It’s no secret that obesity rates are rising — quickly.  Between 2000 and 2005 the prevalence of obesity rose by 24%.  Extreme obesity increased by more than 50%.  If current trends continue, more than half of all Americans will be clinically obese by the year 2030.

Rapid changes in the prevalence of a disorder suggest that environmental rather than genetic factors are to blame. But scientists know from twin and adoption studies that body mass index (BMI) is highly heritable.  So which is it: nature or nurture?

As with many aspects of human health, it’s both.  Some people have the bad luck to have inherited genetic variations that together with the modern environment – sedentary jobs and hobbies, easy access to calorie-dense foods – create the perfect storm for the onset of obesity.

Changing the environmental factors that lead to obesity in some people seems simple enough – more exercise, less food.  But public health campaigns touting these commonsense fixes have had little effect against the obesity epidemic. By understanding the genetic aspects of obesity, and how they interact with the environment, scientists may be able to develop more effective treatments and prevention strategies.

In the July issue of Nature Reviews Genetics Andrew J. Walley of Imperial College London and colleagues review the current state of obesity genetics research.  While much progress has been made, the authors make it clear that there is still a long way to go, as the genes identified thus far explain only a tiny fraction of the total genetic component of obesity.

One key to future advancements in obesity genetics research, say Walley et al., lies in improvements to current genomewide association study (GWAS) methods.

First, the authors recommend that researchers focus on recruiting extremely obese people for their studies to increase the likelihood of finding genes with large effects. They also suggest that scientists should stop using BMI as their primary measurement of obesity.  While simple and cheap, this method does not take fat distribution or the ratio of fat to muscle into account.  There are more sophisticated methods, such as CT scans, MRI scans and ultrasound imaging, as well as machines that use air displacement to measure body volume and weight and can calculate fat and fat-free body mass.  Technological advances that will reduce the costs associated with genotyping, and ultimately genetic sequencing, are also needed so that larger numbers of subjects can be studied.

Beyond these improvements to current GWAS methods, Walley et al. say studies of more than just common variations are needed.  They suggest that investigations of rare SNPs, copy number variations (duplications, insertions and deletions of DNA) and inherited changes that don’t affect the actual DNA sequence will be needed to fully understand the genetics of obesity.

There are several competing theories about the overall biological basis of obesity.  Some suggest that obesity is a disorder of energy balance in the body, while others think regulation of the growth of fat cells is the key.  Still others think obesity may be due to defects in the neurological control of appetite and food intake.  Continued advancements in understanding the genetics of obesity will help scientists tease these theories apart, and hopefully lead to a healthier future.

(23andMe customers can check their data for a SNP in the FTO gene in the Obesity Research Report.  So far, this is the genetic variant most strongly associated with the risk of obesity.  There is also an Obesity Preliminary Research Report.)

Related posts in the Spittoon:

SNPwatch: New Obesity SNPs Point To The Brain’s Role In Regulating Appetite

SNPwatch: Gene Variant Linked To Obesity Affects Food Choices In Children

Genetics May Dull Brain’s Pleasure Response To Food, Causing Weight Gain

SNPwatch: Genetic Variants Affect Weight Loss Drug Effectiveness

SNPwatch: Genetic Link Between Obesity and Colorectal Cancer

It’s Not Genes Or Environment, It’s Genes AND Environment

SNPwatch: Researchers Find Genetic Variants That May Influence Risk For Obesity

SNPwatch: MC4R Gene Associated With Body Mass

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First came the Human Genome Project when, in the year 2000, an international team of scientists began mapping all 23 pairs of our chromosomes.  Then in 2005, the Chimpanzee Genome Project took off, attempting to do the same for the 24 chromosomes of our species’ closest living relative.  With intimate knowledge of the genetic make-up of both species, scientists could decipher the evolutionary changes that took place in the 7 million years since the time of our last shared ancestor.

Now, a joint research team led by Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology has gone one step further by mapping the complete genome of our nearest extinct relative. Pääbo and his colleagues announced the completion of a draft Neanderthal genome sequence today in Chicago at the annual meeting of the American Association for the Advancement of Science.

Neanderthals – our short, stocky, evolutionary cousins – lived in Europe during the harshest conditions of the Ice Age.  They survived in regions where few other animals could.  Neanderthals first came on the scene over 350,000 years ago, but seemed to dwindle in numbers with the arrival of humans about 40,000 years ago.  By 25,000 years ago they had disappeared completely.

But there are still many questions surrounding the fate of the Neanderthals.  While most scientists argue that Neanderthals were simply out-competed by the arriving humans, some believe that Neanderthals and early humans may have interbred, and that many modern Europeans have Neanderthal DNA interspersed throughout their genome.  Others believe that Neanderthals and early humans were in fact members of the same species, and should therefore have very similar DNA.

Solving the mystery has been no easy task. Because the archaeological samples available to Pääbo and his colleagues — three bone fragments from a cave in Croatia — are 30,000 years old, what little DNA they contain has been broken down into short fragments of just a few hundred base pairs each — a fraction of the billions that make up a complete genome.

Initially, the researchers focused on the mitochondrial DNA, because it is so prevalent in each cell.  When comparing the mitochondrial DNA of Neanderthals to that of modern humans, they found substantial differences between the two – indicating that humans and Neanderthals could not have been members of the same species.

However, the mitochondrial DNA represents only a fraction of the entire Neanderthal genome.  If we want to know the real genetic differences between humans and Neanderthals, then we’ll have to examine not just a small fraction, but the whole genome — all 46 chromosomes of it.

Working with 454 Life Sciences Corp of Branford, Conn., Pääbo and his team have devised a way to extract large amounts of nuclear DNA – DNA from the 23 pairs of chromosomes inside each cell – from prehistoric mammals, including Neanderthals.  All told, the two research teams have so far sequenced over 3 billion bases of Neanderthal nuclear DNA, constructing a ‘rough draft’ of the entire Neanderthal genome.

The sheer difficulty in completing such a task cannot be underestimated.  As soon as these Neanderthals died, tens of thousands of years ago, the DNA inside each cell began breaking down.  Up until recently, extracting the few remaining bits of DNA from fossils like these was virtually impossible.  Now, as Pääbo and others comb through the Neanderthal genome, we can embark on new chapter in the continuing saga surrounding the relationship between humans and Neanderthals.

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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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