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Trisomy 21: How An Extra Little Chromosome Throws The Entire Genome Off Balance
Occurring in about one per eight hundred births, Down syndrome - or trisomy 21 - is the most frequent genetic cause of intellectual disability. It results from a chromosomal abnormality where cells of affected individuals contain a third copy of chromosome 21 (1% of the human genome). A study conducted by Stylianos Antonarakis and his team in the Department of Genetic Medicine and Development at the University of Geneva (UNIGE) Faculty of Medicine, published in Nature, shed light on how the extra chromosome 21 upsets the equilibrium of the entire genome, causing a wide variety of pathologies.
Despite much research, the exact mechanisms causing the various symptoms associated with Down syndrome remain a mystery. According to a hypothesis called "gene dosage disequilibrium", the presence of a third chromosome 21 could influence the expression of all the other genes in the genome. That is, this extra genetic material could disrupt the process through which information carried in the genes is decoded, therefore modifying the cellular function.
Based on this hypothesis, several research groups have tried, so far without success, to identify changes in gene expression within trisomic cells and link them with symptoms seen in patients. However, as the level of most gene expression varies from one person to another, it is extremely difficult to discriminate between changes exclusively linked to trisomy 21 and those due to natural variation between individuals.
Comparing Identical TwinsAt UNIGE, Stylianos Antonarakis's team has the unique opportunity to examine the genomes of two identical twins with the exact same genetic makeup, except for an extra chromosome 21 present in one of them. Indeed, the chromosome 21 distribution error can take place during an early cellular division, after the original fertilized egg splits in two.
To compare gene expression levels between the twins, UNIGE researchers used recent, high-throughput sequencing technologies and other biotechnological tools developed within the Department of Genetic Medicine and Development, or in collaboration with scientists in Strasbourg, Barcelona, Amsterdam, and Seattle. They were thus able to eliminate interindividual variations and identify the changes in gene expression exclusively due to trisomy 21.
Small chromosome, big consequencesThe researchers noticed that the expression of genes located on all the other chromosomes (outside of chromosome 21) were disturbed in trisomic cells. "We were very surprised by this result", explains Audrey Letourneau, who co-authored this study. "It does seem that this extra little chromosome has a huge influence on the entire genome".
Generally speaking, chromosomes are divided into domains that contain genes with rather similar levels of RNA production. RNA is the molecule which transmits the information contained in DNA, before this information is translated into proteins with precise functions. In the twin with Down syndrome, the domains are sometimes over-expressed, and sometimes under-expressed when compared with the healthy twin.
By comparing their results with data previously published by other research groups, UNIGE researchers noticed that this specific chromosomes organization correlates with DNA position in the cell nucleus. Therefore, domains over-expressed in the twin with Down syndrome correspond to portions of DNA known to primarily interact with the nucleus periphery.
This study therefore shows for the first time that the DNA position in the nucleus or the biochemical characteristics of DNA-proteins interactions in the trisomic cells is modified, leading to changes in the gene expression profile. Federico Santoni, who co-authored this study, notes that, "These changes do not only affect chromosome 21, but the entire genome. The presence of about 1% of extra genetic material in the trisomic cells hence modifies the function of the whole genome, and disrupts the general equilibrium of gene expression." "We could make an analogy with climate change", adds Professor Antonarakis. "Even if the temperature rises by only one or two degrees, it will rain a lot less in the tropics, and a lot more in temperate zones. Global climate equilibrium can thus be disrupted by a tiny element."
This study opens the door to a new way of understanding the molecular mechanisms that explain the symptoms of Down syndrome. The UNIGE team will now continue its research to understand molecular mechanisms at stake, and link this disrupted gene expression with the phenotypes associated with Down syndrome. The end goal of this research is to find ways to revert the dysregulation of cellular gene expression back to normal, with the objective to correct the cellular abnormalities in this disease. Progress in this field could also be applied to other diseases with genome imbalance.
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Down Syndrome
Down syndrome results from an extra copy of the 21st chromosome. The three types of Down syndrome can result in different levels of symptom severity.
Down syndrome (sometimes called Down's syndrome) is a condition in which a child is born with an extra copy of their 21st chromosome — hence its other name, trisomy 21. This causes physical and mental developmental delays and disabilities.
Many of the disabilities are lifelong, and they can also shorten life expectancy. However, people with Down syndrome can live healthy and fulfilling lives. Recent medical advances, as well as cultural and institutional support for people with Down syndrome and their families, provides many opportunities to help overcome the challenges of this condition.
In all cases of reproduction, both parents pass their genes on to their children. These genes are carried in chromosomes. When the baby's cells develop, each cell is supposed to receive 23 pairs of chromosomes, for 46 chromosomes total. Half of the chromosomes are from the mother, and half are from the father.
In children with Down syndrome, one of the chromosomes doesn't separate properly. The baby ends up with three copies, or an extra partial copy, of chromosome 21, instead of two. This extra chromosome causes problems as the brain and physical features develop.
According to the National Down Syndrome Society (NDSS), about 1 in 700 babies in the United States is born with Down syndrome. It's the most common genetic disorder in the United States.
There are three types of Down syndrome:
Trisomy 21
Trisomy 21 means there's an extra copy of chromosome 21 in every cell. This is the most common form of Down syndrome.
Mosaicism
Mosaicism occurs when a child is born with an extra chromosome in some but not all of their cells. People with mosaic Down syndrome tend to have fewer symptoms than those with trisomy 21.
Translocation
In this type of Down syndrome, children have only an extra part of chromosome 21. There are 46 total chromosomes. However, one of them has an extra piece of chromosome 21 attached.
Certain parents have a greater chance of giving birth to a child with Down syndrome. According to the Centers for Disease and Prevention, mothers aged 35 and older are more likely to have a baby with Down syndrome than younger mothers. The probability increases the older the mother is.
Research shows that paternal age also has an effect. One 2003 study found that fathers over 40 had twice the chance of having a child with Down syndrome.
Other parents who are more likely to have a child with Down syndrome include:
It's important to remember that no one of these factors mean that you'll definitely have a baby with Down syndrome. However, statistically and over a large population, they may increase the chance that you may.
Though the likelihood of carrying a baby with Down syndrome can be estimated by screening during pregnancy, you won't experience any symptoms of carrying a child with Down syndrome.
At birth, babies with Down syndrome usually have certain characteristic signs, including:
An infant with Down syndrome can be born an average size, but will develop more slowly than a child without the condition.
People with Down syndrome usually have some degree of developmental disability, but it's often mild to moderate. Mental and social development delays may mean that the child could have:
Medical complications often accompany Down syndrome. These may include:
Screening for Down syndrome is offered as a routine part of prenatal care in the United States. If you're a woman over 35, your baby's father is over 40, or there's a family history of Down syndrome, you may want to get an evaluation.
First trimester
An ultrasound evaluation and blood tests can look for Down syndrome in your fetus. These tests have a higher false-positive rate than tests done at later pregnancy stages. If results aren't normal, your doctor may follow up with an amniocentesis after your 15th week of pregnancy.
Second trimester
An ultrasound and quadruple marker screen (QMS) test can help identify Down syndrome and other defects in the brain and spinal cord. This test is done between 15 and 20 weeks of pregnancy.
If any of these tests aren't normal, you'll be considered at high risk for birth defects.
Additional prenatal tests
Your doctor may order additional tests to detect Down syndrome in your baby. These may include:
Some women choose not to undergo these tests because of the risk of miscarriage. They'd rather have a child with Down syndrome than lose the pregnancy.
Tests at birth
At birth, your doctor will:
There's no cure for Down syndrome, but there's a wide variety of support and educational programs that can help both people with the condition and their families. The NDSS is just one place to look for programs nationwide.
Available programs start with interventions in infancy. Federal law requires that states offer therapy programs for qualifying families. In these programs, special education teachers and therapists will help your child learn:
Children with Down syndrome often meet age-related milestones. However, they may learn more slowly than other children.
School is an important part of the life of a child with Down syndrome, regardless of intellectual ability. Public and private schools support people with Down syndrome and their families with integrated classrooms and special education opportunities. Schooling allows valuable socialization and helps students with Down syndrome build important life skills.
The lifespan for people with Down syndrome has improved dramatically in recent decades. In 1960, a baby born with Down syndrome often didn't see their 10th birthday. Today, life expectancy for people with Down syndrome has reached an average of 50 to 60 years.
If you're raising a child with Down syndrome, you'll need a close relationship with medical professionals who understand the condition's unique challenges. In addition to larger concerns — like heart defects and leukemia — people with Down syndrome may need to be guarded from common infections such as colds.
People with Down syndrome are living longer and richer lives now more than ever. Though they can often face a unique set of challenges, they can also overcome those obstacles and thrive. Building a strong support network of experienced professionals and understanding family and friends is crucial for the success of people with Down syndrome and their families.
Shutting Down The Extra Chromosome In Down's Syndrome Cells
Many genetic disorders are caused by faulty versions of a single gene. In the last decade, scientists have made tremendous strides in correcting these faults through "gene therapy"—using viruses to sneak in working versions of the affected genes.
But some disorders pose greater challenges. Down's syndrome, for example, happens when people are born with three copies of the 21st chromosome, rather than the usual two. This condition, called trisomy, leads to hundreds of abnormally active genes rather than just one. You cannot address it by correcting a single gene. You'd need a way of shutting down an entire chromosome.
But half of us do that already. Women are masters of chromosomal silencing.
Women are born with two copies of the X chromosome, while men have just one. This double dose of X-linked genes might cause problems, so women inactivate one copy of X in each cell.
This is the work of a gene called XIST (pronounced "exist"). It produces a large piece of RNA (a molecule closely related to DNA) that coats one of the two X chromosomes and condenses it into a dense, inaccessible bundle. It's like crunching up a book's pages to make them unreadable and useless. XIST exists on the X chromosome, so that's what it silences. But it should be able to shut down other chromosomes too, if we could just insert it into the right place.
That's exactly what Jun Jiang from the University of Massachusetts Medical School has done: she used XIST to shut down chromosome 21. "Most genetic diseases are caused by one gene, and gene therapies correct that gene," says Jeanne Lawrence, who led the study. "In this case, we show that you can manipulate one gene and correct hundreds." It's chromosome therapy, rather than gene therapy.
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So far, the team have only done this in Down's syndrome cells, grown in a laboratory, so the technique is a very long way from any clinical use. But it's a promising first step, and other scientists are very excited. "It's an amazing paper," says Elizabeth Fisher from University College London, who studies Down's syndrome. "The fact that they have silenced the entire chromosome will really help people to dissect what's going wrong in Down's syndrome."
High-risk, high-rewardLawrence has spent years studying XIST, and has always thought about applying this work to Down's syndrome. After all, she used to provide counselling for parents whose babies are born with disabilities, and she regularly talks to families who are affected by Down's, some of whom talk at the genetics course she runs. But while using XIST to inactivate chromosome 21 was an obvious strategy, it was also a risky one.
For a start, XIST is huge—far larger than any other gene that has been deliberately inserted into a genome before. If the team got it into the right place, would it actually silence chromosome 21 without killing the cell? And if it worked, what would stop it from silencing all three copies rather than just one? "None of these challenges made the project impossible, but collectively they made it pretty improbable," says Lawrence. "We didn't know if we'd spend years not getting anything to work."
And yet, after six years of toil, it worked. Jiang used enzymes called zinc finger nucleases, which cut DNA at very specific points, to smuggle the giant XIST gene into a pre-defined spot on the 21st chromosome. She did this in cells from a boy with Down's syndrome, which had been reprogrammed into a stem cell-like state. XIST did its thing, "painting" one of the three chromosome-21s, and condensing it into a tight bundle. The genes on that copy were almost totally inactivated.
In this study, Jiang ensured that XIST only shut down one of the three chromosomes by tweaking its concentration. In the future, the team might target it to sequences found in only one of the three copies.
But does inactivating a copy of chromosome 21 achieve anything useful? Jiang saw some promising signs. For example, after XIST, the Down's cells grew more quickly, produced larger colonies, and were far better at dividing into neuron-making cells. This supports the idea that people with Down's syndrome can't make enough cells (and neurons, in particular) as they grow up.
Benefits"It's an extremely exciting development. It's somewhat surprising that it took so long for someone to apply this to chromosome 21, but the group had to overcome some very significant technical challenges," says Roger Reeves from Johns Hopkins University. "The next step will be to silence an extra chromosome in an animal, as opposed to a dish of cells." For example, they could try the technique on mice that have been bred with extra copies of chromosome 21.
Even if that worked, it would be very challenging to use the XIST technique in people—you'd need to get the giant gene into the right cells at the right stage. "I doubt that XIST by itself has the potential to become a therapeutic agent in patients," says Stylianos Antonarakis from the University of Geneva.
Lawrence agrees, but she thinks there might be exceptions. For example, many children with Down's develop myoproliferative disease, where they produce too many blood cells and run a high risk of leukaemia. If doctors saw kids with this condition, it might be possible to activate XIST in their blood stem cells, to prevent them from developing cancer. "That's one of the more likely possible uses," says Lawrence.
The study also has more immediate benefits: "It's a way of getting at the biology that underlies the different aspects of Down's," says Lawrence. The syndrome includes dozens of symptoms across many different organs, including intellectual disabilities, heart problems, leukaemia and Alzheimer's at an early age. Matching these up to the hundreds of genes on chromosome 21 has been a herculean task. "There are many studies that point to different genes but it's still a pretty confused field," says Lawrence.
Her team's work could help. Scientists could activate XIST in one of two groups of identical cells, and watch what happens to the rest of their genes. They could do this in neurons, heart cells, or any of the other tissues that are affected in Down's syndrome. They could also test drugs that are designed to alleviate the syndrome's symptoms. And, as Antonarakis says, scientists could do this not just for Down's syndrome, but for the many other disorders that are caused by unusual number of chromosomes.
Jiang's work also confirms something important about XIST—it evolved to shut down the X chromosome, but it works on all of them. "It must be acting on something that's found on all chromosomes," says Lawrence. She thinks it might recognise repetitive bits of DNA that are found throughout our genome, but have no obvious purpose.
Indeed, Lawrence suspects that her work on XIST and Down's might eventually tell us more about how the genome is organised. XIST is one of several pieces of RNA that are transcribed from the genome, but never used to make proteins. Because of its large size, it's classified as a "long, non-coding RNA" or lncRNA—a group that includes tens of thousands of members. A minority of these, like XIST, clearly help to control how other genes are used, but there's a lot of debate about what the rest do, if anything (see Carl Zimmer's post for more).
Lawrence's team have moved beyond this debate, and are one of the first to actually use a lncRNA to target and silence a set of genes. "That's one of the aspects that makes it so exciting," says Mitchell Guttman from the California Institute of Technology, who studies lncRNA and recently showed how XIST finds its way around the X chromosome. "The field will surely build upon this in the future as it continues to dissect the roles of other lncRNAs and learns more about the principles governing their localization and function."
Reference: Jiang, Jing, Cost, Chiang, Kolpa, Cotton, Carone, Carone, Shivak, Guschin, Pearl, Rebar, Byron, Gregory, Brown, Urnov, Hall & Lawrence. 2013. Translating dosage compensation to trisomy 21. Nature
http://dx.Doi.Org/10.1038/nature12394
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