Alu is an example of a so-called “jumping gene” – a transposable DNA sequence that “reproduces” by copying itself and inserting into new locations throughout the genome. Alu elements are classified as SINEs, or Short INterspersed Elements. All Alus are approximately 300 bp in length and derive their name from a single recognition site for the restriction enzyme AluI located near the middle of the Alu element. Alus are also classified as retrotransposons, because they need a special enzyme (a reverse transcriptase) to produce mobile copies. However Alus are “defective transposons” as they depend on the enzymes of other transposons for mobility, like the best characterized retrotransposon family called L1, a Long INterspersed Element (LINE).

Once an Alu inserts at a chromosome locus, it can copy itself for transposition, but there is no evidence that it is ever excised or lost from a chromosome locus. So, each Alu insertion gets fixed through evolutionary time. Like genes, Alu insertions are inherited in a Mendelian fashion from parents to children.

First discovered in corn about 60 years ago by Nobel laureate Barbara McClintock of Cold Spring Harbor Laboratory, jumping genes are now known to make up more than 40 percent of the entire human genome and may play an important role in genome evolution by creating new mutations and gene combinations.

Until this recent study, L1 retrotransposition was assumed to take place during early development mainly in germ cells (ovaries and testes) and rarely in somatic tissues (non-sex cells). Now researchers from the Roslin Institute near Edinburgh, Scotland, have capaciously mapped retrotransposon insertion sites in the genomes of normal human brain cells.

The researchers used state-of-the-art DNA sequencing technology to identify retrotransposons in brain tissue samples taken at postmortem from three individuals who were healthy when alive and had no neurological disease, nor signs of abnormality in their brain tissue. Focusing on two regions—the hippocampus and caudate nucleus (that is also involved in memory)—they identified nearly 25,000 different sites for the three main retrotransposon families: L1, Alu and SVA.

The numbers are impressive: their analyses identified a total of 7,743 insertions of L1s in the hippocampus and caudate nucleus, areas that were known to show cell division after embryogenesis. They also found nearly 14,000 insertion sites for the Alu family, which has not been encountered before in the brain.

Interestingly each sample showed its own set of unique retrotransposition events, which meant each one had an individual mutagenesis background. According to the study, retrotransposons more likely to be integrated in genes that were expressed in the brain, perhaps because these genes are more susceptible, as their DNA is packaged in a more accessible way.

So what is the consequence when retrotransposons preferentially jump within genes that play key roles in normal brain function? They cause normal gene expression to shut down, disrupting normal gene function. Affected genes include those genes encoding receptors for the neurotransmitter dopamine and membrane transporters. Others integrated in tumor-suppressor genes, which are deleted in several different types of brain cancer. Jumping genes were also found within genes encoding regulatory proteins linked to psychiatric illnesses, such as schizophrenia and Alzheimer’s disease. As well as generating mutations by inserting themselves into and disrupting genes, retrotransposons can alter gene activity if inserted into adjacent regulatory regions of DNA. Such alterations can have a valuable or harmful outcome, without doubt a powerful tool driving evolution.

The researchers also reported that jumping genes were more active in the hippocampus compared to the caudate nucleus. This is highly interesting, because the hippocampus is known to be critical for memory and learning, and is thought to be one of the few parts of the brain that continues to produce new cells throughout life. Are jumping genes therefore involved in how we learn? Researchers are now beginning to investigate whether jumping genes help us adapt processing information through learning.
So when do jumping genes actually get mobile?  It has to happen during the brain’s development because retrotransposition requires cell division. After early childhood this does not take place in the brain; new neurons are generated in the hippocampus from stem cells, through a process called neurogenesis.  Retrotransposons then take the opportunity to jump randomly (!) into parts of the chromosome that have been opened up for DNA replication.

Once thought to be rare, these neural integration events actually take place surprisingly often. The analyses in this latest study suggested that most brain cells undergo an average of 80 L1 integration events! This means each neuron is likely subjected to a unique combination of insertions, leading to a “genomic plasticity” within populations of cells.

This research completely overturns the belief that the genetic make-up of brain cells remains static throughout life. It indicates that neuronal networks are constantly changing with each new experience as novelty and challenge both trigger neurogenesis. It may finally result in differences in brain function among individuals, even in genetically identical twins.

Further reading:

Video link about Alu elements and Autism.

Nature papers about L1 transposition in human neurons and the impact of Alus on human evolution.

Cholesterol is a crucial fat-like substance produced by the liver that is required for bodily functions. It is the main sterol synthesized and transported in the blood plasma of all animals. Cholesterol is responsible for a number of functions such as:

1. Building and maintenance of the cell membranes
2. Production of sex hormones (androgens and estrogens)
3. Production of bile
4. Metabolism of fat-soluble vitamins, including vitamins A, D, E, and K
5. Insulation of nerve fibers
6. Conversion of sunshine into vitamin D

Cholesterol being a crucial part of our development can have a dark side. The gene DHCR7 (7-dehydrocholesterol reductase) found on chromosome 11 is responsible for the production of cholesterol and mutations in the gene may lead to a metabolic disorder known as SLOS (Smith-Lemli-Opitz Syndrome). This disorder currently occurs once out of every 20,000 births. Individuals with SLOS are unable to produce enough cholesterol to support normal growth and development. This leads to developmental delays, physical malformations, mental retardation and issues with major organs such as the heart. Currently the only treatment for the disorder is cholesterol supplementation to improve growth and developmental progress.

SLOS is inherited in an autosomal recessive pattern, basically both copies of the gene within a cell are mutated. This identifies that the parents of a person with SLOS each carry a mutated copy of the gene, however they do not have any symptoms or signs of SLOS. It may be that genetic counseling may be one form of a preventative method for the disorder. This brings up a great question, should genetic counseling be mandatory for potential parents to decrease transmission of severe genetic disorders?

Biologists would like to understand how a bear, who eats continuously throughout the summer to lay down fat reserves for the winter, can have cholesterol levels that would be high for a human, but not suffer the hardening of arteries that one might expect. And what about the bone loss one would expect from months of inactivity?  Humans on bed rest can lose 3-4% of their hip bone minerals from lack of weight bearing exercise.  Bears show no signs of bone loss or osteoporosis as a result of their long rests.  It is likely that the genes involved exist in our cells too, but they just aren’t being used in the same way.

We clearly have a lot to learn from our hibernating friends. Teams of researchers in Sweden have actually been studying Brown bears to learn about these interesting phenomena.  How do you study wild Brown bears you ask?  You tranquilize them while they are hibernating, collect as many samples as you can, and get out before they wake up!  For the full story on hibernation, go to: http://www.sciencenews.org/view/feature/id/338318/title/Lessons_from_the_Torpid.

So researchers in the UK brought in the big guns – bioinformatics.

Cancer Research UK has set up seven British centers to start collecting 9,000 tumor samples from a wide range of cancer patients to create a DNA database. Researchers will extract DNA from these tumors and scan them for a series of key genes involved in tumor development. The results will then be cross-checked against a range of cancer treatments, to create a map of which treatments work best for cancers associated with which particular genes.

This is based on the concept of pharmacogenomics: certain genes predispose people to respond to certain drugs in certain ways. We can already test a cancer patient for a single gene, knowing how tumors with that gene respond to a particular drug. However currently we don’t have a way of testing a broad panel of genes. And to compound the problem, we don’t have a way of quickly and accurately sharing information between labs in the same city, across the country or internationally.

Again, enter the power of bioinformatics.

With the proposed cancer DNA database, a doctor might analyze a patient’s tumor sample and prescribe a tailored treatment plan within a very short period of time, perhaps as little as two weeks.

As Professor Matthew Seymour, director of the National Cancer Research Network (NCRN) in the UK, recently stated, “We have to get clever about how to target drugs. Medications for cancer have to be personalized because no two cancers are identical.”

Bioinformatics research is increasing at an exponential rate. DNA sequences are available to anyone with an Internet connection – along with free bioinformatics tools to explore sequence data, predict the presence of genes, and compare features shared between organisms.

The DNALC has been working in DNA sequencing and bioinformatics for over a decade, developing intuitive, visually appealing computer tools for teachers and students to quickly learn the rudiments of gene analysis and integrate bioinformatics with biochemistry labs.

If you want to find out more, check out:

• G2C Online Bioinformatics section
• DNAi: Applications > Genes and medicine > Genetic profiling
• Gene Boy, a fun, intuitive Flash interface to analyze DNA sequences.
• Sequence Server, a database and personal workspace for students to conduct phylogenetic analyses using their own DNA sequences.
• DNA Subway, a platform that uses the metaphor of a subway network to provide students access to various bioinformatics workflows.

For most of the year, deciduous trees are green because of chlorophyll in the chloroplasts.  This pigment helps harness energy from the sun to fuel photosynthesis, or food production.  In the fall, days become shorter and sunlight more sparse, so plants begin to prepare for the winter – a period during which they rely on stored nutrients.   Nutrients are stored and superfluous leaves are shed , but before that, the chlorophyll begins to disappear, revealing other pigments such as yellow and orange that weren’t visible before.  Sometimes during this process, new pigments (such as reds) are produced as well.

This is controlled by up to 35 genes that can turn on and off in response to the reduction of sunlight hours.  It is a great example of the interaction between an organism’s DNA and its environment, a phenomenon many people are unaware of.  The traits and characteristics of all living things are the result of a combination of its genetic makeup and its physical and chemical surroundings.  To learn more about this type of interaction, go to chapter 35, “DNA responds to signals from outside the cell.”

So we got into a discussion about model organisms, those that are used as a good system to be able to compare back to human beings, and in what ways they are being used.  That we have to even figure out whether or not something has a genetic basis.  Or maybe a good treatment option for a genetic disease.  If an organism shows similar symptoms as a human disease, this will give us a better understanding on when and how the disease progresses, causes and possible treatment options.

This allowed one student to immediately jump into what causes Autism.  We talked about the controversy that surrounds the disorder, and ways scientists are trying to figure out the genetic basis of the disease, and how much the environment can play a role.  In our current discussion, it was a perfect way for me to bring an actual example of how other organisms are being used to find out more about a specific disorder.

It was shown by a group of researchers at Cold Spring Harbor Laboratory that a deletion of a group of genes on chromosome number 16 causes autism-like symptoms.  They used mouse models with the same genetic alteration to show that when fewer copies of these genes are inherited, it leads to features resembling those that are used to diagnose autism.  Changes were seen in the structure of the mouse brain (see image below) and in their overall behavior of the mice.  Using the mouse model, they are able to mimic the disease to better understand what causes it, better diagnose it, and a new possible target for intervention and treatment.

Image from http://www.cshl.edu/Article-Mills/cshl-team-finds-evidence-for-the-genetic-basis-of-autism

Image from Nature Reviews Genetics 3, 941-955 (December 2002)

While this technology offers the hope to increase the success of IVF, it does raise some concerns about choosing a child in order to meet the needs and desires of parents. While most cases seem to have parents that are trying to increase their chances of having a viable pregnancy, some have raised some major ethical dilemmas. For example, two parents with achondroplasia, a disorder of bone growth that causes the most common form of dwarfism , is caused by having only one mutated copy of a gene. These parents might want to avoid an embryo that receives a mutated copy from both parents, which would be lethal. Instead, would they possibly choose an embryo that only has one affected copy, which would result in a child with achondroplasia, instead of an unaffected embryo? Would an unaffected child suffer more in an achondroplastic family than an affected child in such an environment?

This technique can be applied in a variety of ways, but I wonder if there are more ethical concerns than anything else. With any new technology, just because we can, should we? Are parents going to do this just to have a child free of genetic disease? Or is the future of “designer babies” closer than we think?

In a turn-around of sorts, it may be comforting to know that cancers can become addicted, too. Cancer cells have many different genetic changes, as well as changes in the expression of genes that are not due to mutations called epigenetic changes. Although cancer cells do have many differences from normal cells, they are still very similar to normal cells, making it very difficult to find treatments for cancers that don’t have serious side-effects.

Scientists, however, are beginning to identify genes that appear to be “Achilles heels” for cancers. It turns out that in many cases, reversing a defect in just one gene can have a profound effect on the growth of a cancer. Genes that promote cancer when mutated are called oncogenes, so this dependence on a particular genetic change in a cancer is called “oncogene addiction.” Often, treating these changes can be accomplished with little effect on normal cells, because the biology of cancer cells and normal cells has different wiring. So, a cancer cell may need to express a particular protein to keep dividing, while a normal cell might have other ways to keep going.

For instance, HER-2 is a receptor that is expressed on the surface of many breast cancers. HER-2 expressing cancers are often dependant on HER-2 to keep growing. This dependence is exploited in breast cancer treatments by an antibody drug, called Herceptin, which binds and inhibits HER-2.

Just as you can bring a cigarette smoker to their knees by taking away nicotine, so some cancers are tamed by taking away their favorite oncogene. Unfortunately, just like cigarette smokers who turn to other ways to cope, like caffeine or (more healthily) exercise, cancer cells can also escape their addictions, but that is another story…

It has been amazing to see what we have learned since then, but even more interesting to think of where this could go in the future.  Hopefully soon we will be able to apply this on a more individual basis, with people being able to identify potential risk factors for certain diseases at their primary care physician.  This then will lead to new developments for drug therapy, having a drug that will be able to target a certain pathway that is specific to that patient.  I can only wonder and look forward to what will come next.

For example, when someone has hemophilia (a blood clotting disorder), there is a mutation in a gene that normally tells our cells how to make proteins called clotting factors. The mutation prevents a specific clotting factor from being produced, and as a result, the individual carrying the mutation has the disease and the blood doesn’t clot as it should after an injury. It’s a gene we all have, but if someone has hemophilia, the gene just isn’t working properly.

Another common misunderstanding is that if a disease is genetic, it is always inherited. It is true that many disease-causing mutations are inherited. Sometimes though, the mutations that cause genetic diseases develop over time, after we are born. Many of the mutations associated with the development of cancer, accumulate in our cells as we age, and aren’t inherited. These diseases are genetic, because they are caused by mutations in genes, but they aren’t passed from parent to offspring. Less than 10% of all cancers are inherited!

It’s no wonder that not only children, but adults too, are misinformed. These types of incorrect phrases and misinterpretations are printed all the time in magazine and newspapers. So where do you go for correct information? To learn more about the genetics of cancer, go to: www.insidecancer.org. To learn more about basic laws of inheritance, use DNA From the Beginning (www.dnaftb.org). To learn more about the inheritance of mutations that cause disease, go to: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gnd, the Online Mendelian Inheritance in Men (OMIM) database.