It looks like a loose ball of yarn, as in the picture above. In fact, it’s the genome of a common yeast (S. pombe). The human genome spends most of its time in a ball something like this. The familiar “X” shaped chromosomes occur only at the time of cell division. Like almost everything biologists are discovering about the cell, the shape of the genome isn’t arbitrary. A new study, conducted by Ken-ichi Noma and colleagues at the Wistar Institute (Philadelphia, USA) and published in the October 29, 2010 issue of Nucleic Acids Research [ Mapping of long-range associations throughout the fission yeast genome reveals global genome organization linked to transcriptional regulation ] shows that the shape of the yeast genome has real significance.

‘Shape’ in this case means the three-dimensional structure. By (stretched) analogy it’s like the mess on and in your desk. The important stuff is on top. That includes things you need every day and the current things you’re working on. Less important stuff is buried on top, or jammed into drawers where you (mostly) remember where to find them. The genome ball of chromosomes is something like this. Important genes are placed so that they can be more easily reached by transcription factors (RNA material).

To reach this conclusion Noma and his colleagues combined latest-generation DNA sequencing (equipment) with a technique known as chromosome conformation capture (3C – developed in 2002 by Dekker and colleagues at the University of Massachusetts). The 3C technique is tricky, but it does help clarify the conformation (shape); the researchers used this in conjunction with fluorescent probes to locate specific genes through a microscope. From this they were able to ‘map’ three-dimensional computer models of the yeast genome.

The advantage of their new technique is the ability to view genes as they interact with each other. They were able to identify 465 groups of genes that share a similar function (gene ontology groups). The physical relationship of genes in these groups was often significant:

“When the chromosomes come together, they fold into positions that bring genes from different chromosomes near each other,” Noma said. “This positioning allows the processes that dictate how and when genes are read to operate efficiently on multiple genes at once.”

This structure is not merely an accident of chemical attractions within and among the chromosomes – although that is certainly a part of the larger whole – but an arrangement guided by other molecules in the cell to create a mega-structure that dictates genetic function, Noma says. He envisions a scenario where accessory molecules, such as gene-promoting transcription factors, bind to DNA and contribute to the ultimate structure of the genome as the chromosomes fold together.

[Source: Wistar Institute]

Keep in mind that this research was done on the genome of yeast, a relatively simple beasty with only three chromosomes. The human genome presents a more complex challenge. Nevertheless, Noma and other researchers are turning to new techniques that give them a picture of how elements of the genome interact. The physical relationships can tell them a lot about the timing, priority, and chemical activity of various DNA processes – RNA transcription in particular. The real insights will come from future work.

In addition, work in other areas of genome sequencing will undoubtedly influence the research into the importance of genome shape. For example, a study released on the same day as the Wistar paper revealed new information about the amount and versatility of copied genetic sequences [SciTechStory: DNA redundancy: Genetic sequence copies are more prevalent and important than thought] Almost all genes have a copy in the genome, but some are more copied than others. How these copies interact will also have a physical dimension.

Scientists have identified that the enzyme telomerase prevents the shortening of telomeres. Telomerase is always present in the cell, but its activity is kept in balance by a specific protein (called TRF1), which maintains telomere length. However, over time, another protein (Fbx4) binds itself to TRF1 and degrades it so that it can no longer stop telomerase activity and the telomeres lengthen. Fbx4 is the agent of cancer.

To stop Fbx4 from affecting cells, scientists at the University of Michigan Medical School have discovered a protein (TIN2) that prevents Fbx4 from attaching to TRF1. (Sorry about the alphabet soup of abbreviations, but the real names of proteins are forbidding.) Without all the ‘which protein did what to another protein’, the key here is that nearly all cancers create immortal telomeres; part of cancer’s uncontrolled growth is that old cancer cells don’t die. If scientists can figure out how to prevent Fbx4 from working, they may find a way to treat not just a particular cancer, or a variety of cancer – but all cancers. No doubt there are limitations to this ‘universal’ application; but the concept’s power is obvious.

“In 90 percent of cancers, no matter what caused the cancer to form, it needs telomerase activity to maintain the cell. Without telomerase, the cell will die. Our work is key to understanding a detailed mechanism for how these molecules interact and how to design a drug to block Fbx4,” says senior author Ming Lei, Ph.D., assistant professor of biological chemistry at the University of Michigan Medical School.
…
“If we find a drug that can inhibit telomerase activity in any fashion, that could be a universal cancer drug.”

[Source: University of Michigan Medical School]

As is usually the case when first published, this knowledge is only a step in the direction of finding actual medical applications. The researchers are looking for other substances (peptides) that can mimic TIN2, which could lead to a long series of pharmacological studies.

Note that telomerase activity is also at the center of a very rapidly growing body of research on aging. Scientists are also working on discovery of the processes and meaning of the gradual loss of telomeres as they affect cell longevity. There is considerable anticipation in the biomedical community that the various paths of telomere/telomerase research may lead to some very important applications in both cancer (oncology) and longer lives (gerontology).

To help with the enormous task of searching nearly 3 billion DNA pairs for these switches, the team developed computer routines that looked for sequences related to heart cell development. To their great surprise they didn’t find a few switches, or even many switches, but a whole network of 42,000 potential switches involved with heart cell regulation. That’s more than twice the number of genes in the human genome.

We can finally say that there is a well-defined genetic code hardwired in our genomes that can be used to specifically identify heart regulatory elements in the vast sequence that makes up the human genome,” said Ovcharenko, of the NIH’s National Center for Biotechnology Information. “With the advance of computational methods, we can use computers to break this code, learn its encryption, and understand the signals heart cells receive to regulate genes.”
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The model is not specific to the heart; a shorter experiment in the paper demonstrated that the program can also be used to detect switches important for certain types of brain cells, and the authors note that it can be applied to any organ or tissue. And characterizing the chorus of switches that orchestrate cell development is more than just mere code-breaking; knowledge about what needs to go right can turn up clues about what goes wrong in cases of heart disease or other illnesses. One such instance of a “junk DNA” sequence causing heart disease was described yesterday in Nature – deletion of a non-coding sequence in mice dramatically affected the expression of two genes and caused the mice to die earlier than normal.

“For some of these diseases, there’s nothing wrong with the protein sequence itself,” Nobrega said. “But there may be an alteration in how and when the protein is made, which can lead to disease as well. That’s the urgency and need for this kind of work to basically crack the other codes that are present in the genome.

[Source: A fishfinder for the junk dna seas]

Finding a ‘network of 42,000 potential switches’ is like opening a can of worms – or maybe 5,000 cans, give or take. It means there are more complications to the story of ‘junk DNA’ than scientists had bargained for (by misreading these huge tracts of DNA as junk). This and other studies indicate that at least some of these segments of DNA are vital for the proper differentiation and development of cells – or conversely, may be responsible for some of the diseases caused by malfunctioning cells.

There’s a lot of work to be done, but it does seem like it’s going through an appropriate course correction.

The initial tests of the procedures were on six patients with two kinds of cancer. For each of the patients, researchers looked for a variety of gross errors in the DNA of the cancer, especially those caused by fusing of chromosomes. Larger errors, usually several, make a reliable ‘fingerprint’ of the type of cancer in that patient’s body. Detecting it later is mostly a matter of getting a positive match from fragments of tumor DNA in the blood.

The combined tests, now called the ‘Personalized analysis of rearranged ends’ or Pare, is rather expensive owing the cost of the initial cancer DNA sequencing (roughly $7,000-$12,000), but this cost is falling very rapidly. The researchers estimate that within a year or two, the Pare testing will cost no more – and probably less – than today’s CT scan (Computer Tomography). CT is also used to detect cancerous elements, but is almost totally ineffective for microscopic particles.

The Pare test is aimed at detecting cancer after surgery (or other primary treatment). It can be used to monitor for the effectiveness of treatment, for example, if many of the cancer’s signatures are discovered, it may mean there is still cancerous material that has not been treated. It can also be used for long term monitoring of cancer remission.

“Eventually we believe this type of approach could be used to detect recurrent cancers before they are found by conventional imaging methods, like CT scans,” said Luis Diaz, an oncologist at Johns Hopkins who took part in the study.

Professor Peter Johnson, chief clinician at Cancer Research UK, said: “This is another exciting step down the road towards personalised cancer medicine. The detection of DNA changes unique to individual cancers has proved to be a powerful tool in guiding the treatment of leukaemia. If this can be done for other types of cancer like bowel, breast and prostate it will help us to bring new treatments to patients better and faster than ever.”

[Source: The Guardian]

Telomeres are ‘tag ends’ of our DNA chromosomes. In the process of reproducing cells, the telomere signals where to stop transcribing genes. However, during the process of mitosis, when the DNA duplicates and a new cell is created, sometimes the telomere is cut (snipped) before the end. It becomes shorter. Eventually there may be no telomere remaining, and the cell will fail to replicate. This has been shown to relate to the aging process (SciTechStory, November 9, 2009: Study confirms telomere’s role in living longer).

Normally DNA attempts to keep the chromosomal telomeres at the proper length. In fact, it has at least one gene associated with the task: telomerase RNA component or TERC. The research shows that some people have variations, either in TERC or genes associated with it that prevent TERC from working properly. These people age early, or fall prey to diseases of old age earlier.

Professor Tim Spector from King’s College London and director of the TwinsUK study, who co-led this project, added:

“The variants identified lies near a gene called TERC which is already known to play an important role in maintaining telomere length. What our study suggests is that some people are genetically programmed to age at a faster rate. The effect was quite considerable in those with the variant, equivalent to between 3-4 years of ‘biological aging” as measured by telomere length loss. Alternatively genetically susceptible people may age even faster when exposed to proven ‘bad’ environments for telomeres like smoking, obesity or lack of exercise – and end up several years biologically older or succumbing to more age-related diseases. ”

[Source: EurekAlert]

Identification of the variant genes is, of course, just a start. Analyzing the relationship between ‘normal’ and ‘variant’ genes and how they affect the reproduction of telomeres is a next step. As with much of the work on gerontology – this avenue of approach is many years away from producing something to counteract the effects of aging.

In research published last week by Nature, an international team describes the finest map of changes to the structure of human genomes and a resource they have developed for researchers worldwide to look at the role of these changes in human disease. They also identify 75 ‘jumping genes’ – regions of our genome that can be found in more than one location in some individuals.

“The genetic ‘blueprint’ of humans is the human genome,” says Sir Mark Walport, Director of the Wellcome Trust. “But we are each unique as individuals, shaped by variation in both genome and environment. Understanding the variation amongst human genomes is key to understanding the inherited differences between each of us in health and disease. A whole new dimension has been added to our understanding of variation in the human genome by the identification of copy number variants.”

“CNV studies have made huge advances in the past few years, but we are still looking only at the most common CNVs,” explains Dr Steve Scherer of the Hospital for Sick Children, Toronto. “We suspect that there are many CNVs that have real clinical consequences that occur in perhaps one in 50 or one in 100 people – below the level we have detected. Success in the hunt for the missing genetic causes of common disease has become possible in the last few years and we expect to find more as higher resolution searches become possible.”

[Source: CellNEWS]