How do you get three billion pairs of As, Cs, Ts and Gs—about six feet worth of DNA—into the nucleus of a tiny cell?

Most students of biology would answer by saying that this is accomplished by tightly coiling up the DNA.

Oh yeah?  Well, how is it coiled?

As cells perform different functions and respond to different environmental signals, proteins that help turn genes on and off need to quickly gain access to different parts of the genome.  That means DNA needs to be arranged in such a way that it won’t get all tangled up.  Packing DNA like luggage at the end of a vacation, with everything smashed together and shoved in any which way, just won’t cut it.

Using a new technique called “Hi-C,” researchers at Harvard, MIT and the University of Massachusetts appear to have solved the riddle. Their results, published today in the journal Science, show that nature has devised quite an elegant storage solution.

Equilibrium (top) and fractal (bottom) globules. Nearby regions on a chain of DNA are indicated using similar colors. The equilibrium globule is highly entangled; regions nearby along the chain are far apart in 3D. In the fractal globule, regions nearby along the chain are also nearby in 3D. Images: Leonid A. Mirny and Maxim Imakaev

The scientists first treated cells with formaldehyde to freeze the DNA in place.  They then used enzymes to break the DNA apart and put it back together in a different configuration.  A final step of sequencing allowed them to identify pieces of DNA that are naturally close together in the nucleus.

“We made a fantastic three-dimensional jigsaw puzzle and then, with a computer, solved the puzzle,” said co-first author Nynke van Berkum in a statement.

Two important aspects of DNA organization emerged.  First, there are two main compartments in the nucleus – one for DNA that is in use and one that acts as a storage facility for unneeded sequences.

“Cells cleverly separate the most active genes into their own special neighborhood, to make it easier for proteins and other regulators to reach them,” said one of the paper’s senior authors, Job Dekker of UMass Medical School, in a statement.

The other striking aspect of the nucleus is that chromosomes appear to be folded up into an arrangement called a fractal globule, which the authors described as a “beads-on-a-string” configuration.  Multiple rounds of “crumpling” of the DNA into beads leads to a “globule-of-globules-of-globules.”

Previous models suggested that DNA was in a more random arrangement called an equilibrium globule.  This configuration, however, is known to be prone to dense knotting.  Fractal globules are knot-free.

Image Source: Harvard School of Engineering and Applied Sciences

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Diabetics have to be worried about more than just their cholesterol when it comes to the health of their arteries. They also have to watch their blood sugar to help prevent the build up of fatty plaques that can block blood flow.

But new research from the Joslin Diabetes Center and Harvard Medical School shows that high blood sugar may be more dangerous to some diabetics than others.

Dr. Alessandro Doria and colleagues found that a genetic variant on chromosome 9 previously associated with coronary artery disease (CAD) risk in the general population has an even greater effect in diabetics with poor blood sugar control. These results, published online today in the Journal of the American Medical Association, could someday help doctors identify people with diabetes who are at higher risk of CAD earlier, allowing them to aggressively target these patients for intervention.

People with diabetes are at least twice as likely as those without to have heart disease. Some studies suggest that middle-aged diabetics have the same high heart attack risk as people without diabetes who have already suffered a heart attack.

The first of two study groups was composed of 322 diabetics with coronary artery disease and 412 without. The researchers found that the risk for CAD was about the same in people with either the AA or AG genotype at rs2383206, even if they had poorly controlled blood sugar.

Having the GG genotype at rs2383206, however, increased the odds of CAD by about two-fold for diabetics with well-controlled blood sugar. And when high blood sugar was thrown into the mix, the odds of CAD for people with two Gs went up higher still – about four times compared to the lowest risk group.

In people with the GG genotype and a long history of high blood sugar, the odds of CAD were increased about seven times compared to diabetics with a history of well-controlled blood sugar.

(The study looked at rs2383206, which is available to 23andMe customers who were genotyped on the second version of our custom chip. But people who were genotyped on the first version can use rs2383207, the SNP we feature in the Health and Traits research report on Heart Attack, as a substitute. The G version is riskier for both SNPs.)

In a separate study group of 475 diabetics who were followed for 10 years, people with the AA or AG genotype at rs2383206 had the same risk of dying in general, or from cardiovascular disease in particular, regardless of their blood sugar. But for people with the GG genotype, the risk of death went up by a factor of two when blood sugar was not under control.

Both groups of diabetics Doria et al. studied were of European ancestry.

“While good glucose control is important for all people with diabetes, testing for this predisposing variant may help doctors identify patients for whom better control is an absolute necessity,” said Doria in a statement. The authors estimate that 30% of diabetics will have two Gs at rs2383206.

The probability of clinically significant CAD is about 30% for type 2 diabetics in general. The authors say this number could shoot up to 60% for diabetics with the GG genotype at rs2383206 and poorly controlled blood sugar.

The authors admit that this is a small study that will need verification. They also note that their findings are at odds with a previous report that found no difference between the risk conferred by SNPs in the 9p21 chromosomal region (where rs2383206 lies) in diabetic vs. non-diabetic subjects. Due to a number of methodological differences between the two studies, Doria et al say that no direct comparison of the results is possible.

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