in his laboratory, Andreas Hecht, had shown that a point mutation on the tail of histone 4 affected silencing by impairing Sir3 binding. Thierry and I then showed that the same point mutation caused the dispersion of Sir proteins and Rap1 from the telomeres. This suggested that the Sir proteins were involved in tethering telomeres, and that the deacetylated histone tails were important for the binding and spreading of Sir proteins.5

At that point, we felt that we had a firm understanding of the sequestration of Rap1 and Sir proteins by telomeres, and the fact that the foci helped nucleate Sir-mediated repression, which then was propagated by contact with deacetylated histone tails. We found that mutations that interfered with the binding of Rap1 to Sir4, and/or mutations of the histone tail modification sites, disrupted both nuclear organization and silencing.


Yet we had one curious finding from our immunofluorescence studies of sir mutations that we couldn’t quite explain. In cells lacking Sir proteins, only about 50% of the telomeres released their hold, suggesting that other proteins that we hadn’t yet found were also involved in tethering. Over the next several years, my lab sought to identify additional candidates that served as anchors for telomeres at the nuclear membrane. A breakthrough came when we invited Edward Louis, then at the Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, to give a seminar. Ed had a curious finding of his own. He had found that yeast telomeres did not recombine efficiently with internal sequences, although they recombined among themselves just fine. During that visit, we suggested that telomeric tethering might restrict the freedom of movement that telomeres would need to interact with internal sequences, and at the same time might favor exchange with other telomeres. Ed had performed a screen for mutations that released telomeres and isolated genes encoding the yKu70 and yKu80 proteins. This was surprising but also tantalizing: the Ku protein plays a key role in nonhomologous end-joining in all eukaryotes by binding free DNA ends, just like one finds at telomeres.


Here we visualize the nucleolus (red), the yeast spindle pole body (white) and the nuclear envelope (green ring) and track GFP-tagged telomere (brighter green spot) with live imaging. The cells shown here are at different stages of the cell cycle and illustrate the organization within the nucleus.

We immediately tested telomere positioning in mutants that lacked the yku70 and yku80 genes and sure enough, telomeres released their grip on the nuclear envelope and Sir proteins were dispersed from the telomeres.6 A series of papers were published in 1998, implicating yKu in telomere biology, and like so many discoveries, many labs came upon yKu as a key telomeric factor at once. It also made us curious as to the relationship of telomeres to double-strand break (DSB) repair. We found it hard to imagine that yKu could both protect telomeres from recombination by sequestering the chromosomal end and promote end joining, but it does just that.

To figure out whether there was any overlap in mechanisms used to heal breaks and those that tether telomeres, we induced DSBs in a strain in which we could follow Sir proteins by chromatin immunoprecipitation (IP) and live imaging. Amazingly, upon inducing a break, Sir3 and Sir4 were released from telomeres, as was yKu, and both bound near the break. The kinetics of recruitment were very different, however: yKu bound immediately and transiently to the DSB, while Sir proteins accumulated only after 2 to 4 hours, which was so long (on a yeast scale) that we figured that the cell had probably given up on trying to repair the cut (see The Silent Chromatin Anchors graphic).7 Telomere-bound yKu and Sir proteins were also released when the cell arrested its progression to mitosis and it was shown by others to be provoked by other types of genomic stress as well. This led to the model that the telomere serves as a reservoir for proteins that could-under appropriate conditions-be released to function elsewhere. Recently, we have pursued this concept further, and have shown that Sir proteins “released” from telomeres can still function. They repress promiscuously at internal genes, altering patterns of gene expression,8 as part of a survival mechanism. Indeed, the redirected Sir proteins repress genes involved in ribosome biogenesis.

We could see the nuclear core was full of rapidly moving chromatin, a riot of movement that could be described biophysically as a constrained random walk.

Our studies of telomere and Sir protein foci in yku mutants showed that yKu might provide an anchor for telomeres even in the absence of silencing. This was nailed in a series of papers in which we monitored telomere position by live microscopy. We came to the conclusion that there are partially redundant pathways, involving yKu and Sir4, that promote telomere tethering at the nuclear rim both in the absence and presence of silent chromatin. The yeast nucleus now seemed to be divided into zones of concentrated Sir proteins, which both promoted their own attachment or helped yKu anchor them, and regions depleted of Sir proteins, in which promoters were more likely to be transcriptionally active.


Filming the movement of telomeres and other tagged loci in real time was pioneered by a graduate student in my lab, Patrick Heun.   Under the careful tutelage of Thierry Laroche, the two watched and filmed, optimizing conditions so as not to perturb cell growth or induce damage by the imaging itself. We, of course, confirmed that telomeres were enriched at the nuclear envelope, but could also see telomeres stray away, albeit never for very long. The biggest surprise came from studying loci that were located at the center of the nucleus in transcriptionally active zones: We could see the nuclear core was full of rapidly moving chromatin (see graphic on p. 34 and 35, a riot of movement that could be described biophysically as a constrained random walk. This means that movement goes in random directions, yet the ultimate limits of movement are restricted. John Sedat at the University of California, San Francisco had observed the limited movement of a centromere proximal gene in yeast, and had proposed this kind of movement. Building on his work, we plotted the dynamics of many loci under various conditions, showing that telomere tethering could impair but not eliminate movement, and that chromatin dynamics fluctuated both with stages of growth, the cell cycle, and metabolic state.


When the nucleus detects a DNA double-strand break, the Ku and Sir proteins are partially released from telomeric chromatin (aqua), which leads to a partial release of the telomeres themselves. The Ku protein is rapidly recruited to the breakpoint (not shown), but soon-if the damage cannot be repaired by end-joining or recombination- the DNA shifts to the nuclear pore. There, the StUBL protein helps channel the DNA to an alternative pathway of repair.

We used this tool to further our study of double-strand breaks. A postdoc, Karine Dubrana, GFP-tagged a site at which a double-strand break could be induced, and saw that after a while these cut sites traveled to the periphery. However, they did not shift to telomeric foci as we expected. (The telomeric environment might, after all, have helped heal or protect the DNA ends from exonuclease or recombination.) Rather, the irreparable DSB ended up at nuclear pores, where they were worked on by a bizarre new enzyme complex called a StUBL. The StUBL recognizes one post-translational modification on proteins (SUMO) and adds another (UB) to target modified proteins for degradation. We inferred that at pores, StUBL targets one or more proteins for degradation, since the proteasome-the cell’s degradation and recycling machine-is also recruited to irreparable DSBs at the pore (see graphic above). Genetic analysis showed that StUBL was working on the same pathway as factors for DSB repair, and might even be in a shared complex. Based on our results, our best guess of how DSBs are trafficked in the nucleus is that they shift to the nuclear envelope for processing and are then channeled either into a pathway of recovery or degradation.

DNA thus seems to have a reason for moving. The nucleus is clearly as compartmentalized as the cytoplasm despite an absence of membrane-bound organelles. With sites along the nuclear envelope for silencing, DNA repair, and gene expression, we can imagine it like a ballet studio, with some dancers warming up on the bars at the periphery, waiting for their turn to dance, while those at the center sweep across the floor in tune with their music. A strained muscle, and the dancer is back to the edge for repair. Intriguing are genes that dance at different tempos-perhaps we will find that they listen to histone modifications, as well.

Susan M. Gasser is the director of the Friedrich Miescher Institute for Biomedical Research in Basel, and is a professor of molecular biology at the University of Basel.