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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Can you explain why there’s no gene for Crohn’s disease?

If you know the answers to these questions, we want you to know this: 23andMe is looking to hire an editor who is adept with scientific copy and concepts. The Science Editor will edit copy generated by 23andMe scientists and science writers for grammar, style, scientific accuracy and clarity. The position requires both excellent editing skills and an ability to convey difficult scientific concepts for an audience that encompasses all levels of expertise.

Qualifications:

• Bachelor’s degree in a relevant field.
• Graduate training desirable, but not required.
• Journalism training and/or experience preferred.
• Ability to convey complex scientific concepts in clear and entertaining prose for non-scientists.
• Interest in or basic knowledge of genetics and anthropology.
• Broad familiarity with different biological disciplines.

Interested? Feel free to email us directly at jobs@23andme.com, or head over to our careers site and apply directly at https://www.23andme.com/about/jobs/ (it’s listed under ‘Science’).

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A study published online yesterday in Science Express suggests that for schizophrenia at least, and perhaps other mental disorders, that approach might not be the way to go.

Schizophrenia is a debilitating psychiatric disorder that affects approximately one percent of the population. People with schizophrenia suffer from hallucinations, delusions, and disorganized thinking. The illness greatly impacts social and occupational functioning and has enormous public health costs.

The authors of the paper propose that a genetic predisposition to schizophrenia is caused by structural variations in the genome such as deletions, duplications, and re-arrangements of genetic material instead of variation at SNPs. Furthermore, they think that these structural variations might be different for different patients, meaning that it would be difficult to ever find DNA markers that are predictive for the disease.

The researchers used new technologies to look for structural variations in 150 people with schizophrenia or schizoaffective disorder and 268 healthy controls with no history of neurological or psychiatric illness. They found that individuals with schizophrenia were much more likely than controls to have structural variations that affected genes (as opposed to non-coding parts of the genome). The association was strongest in people who developed symptoms while 18 years old or younger.

Virtually every structural variant the researchers detected in the individuals with schizophrenia was unique, though sometimes patients had differing mutations in the same genes. Genes involved in brain development were the most affected.

The results of this study don’t prove that any one gene is associated with schizophrenia, but they do suggest that researchers who want to understand the genetics of this illness, and maybe other complex psychiatric disorders, should perhaps focus their efforts on structural variations instead of SNPs.

That doesn’t mean SNPs aren’t useful. Almost every day we’re learning something new about how subtle single-letter DNA variations between people may affect their health. But some questions won’t be answered until scientists have a better understanding of many other types of genetic variation as well – not to mention the contribution of other factors such as diet, personal habits and environmental exposures.

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If you take two members of the human race at random and ask how much their genomes differ, you’ll get a surprising answer: they’re almost identical.

On average, for every 1,000 DNA bases you have, 999 or so of them are exactly the same between you and your neighbor – and for that matter, between you and your neighbors on the other side of the planet. Over your entire 6 billion DNA base pair genome, however, that one difference in a thousand adds up to several millions of differences.

In studies published by Science and Nature this week, scientists have taken their most detailed look yet at these genetic differences. In this blog post, we’ll take a brisk stroll through their findings.

Both studies are based on around 600,000 SNPs genotyped in individuals (i.e., people) from the Human Genome Diversity Panel(HGDP-CEPH). HGDP-CEPH is a remarkable scientific resource. It consists of immortalized cell lines from 1064 individuals in 51 populations scattered around the globe. The idea guiding the creation of the panel was to take a wide-angle snapshot of human genetic diversity. This explains the presence in the panel of little-known populations like the Uygur, the Surui, and the Xibo, alongside more familiar populations like the Japanese, Palestinians, and French. This polyglot collection reposes at the Fondation Jean Dausset in Paris, as it has now for nearly a decade.

The Science study peers closely into those one-per-thousand differences between people, asking: Of all the genetic diversity seen in the panel, how much is found between people from the same population, how much between people from different populations in the same geographic region, and how much between people from different geographic regions?

For example, if there were no within-population diversity that would mean that all Russians are genetically identical, all Surui are identical, and so on, and therefore that all human genetic diversity must exist at the population and regional levels.

The paper finds nearly the opposite. About 90% of human diversity exists within populations, with most of the remaining 10% existing between geographic regions. This strongly confirms a decades-old result in human genetics: of those very few DNA bases which differ between people, a small minority of these differ between peoples.

Even so, 10% of several million differences is still a lot of differences between populations. Both studies zoom in on these differences, mustering some mathematical machinery called Bayesian cluster analysis, and ask: how easy is it to guess someone’s ethnicity based on their genotype? The answer the two papers find is that it’s pretty easy, at least on the regional scale. The following figure, drawn from earlier work done by many of the same researchers that was published in the open-access journal PLoS Genetics in 2005, illustrates the results of the analysis; these are qualitatively the same as the results shown in the fancifully-priced Science and Nature figures.

Each one of the (very) thin vertical lines in the figure represents a person, and the colors comprising each line correspond to the inferred proportion of ancestry from each of seven world regions. The key here is that the cluster analysis has no notion of a region or a population. It is simply told to divide up the genetic diversity into seven clusters (or six or eight – the results don’t change much), and then to guess which cluster or clusters each individual belongs to. The ethnic and regional labels are only applied once the analysis is through and, as is plain, the agreement between the donor-supplied ethnic label and the assignment is quite strong.

The papers go much further than we’ve seen here, looking into the history of human migration and exploring what happens when you use DNA insertions and deletions instead of SNPs to ask the same questions.

It’s worth noting that 23andMe is proud to have cosponsored the genotyping of the HGDP-CEPH that was conducted by the authors of the Science paper. The genotypes are available, gratis, at the CEPH website. We downloaded them ourselves, and now our customers can compare themselves to these very same populations using our Global Similarity feature.

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A report released today in the online edition of Science magazine demonstrates that two SNPs influence the amount of chromosome shuffling that takes place during the production of sperm and eggs. Surprisingly, the versions of the SNPs that increase the rate of shuffling in men actually decrease it in women, and vice versa.

Geneticists use the term “recombination” to describe the shuffling of chromosomes that takes place when gametes are made. Recombination helps to generate human diversity by mixing up a mother’s and father’s chromosomes, respectively, during the production of egg and sperm cells. The rate of recombination determines how much of this chromosomal shuffling happens.

Previous studies have shown that the amount of recombination varies between people and that this variability is at least partially heritable. The mechanism controlling variation in recombination rates, however, remains unknown.

Augustine Kong and co-workers conducted a genome-wide search in more than 6000 people of European ancestry to find variants that correlated with recombination rate. This rate was determined by looking at the chromosomes of both subjects and their children.

The researchers found that men who had at least one G at rs3796619 and at least one A at rs1670533 had higher rates of recombination. In women, the opposite was true: at least one A at rs3796619 and at least one G at rs1670533 was associated with high rates of recombination. Customers can look up their data on both of these SNPs in 23andMe’s Genome Explorer (now called Browse Raw Data).

The report’s authors suggest that the opposite effect of these SNPs in men compared to women may help to keep the pace of change in the genome relatively constant. By balancing high rates of recombination in one sex with low rates in the opposite sex, nature may have found a way to maintain stability in the human genome and ensure the evolutionary success of the species.

Both SNPs identified in this study are located in a gene called RNF212. Scientists don’t yet know much about this gene. They do know that RNF212 is similar to genes important for recombination that are found in yeast and small worms called C. elegans.

Recombination is an important concept in genetics, but it can be hard to visualize. Read on for an illustrated example that will make things clearer.

In this example of meiosis, the process by which egg and sperm are made, we’re only going to show two pairs of chromosomes (a pair of long ones and a pair of short ones) instead of the usual 23 pairs for humans. Let’s say that we’re talking about what happened in your mother’s body when she produced eggs (the exact same process applies to dad’s sperm). We’ll designate the orange chromosomes as the ones contributed to your mom by your maternal grandma, and the purple chromosomes as those from your maternal grandpa.

Step 1: Each chromosome is copied, creating doublets that stick together.

Step 2: The pairs of doublets line up across from each other and swap random chunks of DNA. This is recombination. The recombination rate determines how many swaps take place

Step 3: The pairs of doublets separate and the cell divides.

Step 4: The doublets separate and the cells divide again. The cell that began this process with pairs of chromosomes has now been turned into 4 gametes, each containing one of each type of chromosome (a long one and a short one in this example). These cells become eggs.

Step 5: If one of these eggs is fertilized by a sperm cell (which was produced in the same way as the egg cells), the resulting cell will get one set of 23 chromosomes from the egg and the sperm, respectively, resulting in a cell that has 23 pairs of chromosomes, just like the adult cell we began with. This cell will then go on to become an embryo and eventually a child.

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