A new genetic screening process has helped researchers understand the genetic causes of cancer, such as how mutations accumulated in a person’s life can cause leukemia.

The study shows that by comparing a person’s own DNA to that of their cancerous cells, researchers can find DNA mutations that may have led to abnormal cell growth, or cancer.

After sequencing a single leukemia patient’s healthy and cancerous DNA, researchers at Washington University School of Medicine in St. Louis were able to pinpoint several mutations out of hundreds that appeared likely to have contributed to his cancer’s development. He is the second patient with acute myeloid leukemia (AML) to have his entire genome and that of his cancerous tissue fully sequenced, rather than just the portions that are known to be prone to cancer-causing mutations.

“If we only look at genes with known or suspected links to cancer, we’ll miss many mutations that are potentially relevant,” co-author Richard Wilson said in statement.

The study by Mardis et al., published in The New England Journal of Medicine, identified a total of 750 mutations in the patient’s AML genome. Most of them proved irrelevant, but 64 were likely to be cancer-related. Two previously known mutations were newly linked to leukemia.

Timothy Lay, senior author of the study, explained in a statement that most patients with this type of leukemia are treated similarly, at least in the beginning. This study’s patient, for example, received various chemotherapy drugs. Defining cancer mutations could help determine which patients need aggressive treatment, such as a stem cell transplant, and which could be effectively treated with less intense therapies.

Personalized sequencing of entire cancer genomes is possible now because the accuracy and cost of genome sequencing technology has dramatically improved. This study took only a few months at one-third the cost of the first AML patient, who was sequenced only one year ago.

To date 350 cancer mutations are known, but thousands of cancer genomes will need to be screened to truly explain the genetic basis for cancer. This information could be used not just to guide physicians to the most effective treatment, but also to inform patients about their prognosis.

But do patients even want to know?

A recent study published in the Journal of Genetic Counseling suggests they do. Researchers found that 98 of 99 patients with ocular melanoma, a rare, untreatable eye cancer, said they wanted to know if their cancer had a genetic marker that gave them a 50 percent chance of dying within five years. Patients were relieved when the risk was low, but even when the risk was high they were enabled to plan financially and make the most of their time alive.

This very personalized medicine will continue to be driven by improved diagnostic testing, finding more predictive disease markers, and new therapies directed at cancer-specific mutations, James Downing wrote in a recent editorial published this month in The New England Journal of Medicine. He believes this technology will likely be used clinically long before we have a complete knowledge of cancer genes.

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Not long after Karl Landsteiner first described the different ABO blood types, scientists started looking for associations between blood type and other human traits.  Some of their theories were truly weird (more on these tomorrow!), but some have held up to scientific scrutiny.

Venous Thromboembolism (VTE)
People with non-type O blood (A, B and AB) have been shown to be at increased risk for VTE.  The reason is thought to be that these people have higher levels of the clot-inducing proteins factor VIII and von Willebrand factor in their blood.  Having non-type O blood further raises the already increased risk for VTE in people who carry the Factor V Leiden and prothrombin G20210A mutations.

Cancer
Since the 1950s, scientists have found that people with type O blood have decreased risk for stomach cancer compared to people with type A.  Other cancers (pancreatic, breast, ovarian, cervical) also occur at lower rates in people with type O blood.  No one is quite sure why this is.  It could be that the sugars found on type A blood cells, which are also expressed by other cells in the body, might somehow help cancers grow more aggressively.  Alternatively, some research has shown that regardless of person’s own blood type, tumors express the type A sugars. In people with type A blood, these sugars go unnoticed by the immune system because they are considered normal.  But in people with type O blood, these new sugars are recognized as foreign, spurring the immune system to destroy the tumors.

Stomach Ulcers
Although stomach cancer is less prevalent in people with type O blood, stomach ulcers are more common in people with this blood type.  The sugars that define the different blood types are also found on cells in the gastrointestinal tract.  Research has shown that these sugars influence the ability of H. pylori, a type of bacteria responsible for a large number of stomach ulcers, to attach to the lining of the stomach.  People with type A or B blood (and hence A or B sugars on their stomach cells) have fewer H. pylori receptors than people with type O.

Severe Malaria
In people infected with malaria, more severe disease is seen in those whose red blood cells are induced to form rosettes, large aggregates that block small blood vessels.  Studies have shown that people with type O blood form fewer, smaller and more easily broken up rosettes than people with type A, B or AB blood.  This is probably because the sugars found on the non-O blood cells end up helping to create larger clumps of cells.

Infectious Disease
Some studies have shown that certain bacterial and viral infections are more or less likely in certain blood types.  For example, type A blood has been linked to a predisposition to “glue ear,” which is caused by infection with Pseudomonas aeruginosa. And some studies suggest that people with type O or B blood are less susceptible to smallpox. The research supporting these and other claims of an impact of blood type on infectious diseases are not as strong as the other associations listed above, however.

(23andMe customers can get a prediction of their ABO blood type based on their DNA data through the new ABO Lab feature.)

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It’s well established that defects in the cellular machinery that controls cell division can lead to cancer.  Now, new research shows that the risk for both brain and skin cancer can also be impacted by common DNA variations near a set of growth-regulating genes.

Five reports, published online this week in the journal Nature Genetics, show that variants near the CDKN2A and CDKN2B genes increase the risk of certain types of tumors.  Previous research has implicated these “tumor suppressor” genes in both skin and brain cancer. Mutations in CDKN2A are found in about 2% of all people with melanoma, and outright deletion of CDKN2A and CDKN2B is seen in approximately half of all brain tumors.

Two of the reports (Wrensch et al. and Shete et al.) focused on gliomas, which account for approximately 80% of all primary brain cancers and generally have a dismal prognosis.

The remaining three papers were skin cancer studies.  Two of these (Bishop et al. and Falchi et al.) focused on melanoma, while the third (Stacey et al.) looked at basal cell carcinoma.  Melanoma accounts for less than 5% of all skin cancers, but is responsible for most skin cancer deaths. Basal cell carcinoma is also serious, though not usually deadly, and is the most common type of cancer overall in people with European ancestry.

(In addition to SNPs near the CDKN2A and CDKN2B genes, several other SNPs were identified for each type of cancer.  23andMe customers can use the links in the table at the end of this post to see their data for all of these SNPs using the Browse Raw Data feature.  SNPs near the CDKN2A/CDKN2B genes are in bold.)

The disease-associated variants near the CDKN2A and CDKN2B genes were distinct for the three types of cancer studied.  This could mean that they each have separate risk-increasing effects, or that they are all pointing researchers in the direction of a single variant in the region that is involved in glioma, melanoma and basal cell carcinoma.

It’s no surprise that these genes, which play important roles in some of the most basic cellular processes, appear to be involved in several types of cancer. In fact, variation in and around CDKN2A and CDKN2B might be important for other diseases as well.  Previous research has also implicated SNPs near these genes in coronary artery disease and type 2 diabetes.

As more research is done, we can probably expect to see more variants in this region of DNA associated with more diseases.  It will be fascinating to see how they all connect to each other, and more importantly, what new insight they give scientists into how tiny DNA changes can have big health consequences.

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Much to the surprise of many scientists, a lot of the SNPs identified in genomewide association studies have not been in the parts of genes that encode the molecular machinery of a cell.

Instead, many SNPs have been found on the edges of genes, in regions of DNA that control when the genes get turned on or off, in parts of genes that get cut out before the final proteins are made, or even in so-called “gene deserts,” areas of DNA that don’t seem to contain any genes at all.

Rs6983267 is one of these gene desert SNPs.  People with two copies of the G version of this SNP have about 1.4 times the odds of developing colorectal cancer compared to people who have two Ts, but so far no one has been able to figure out why.  Two new reports show that, even though this SNP seems to be out in the middle of nowhere in the genome, it can interact with components of a signaling pathway known to be overactive in more than 90% of all colorectal cancers.

(23andMe customers can see their data for rs6983267, as well as two other SNPs associated with increased colorectal cancer risk, in Health and Traits.)

Results from Tuupanen et al. and Pomerantz et al., both published online this week in the journal Nature Genetics, show that the region of DNA containing rs6983267 is an “enhancer” that can turn up the amount of protein made from the MYC gene. The riskier G version of the SNP appears to make the enhancer stronger than the T version.

In colorectal cancer, increased MYC expression can often be traced to overactivity of a molecular signaling pathway known as Wnt.  Both groups of researchers found that the region of DNA containing rs6983267 was responsive to Wnt signaling, thus connecting this SNP to a well-established cancer mechanism.

Drugs that attack the Wnt pathway are attractive candidates for cancer therapies.  According to Tuupanen et al., the new results suggest that these same types of drugs might be useful for personalized cancer prevention treatments in people who carry the riskier version of rs6983267.

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Each type of cancer has its own idiosyncrasies, but when it comes down to it, they all have one thing in common: failure to control cellular growth. So it’s somewhat surprising that when genome-wide association studies have looked for single common variations associated with the risks for multiple types of cancer, they have for the most part identified only SNPs that are peculiar to just one form of the disease.

A new study published online Sunday in Nature Genetics may signal a change in this trend. A team of researchers led by Thorunn Rafnar and Patrick Sulem of deCODE Genetics in Iceland describes how a SNP they originally found to be associated with the risk for developing basal cell carcinoma (BCC), a type of skin cancer, is also linked to increased odds for four other cancers.

In a study of more than 33,800 cancer patients and 45,800 controls, the scientists found that the C version of rs401681 is associated with increased odds of lung, bladder, prostate and cervical cancer, in addition to the previously found association with BCC. This variation decreases the odds of cutaneous melanoma, another type of skin cancer.

(23andMe customers can check their data for this SNP, rs401681, using the Browse Raw Data feature. A table at the end of this post provides details about its effect on different cancers).

The C version of rs401681 was also marginally, although not significantly, associated with increased odds of endometrial cancer and decreased odds of colorectal cancer.

There was no association of the SNP with cancer of the breast, kidney, stomach, thyroid, ovary or pancreas, nor with lymphoma, multiple myeloma or squamous cell carcinoma (a third type of skin cancer). The authors say that further investigation in even larger samples will be needed to determine if there truly is no association, or if they just haven’t picked it up yet.

An association was also found between rs2736098, a nearby SNP, and four of the five cancers that were associated with rs401681. 23andMe does not currently provide data for rs2736098.

Both SNPs are near a gene involved in maintaining the protective stretches of DNA attached to the ends of chromosomes called telomeres. The authors suggest that these SNPs, or other nearby variations, may lead to shortened telomeres, which are associated with several types of cancer.

Telomere length is determined in part by genetics, but environmental factors such as smoking and radiation can also shorten them. The authors note “four of the five cancers associated with the risk variants are cancer types that have strong environmental contributions to risk – smoking and occupational exposures for lung and bladder cancer, UV irradiation for BCC and infection with human papillomavirus for cervical cancer.” More research could help explain the exact relationship between the genetic variations found in this study and the environmental causes of these cancers.

*Effect is the increase or decrease in odds compared with someone with two copies of the T version of rs401681.

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Understanding the genetic changes that lead to different cancers is key to more effective diagnosis and treatment of the disease. And thanks to the availability of faster, cheaper genome sequencing technologies, researchers are now able to peer more deeply into the DNA of cancer cells than ever before.

Recent studies have sequenced more than 600 genes in both brain and lung cancer samples and found novel patterns of gene mutation. But in both of these studies, the findings were limited to genes the researchers already suspected of involvement in cancer.

Now researchers from Washington University in St. Louis have taken an unbiased approach to finding mutated cancer genes and found that half of the ones they identified were completely unexpected. The researchers describe their work in a paper published online today by Nature.

“In the past, cancer researchers have been ‘looking under the lamppost’ to find the causes of malignancy – but now the team from Washington University has lit up the whole street,” said Francis Collins, former director of the National Human Genome Research Institute, in a statement.

Instead of looking at a subset of genes already thought to be involved in cancer, the Washington University researchers cast their net as broadly as possible by sequencing the complete genomes of an acute myeloid leukemia (AML) patient’s normal and tumor cells.

Nearly 2.7 million variations in the DNA of the patient’s tumor were initially flagged, but almost 98% of these were also found in the patient’s normal cells, indicating that these mutations were in her genome from the beginning and not the root of her cancer.

The researchers then used a variety of methods to further narrow down the field of mutations that might be responsible for the patient’s cancer. They were ultimately left with single-base mutations in just eight genes. Half of those eight were in gene families already strongly associated with cancer in general, while the other four occurred in genes not previously implicated in the disease. None of the eight mutations had previously been reported for AML before. Nor could any of them be found in the tumors of an additional 187 AML patients the researchers tested.

“This suggests that there is a tremendous amount of genetic diversity in cancer, even in this one disease,” team leader Richard Wilson said in statement. “There are probably many, many ways to mutate a small number of genes to get the same result, and we’re only looking at the tip of the iceberg in terms of identifying the combinations of genetic mutation that can lead to AML.”

Although the results of this study can’t tell a doctor how to treat better treat a patient, the research is an essential first step down the path towards developing targeted therapies, said Brian Druker, a cancer genetics researcher whose own work helped with the development of the targeted cancer drug Gleevec, in a statement.

“This tour-de-force effort identified a small number of mutations in genes that no one predicted, and their uniqueness for this patient begins to give us a glimmer of the genetic complexity and diversity of this disease,” he said.

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One of the best parts about working at 23andMe is being surrounded by people who are active and love taking on new challenges. We exercise together regularly and are always looking for new ways to contribute to our community, so we recently decided it was time to take on our first race. We chose the LIVESTRONG Challenge in San Jose on July 13th – a combination of 100, 65, 50, and 10 mile bike races, a 5k run, and numerous volunteer opportunities – because it would give our diverse group a chance to be active at all different levels while raising money for a good cause. What we didn’t know when we began this challenge was how much of an impact this race would have on all of us.

Team 23andMe consisted of eight riders, seven runners and seven volunteers. Together, we raised close to $2,000 for the Lance Armstrong Foundation (LAF), which helps serve the 12 million Americans fighting against cancer.

Lance Armstrong founded LAF after he was diagnosed with testicular cancer at the age of 25, in order to help others who were going through the same struggle. In the past ten years, LAF has raised more than $250 million for research, increased awareness of cancer and empowered survivors throughout the country.

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Excitement filled the air Sunday morning as Lance stood on the podium to address the racers and explain why we were crazy enough to get up at 6am on a Sunday morning to put our bodies through pain. We were there to help those suffering from cancer and to honor those who succumbed to their illness. He reminded us that although we were amongst many survivors, an even greater number had not won their battle. In fact, more than 550,000 people will die this year alone from various forms of cancer. Lance was there to motivate us to run faster and ride stronger – and it was working.

At a typical race start, I put on my iPod and bounce around eager for the gun to go off, but the LIVESTRONG Challenge was different. Waiting for the start, I looked around and saw that nearly everyone had a special bib pinned to his or her jersey honoring someone who had been affected by cancer. It was emotional and inspiring.

Then I saw the faces of the children, some as young as three years old, who were currently undergoing cancer treatment and being carried in pedicabs so they could participate in the race. At that point, I lost it. It was no longer about setting a personal record or witnessing one of sport’s greatest legends, it was about picking a fight with cancer. It was about helping those who had suffered, who are suffering, and who will suffer from this brutal illness.

Each member of Team 23andMe had his or her own personal motivation going into the race. Each one of us gave it everything we had (I could really tell we’d all given it everything we had when no one wanted to walk around looking for free stuff at the post-race party).

A big congratulations to Oliver Ryan, our Director of People, who finished 4th in the 50 mile bike race. And Brian Naughton, one of our Founding R&D Architects, finished 17th overall in the 5k! I set a new personal record. I guess having motivation beyond just racing can push you farther and faster than you knew possible.

After a few pats on the back, a hot shower, a good meal and some cold beer, several of us jumped back out on the race course to volunteer, running yellow roses (LAF’s signature color) to cancer survivors who crossed the finish line. We shed a few tears and cheered our way through the sticky afternoon while riders of all sizes and shapes came racing through the finish line to earn their yellow rose and my deepest respect. After watching survivors finish strong after riding 100 miles through the South Bay summer heat, I realized it really is all about the fight.

The LIVESTRONG Challenge was a spectacular event and I can’t wait for next year. I have never been so proud to be part of such a special company, with people who can see beyond themselves and want to help those in greater need. We united on Sunday to pick a fight against cancer and I think we’re on our way to winning.

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Aspergillus fumigatus

Many cancer patients who receive high doses of chemotherapy or radiation undergo a bone marrow transplant to replace blood cell-generating tissues that are killed as part of their treatment. But after a transplant these patients face a new challenge – opportunistic infections that take advantage of their weakened immune systems.

One common and life-threatening infection among bone marrow transplant patients is invasive aspergillosis (IA), which is caused by the fungus Aspergillus fumigatus. About 10% of bone marrow transplant recipients are affected by invasive aspergillosis (IA). An estimated 30% of those affected will die within three months.

A study published in the June issue of PLoS Genetics shows that a SNP in the gene encoding a protein called plasminogen significantly affects the risk of developing IA after a bone marrow transplant. Compared to transplant patients with the GG genotype at rs4252125, the risk of developing IA was increased 3.0 fold in people with the AG genotype, and 5.6 fold for people with the AA genotype.

Zaas et al began their study of IA in bone marrow transplant patients by looking for clues in several genetically distinct strains of mice. The researchers mimicked a bone marrow transplant in the mice by giving them drugs that suppressed their immune systems. They then exposed the animals to the Aspergillus fungus.

The researchers found that some mouse strains survived Aspergillus infection, while others did not. A SNP in the plasminogen gene correlated with Aspergillus susceptibility, and the researchers considered it a likely candidate because other scientists had recently indicated that proteins in the same biological pathway as plasminogen are important for fighting off infectious pathogens.

Armed with this clue from mice, Zaas et al turned their attention to humans. They followed a group of 230 immunosuppressed bone marrow transplant recipients for one year. Just as they had seen in the mice, the researchers found that IA was associated with a SNP (rs4252125) in the plasminogen gene.

Oddly, the association between rs4252125 and IA applies only 40 days or more post-transplant. The authors aren’t exactly sure why this is the case. It could be due to the low proportion of patients who are infected with Aspergillus in the first 40 days after their transplants. It could also be that until 40 days, when the transplanted bone marrow really starts to take hold, other risk factors swamp out the effect of rs4252125.

Laboratory tests showed that the plasminogen protein encoded by rs4252125, which is made in the liver, binds to Aspergillus fungus. And computer models indicate that the SNPs found in both mice and humans change the protein in a way that alters binding to the fungus, giving a possible explanation for why the SNP affects susceptibility to IA.

Though more research and evaluation is required before clinical applications can be developed based on this research, the authors write in the conclusion of their report that their results have “important implications for pre and post transplant care, and may also have implications for the management of other immune-compromised patients. For example, genetic testing could identify high risk individuals who may benefit from use of broad-spectrum antifungal agents or enhanced monitoring for infection.”

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A new study in Nature Genetics shows that the increased risk of developing cancer in the mouth, throat, voice box and esophagus due to drinking is partially offset by the rarer versions of two SNPs associated with alcohol metabolism.

Cancers of the oral cavity, throat (also called the pharynx), voice box (or larynx) and esophagus are collectively known as upper aerodigestive (UAD) cancers. Alcohol consumption is known to be a significant risk factor for these cancers. Studies have shown that the areas of the body that come into closest contact with ingested alcohol are at highest risk of being affected by cancer.

The two SNPs associated with UAD cancers are both located in genes that are part of the alcohol dehydrogenase (ADH) enzyme pathway, a group of proteins that aids the body in metabolizing alcohol. The authors of the study hypothesize that the protective versions of the SNPs they found exert their effect on UAD cancers by changing the carcinogenic effects of alcoholic beverages. These SNPs had no effect among non-drinkers.

Hasibe et al studied six SNPs in ADH pathway genes in a total of 3,876 people with UAD cancers and 5,278 healthy controls, in hopes of finding DNA variants associated with these diseases. This large study group was comprised of three smaller study groups: one group from eastern Europe with 809 patients and 2,586 controls; one group from western Europe with 1,356 patients and 1,407 controls; and a final group from Latin America with 1,711 patients and 1,285 controls.

Both rs1229984 and rs1573496 were significantly associated with UAD cancers in the large study group and each of the smaller study groups individually.

When the researchers broke the patients into groups based on specific cancer type – oral/throat, voice box, and esophagus – they found that both SNPs impacted the risk of developing the subtypes of cancer to different extents (see the chart at the end of this post for details).

About 19 out of every 100,000 people is diagnosed with UAD cancer per year in the United States. Individually, the lifetime risks of developing these cancers are: oral/throat, 1 in 99; voice box, 1 in 274; and esophagus, 1 in 198.

Those who have one or two copies of the T version of rs1229984 were found to have 0.56 times the odds of developing UAD cancer compared to those with two C versions. For those who carry one or two copies of the G version of rs1573496, their odds of developing UAD cancer were 0.68 times those with two C versions. People who carry at least one T at rs1229984 and one G at rs1573496 were found to have 0.45 times the odds of developing UAD cancer compared to people who had no protective versions of either SNP.

The authors say that the exact mechanism by which the protective versions of these two SNPs are working is not clear. It is known that people with one or two copies of the T version of rs1229984 metabolize ethanol up to 100 times faster than people with two copies of the C version. The authors of this study speculate that this faster metabolism may protect tissues by reducing their exposure to the effects of alcohol.

23andMe customers can check their data for rs1573496 (rs1229984 is currently not available). The tables below sum up the results of this study. The “effect” of each SNP is the change in odds for carrying either one or two copies of the protective version.

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It turns out that the riskier version of this SNP increases the amount of the FGFR2 protein that is made by cells, which can stimulate cells to grow – and increases the chance that they will proliferate out of control and lead to cancer.

Though the number of genome wide association studies is growing every day, very few of these studies have been able to explain why the SNPs they find are associated with a particular disease. Understanding how SNPs impact the biology of cancer and other common diseases will be critical for developing new treatments.

The FGFR2 gene encodes a protein that is inserted through the surface of cells where it acts as a receptor for certain growth factors. A growth factor is a chemical signal in the body that can tell cells to divide, move around, or differentiate into more specialized types of cells.

While several genetic mutations have been found that confer a high risk for breast cancer (most famously BRCA1 and BRCA2), these known genetic changes are actually relatively rare. There are probably many more common genetic changes that on their own don’t pose much of a risk, but in certain combinations can cause disease. The SNP in FGFR2 was one of the first of these common variants to be found.

On average, a woman’s chances of developing breast cancer some time during her life are one in eight. Having two copies of the G version of SNP rs1219648 (instead of the most common genotype: AG) increase her chances to about one in six. Two copies of the A version of this SNP, on the other hand, reduce a woman’s chances to about one in 10. (These numbers apply only to women with European ancestry. 23andMe customers can learn more in My Gene Journal (now called Health and Traits).)
Meyer et al showed that the cells of women who had two copies of the G version of rs1219648 expressed significantly more FGFR2 than women with two copies of the A version (the study actually looked at another SNP that is thought to be universally linked to rs1219648).

It’s known that in 5 to 10% of breast cancers, the FGFR2 gene is turned on at unusually high levels. And laboratory experiments have shown expressing extra FGFR2 in cells can cause them to take on cancer-like traits.

When they investigated further, the researchers found that the G version of rs1219648 was associated with increased expression of FGFR2 because the versions of two SNPs (located very near rs1219648) that are inherited along with the G version of rs1219648 have a greater affinity for DNA-binding regulatory proteins that help turn on the FGFR2 gene.

Meyer et al believe that theirs is the first study to address the function of the SNPs associated with breast cancer.

“Our study demonstrates that SNPs identified by whole-genome scans can be used as valid starting points for studying the underlying biology of cancer,” the authors write.

Like many of the SNPs found in genome wide association studies, rs1219648 and other SNPs in FGFR2 that regulate the binding of regulatory proteins are in a non-coding part of the gene called an “intron”. Many other SNPs found in these types of studies are in non-coding regions of the genome located between genes.

The authors speculate that their finding that SNPs in non-coding parts of the DNA can regulate gene expression will be a common theme.

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