Philadelphia, U.S.A – Researchers studying rare genetic disorders have uncovered insights into those diseases in biological structures that regulate chromosomes when cells divide. Focusing on the cohesin complex, a group of proteins forming a bracelet that encircles chromosome pairs, scientists have discovered mutations that disrupt cohesin, causing a recently recognized class of diseases called cohesinopathies.

“We are learning more about how these genetic abnormalities that affect cohesin play a role in human development,” said study leader Matthew A. Deardorff, M.D., Ph.D., a specialist in pediatric genetics at The Children’s Hospital of Philadelphia’s Center for Cornelia deLange Syndrome and Related Diagnoses.

The research, carried out in children, cell cultures, and zebrafish, appeared May 24 in the American Journal of Human Genetics. Deardorff’s co-study leader was Frank J. Kaiser, Ph.D., of the University of Lubeck in Germany.

The cohesin complex is already known to be involved in Cornelia deLange syndrome (CdLS), a multisystem genetic disease affecting an estimated 1 in 10,000 children. The disease has a range of severity, but classically includes mental retardation, impaired growth, heart defects, feeding problems, deformed arms and hands, and distinctive facial features.

Researchers at The Children’s Hospital of Philadelphia previously were the first to discover gene mutations that cause CdLS, including forms of the disease with mental retardation and often severe limb abnormalities. The current study identified another gene, RAD21, that when mutated, causes very mild cognitive and physical impairments.

The study team first performed a genome-wide analysis of 101 children with typical CdLS and 189 children having overlapping features of the disease. None of the children had mutations in the three genes already known to cause CdLS. They identified a six-year-old boy with a deletion in a section of chromosome 8 that contains the RAD21 gene, which was known to express a cohesin protein but not previously known to cause disease. As an infant, the boy had been diagnosed with facial features similar to those of CdLS, and subsequently experienced growth retardation, but had normal cognitive development.

The researchers then focused on three additional children with deletions in RAD21 and two children with mutations within the gene, and found a similar pattern—physical features, such as short stature and distinctive facial features, overlapping with some of those seen in cohesin disorders, but with only minor cognitive delays. “These findings suggest that children who are very mildly affected may go undiagnosed,” said Deardorff.

The research team did further studies in cell cultures and a zebrafish model to investigate molecular mechanisms involved in cohesin disorders. The cohesin complex includes four proteins that join in a bracelet-like structure that surrounds sister chromatids, the identical pairs that result from chromosome duplication prior to cell division. RAD21, the protein expressed by the gene with the same name, forms a clasp that closes the bracelet. A mutated RAD21 gene weakens that clasp, impairing cohesion’s normal abilities to repair damage to DNA.

However, Deardorff added, the lab research does not currently explain the full sequence of molecular events, and further studies will investigate knowledge gaps in the process.

As the cost of whole-genome sequencing is rapidly dropping, Deardorff expects researchers to discover additional genes involved in cohesinopathies, offering further clues to how these diseases function in human development. “For now we can expect that patients with the RAD21 mutation will be less severely affected than those with classical CdLS,” he said. “As we better understand the mechanisms of these congenital diseases, we’ll continue to seek opportunities to devise more effective treatments.”

The National Institutes of Health, the U.S.A. Cornelia deLange Syndrome Foundation, The Children’s Hospital of Philadelphia and the University of Lubeck were among the organizations supporting this study.

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That our chromosomes can break and reshuffle pieces of themselves is nothing new; scientists have recognized this for decades, especially in cancer cells. The rules for where chromosomes are likely to break and how the broken pieces come together are only just now starting to come into view.

Researchers at Children’s Hospital Boston and the Immune Disease Institute (IDI) have helped bring those rules into clearer focus by discovering that where each of the genome’s thousands of genes lie within the cell’s nucleus – essentially, the genome’s three-dimensional organization – holds great influence over where broken chromosome ends rejoin, knowledge that could shed light on fundamental processes related to cancer and normal cellular functions, for example in immunity.

The study team, led by Frederick Alt, PhD, director of the Program in Cellular and Molecular Medicine at Children’s Hospital Boston and the IDI; and Job Dekker, PhD, co-director of the Program in Systems Biology at the University of Massachusetts Medical School, reported their results online on February 16 in the journal Cell.

In cancer cells, the process of chromosome rearrangement, or translocation – marked by stretches of DNA physically breaking and swapping – often results in the creation of new cancer-promoting “fusion” genes. Similarly, when a naive B cell starts to produce antibodies for the first time, it establishes its choice of target by breaking and recombining genes for antibody diversity.

“While chromosomal breaks and translocations are fundamental to many cancers, historically we’ve had no approaches to systematically study how they are generated,” said Alt, who is also a Howard Hughes Medical Institute investigator and the Charles A. Janeway Professor of Pediatrics and Professor of Genetics at Harvard Medical School. “About five years ago, our group set out to generate a high-throughput approach to address this important problem in cancer biology.”

To accomplish this goal, the Alt lab developed high-throughput genome-wide translocation sequencing (HTGTS, which maps “hot spots” in the genome where chromosome breaks and translocations are more likely to occur) and at a level of resolution not previously thought possible.  In early HTGTS studies, they found that broken chromosomes often rearrange within themselves, as opposed to sharing pieces across different chromosomes.

To probe these findings more deeply, his laboratory joined forces with Dekker’s to combine HTGTS with a method called Hi-C. Developed by Dekker’s group, Hi-C measures how all the sequences in the genome are organized relative to one another in three dimensions.

The combined data revealed several related but distinct principles of how genomic organization governs chromosome rearrangements. The first is based on the slight differences in how each cell organizes its genome compared to its neighbors (referred to as cellular spatial heterogeneity of genome organization).

While the genome is organized in an average fashion that is largely common across all cells of a population, each individual cell harbors small deviations from that average. This latter property allows many genes to be physically close to each other in just a small subset of cells, even if they are not close to each other in the majority of cells.

The second principle involves proximity. If two broken chromosome strands lie in close proximity within the three-dimensional space of a given cell’s nucleus, they are more likely to connect. This finding is of particular importance for translocations involving DNA sequences that do not break frequently, such those involved in translocations found in various non-lymphoid tumors.

The third principle applies the first two to DNA sequences that do break frequently (such as those that drive antibody gene rearrangements during B cell development). Such sequences tend to reshuffle with the same partner sequences in those subsets of cells where the partners lie physically close together, even if the partners do not within most cells. This can fuel recurrent translocations like those seen in many lymphoid tumors.

Together, the principles highlight the relationship between proximity, genomic organization, and break frequency. “Two sequences have to be broken and physically proximal to join,” Alt explains. “If two sequences are together in most cells and frequently broken, they will translocate in many cells.

If they are frequently together but one of them doesn’t break, or if they both break frequently but always lie on opposite sides of the nucleus, the chances that they will translocate are very low or zero. However, if both sequences break very frequently and are close together in a subset of cells, they will very frequently translocate in that subset, contributing to recurrent translocations.”

“Our finding that broken chromosome segments are more likely to join with other segments within the same chromosome, rather than other, more physically distant segments from other chromosomes, likely has great relevance to cancer genomes,” Alt continued. “For example, cancer treatments that cause breaks may preferentially lead to intra-chromosomal rearrangements.

It may also have relevance for ‘chromothripsis,’ a recently discovered phenomenon in many cancers in which the sequences of one chromosome become scrambled.”

The new understanding of the roles of physical spatial proximity and overall three-dimensional genome structure in chromosomal translocations opens up new avenues for deciphering how the way a cell’s nucleus is organized affects the genomic disarray found in cancer and other diseases characterized by chromosome reshuffling.

The study also shows the power of combining two high-throughput genomic assays – Hi-C and HGTGS – for studying how the organizational plan within the nucleus influences fundamental biological processes. ”We feel that our findings and the application of our approaches will provide a new lens through which to view the genomes of many different types of cancer,” Alt concluded.

This study was supported by the National Cancer Institute, the National Human Genome Research Institute, the Howard Hughes Medical Institute, the Leukemia and Lymphoma Society, the W.M. Keck Foundation, the Cancer Research Institute, and the German National Merit Foundation.

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A recent study published in Nature Methods reports that the Northern White Rhinoceros and the Drill have become the first endangered animals to have their cells transformed into stem cells. Combining conservation and modern cell biology, scientists have opened a new door for the preservation of endangered species, potentially providing a method of ensuring their survival.

Stem cells are unique cells found in all multicellular organisms that have the capability to develop into different kinds all specialized cells, ranging from blood, nerve or muscle cells. They are also able to divide infinitely to self-renew, continuing to produce more stem cells.

The northern white rhinoceros and the drill, an African short-tailed forest baboon, have become the first two endangered species to have their cells transformed into stem cells. In order to save fertilized embryos of both species, they were instead made by “re-programming” frozen skin cells of each animal.

Through this process the cells were brought back to earlier stages of development from which various forms of specialized cells could be induced. There are various uses of this research that is debated among scientists. Dr. Jeanne Loring, a world-renowned stem cell research who heads the Center for Regenerative Medicine at the Scripps Research Institute in California, is one of the researchers of the study.

She believes that creating new embryos through this process is even better than the method of cloning endangered species. According to Dr. Loring, “Cloning has not worked well for endangered species – the frequency of success is very low…here, you have the possibility to make new genetic combinations rather than cloning which simply reproduces existing animals.”

By inducing stem cells to make gametes, or eggs and sperm, test-tube babies of endangered species would become possible. Embryos created this way could potentially be raised by surrogate mothers from closely related species. Dr. Loring reports that though making gametes from stem cells is not yet routine, there are reports of it being down with laboratory animals already.

Other scientists are skeptical about this approach and believe that there needs to be more research, conservation and assistance of endangered species before turning to measures of stem cells. William Holt, a reproductive biologist at the Zoological Society of London, is involved in a collaboration called ‘Frozen Ark’, a project that collects DNA and cells from endangered animals.

He has said that scientists do not know enough about the reproductive biology of animals which is essential to support assisted reproduction programs. “With so few individuals remaining, there is little opportunity to learn more.”

Initially the applications of this research could be strictly medicinal as well. An animal suffering with some form of degenerative disease could benefit from stem cells to create replacements for the cells that have stopped working. This method has continued to be investigated for human use as well.

However, time may be running out for many endangered species that are declining in numbers due to hunting and habitat loss. The northern white rhinoceros, which the research was based on, may only have seven individuals living in captivity left in existence.

While Dr. Loring agrees that much work must still be done before stem cells can be used to save these species, she supports the research and asserts that even if the methods have yet to be perfected, stem cells offer a way of preserving genetic diversity of individual animals. Dr. Loring’s research team plans to replicate their work with the northern white rhinoceros with ten other endangered animals.

Sources:

http://www.enn.com/wildlife/article/43205

http://blog.arkive.org/2011/09/could-stem-cells-save-endangered-species/

http://en.wikipedia.org/wiki/Stem_cells

http://www.bbc.co.uk/news/science-environment-14765186

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No one likes stepping in a mess left by another person’s dog. A new company, PooPrints, has begun offering its services to owners of apartment complexes to help motivate owners to pick up after their pets. Using DNA testing, apartment complexes in Lebanon, New Hampshire and Rockville Center, Long Island are now able to match a saliva sample from all of the dogs that live in the complex with any offending dog excrement.

PooPrints is a subsidiary of BioPet Vet Labs Inc. and was created with a number of goals in mind. Keeping public grounds clean has aesthetic and cost considerations, but the most important reason for using this service is environmental. According to PooPrints’ website, an average of 276 pounds of waste are produced each year by just one dog. After combining that number with the large number of dogs owned by people worldwide, that number grows to 20 billion pounds of waste produced each year, 40% of which is not picked up.

If it is not properly disposed of, that waste can cause a number of health and environmental concerns. It can easily enter local lakes, streams, and ponds, carrying a number of diseases such as parasites, bacteria, and viruses. This creates the risk of spreading these diseases directly to humans through accidental contact with these bodies of water. The danger increases when dog excrement is left in areas where children play. Children often put their hands in their mouths, which can lead to transmission of these diseases to humans.

Reception to this new method of holding owners accountable for cleaning up after their dog’s messes has been mixed. Some people had no problem with giving out their animal’s DNA, or even paying another small fee if it means their precious pooch is still able to reside with them. After all, it only gets expensive if they neglect to pick up after their dog.

However, there are those who feel that this method of tracking is too invasive. Some people are very private, and even something as seemingly small as tracking dog excrement is seen as a violation of that privacy. It makes people worry about the possibility of more and more control being exerted over the individual until almost no rights exist anymore.

Others are concerned about malicious actions from their neighbors such as at the apartment complex in New Hampshire. The only repeat offender denied the second charge, claiming that someone else in the complex was trying to deliberately get this person in trouble. This person claimed that someone must have watched where the excrement was thrown away, removed it, and placed it back on the ground. While this claim is not completely impossible, the complex owner did not see the possibility of such malicious intent and dismissed the argument.

This creative new method of catching lazy owners may not be the only solution to the problem, but it is certainly the most interesting. Only time will tell if this catches on, becoming a common practice in gated communities and apartments, or if it is only a fad that will fade away with time.

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When sex slavery comes to mind, most people think they cannot relate. What you should relate to is that it is happening a lot closer than you think. Sex slavery is one of the biggest and less noticed issues in the United States; even though it’s a billion a year enterprise and composed of mostly teen girls. Known for occurring overseas, sex trafficking is a commercial form of slavery a person under the age of eighteen is forced into. It is led by fraud and force. Thriving each and every minute, sex slavery is becoming more and more common in the United States, which has grew into over a twenty-eight billion dollar enterprise. Even though the sex industry is one of Americas booming industries, the consequences and downfalls of the industry are ignored. There are over one million slaves worldwide and about 17,000 end up working in the United States. Trapped with no way out, sex slaves have little hope, but is there hope? Celebrities and founders are known for helping charities, organizations, and finally there is someone who took on the war against sex slavery.

Demi Moore and Ashton Kutcher launched their own non profit foundation against child sex slavery in 2007. DNA’s, the Demi and Ashton foundation, purpose is to hopefully abolish sex slavery by raising awareness through award shows, events, and communication with sex slave survivors. Phrases such as “Freedom.. its in our DNA” and “Real Men Don’t Buy Girls” are raising attention to not only the government, but celebrities. Bradley Cooper well known from the Hangover, just recently joined the Real Men Don’t Buy Girls campaign by creating a video on what real men do. Music Superstar Drake, Justin Timberlake, and even Eva Longoria have joined the fight against sex slavery. Sex Predators use social media and the internet on about 77% of deals made within sex trafficking. Demi Moore and Ashton Kutcher hope to use that against them by using Social Media to raise awareness and hopefully prevent it from happening. Getting to the “heart” of sex transactions is where DNA will try to take a stand.

Appearing on Regis and Kelly, CNN, and the Pepsi Research Project, Demi and Ashton’s goal was to reach out to as many people as possible. With Facebook and Twitter created for the organization, DNA hopes to use social media as a backfire to all sex traffickers. They are working and combining forces with other sex slavery projects, such as the Polaris Project in Washington D.C., to help Americans understand the issue of sex slavery and how it can happen to anyone, no matter your location or gender.

Most Sex Slaves are enticed by fake ads and job opportunities, such as housekeeping and dressmakers in papers in countries like Ukraine. Once arriving at there fake job, women are enslaved and forced to have sexual encounters with over twenty men a day. Most of this happens in rural areas where there is nowhere to escape. Most sex slaves are women, but the scary part is most of them are under the age of 18, with the average age for a sex slave in the United States being thirteen years old.

Every ten minutes another sex slave is trafficked into the United States, so what can you do about it? Demi Moore and Ashton Kutcher provided a three step process for people to help take a stand against sex slavery on demiandashton.org. First, join the “Real Men Don’t Buy Girls” campaign by creating a video on what real men do instead. Justin Timberlake showed the men shave instead of buying girls on his video. The Real Men videos can be viewed on the website. Next, reporting any sex slavery seen on the internet or suspicions can help end sex trafficking online. This can be done by reporting to Craigslist, Facebook, and cybertipline.com. Finally, you can help raise money and awareness by doing it in style. The DNA t-shirt can be found online at stevenalan.com and all funds go to the DNA foundation. All of these actions can finally help put an end to sex slavery in the United States. Raising awareness is the first step to stopping the traffickers. So, go out and help put an end to sex slavery by showing that Real Men Don’t Buy Girls.

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