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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Through the millennia wave after wave of migrants – often in the form of invading armies – have descended upon the British Isles.

The first people to arrive after the Ice Age were hunter-gatherers who followed their prey north from southern Europe about 12,000 years ago. The Celts came from central Europe about 3,000 years ago. Then came the Romans, followed by the Anglo-Saxons, Vikings and finally the Normans in 1066 AD.

With each successive invasion, the previous people were either absorbed by the invaders, or retreated to the isolated corners of the Isles. Often called the “Celtic Fringe,” these regions have been studied as a window into the ancient history of the British Isles. Some scholars even propose that the present-day people of the fringe could be direct descendants of the earliest humans to arrive on the Isles after the Ice Age.

But despite exhaustive research into the history and genetics of the Celtic Fringe, its prehistory remains mysterious, forcing scientists to think outside the box. In the September 30 issue of the Proceedings of the Royal Society B: Biological Sciences, biologist Jeremy Searle and his research team did just that, devising an unconventional method to study the prehistoric peopling of the British Isles.

They could have examined the DNA of the Celts themselves. But that’s already been tried, so Searle and his colleagues turned their research underfoot.

Earlier analysis found similar genetic patterns in populations of both common shrews and humans inhabiting the Celtic Fringe. Using those results as a benchmark, Searle and his team expanded the genetic analysis to the pygmy shrew as well as two species of voles.

Searle reasoned that if these shrews and voles had similar immigration patterns to early humans, perhaps those patterns would show up in their DNA. Specifically, he believes that “this study can help us understand why humans in the British Isles form a Celtic Fringe.”

Interestingly, Searle and his colleagues’ analysis revealed a division in DNA types for the shrews and voles similar to that separating the people of the Celtic Fringe and the rest of the British population. Further analysis revealed that the DNA types for the mammals living in the Celtic Fringe were quite old. So old, in fact, that Searle and his team propose that the arrival of these mammals traces all the way back to the post-Ice Age arrival of humans 12,000 years ago.

If the mammals living in the Celtic Fringe date back 12,000 years, the people living there could as well.

There is one problem with this hypothesis. The Celts themselves only arrived from mainland Europe 3,000 years ago, not 12,000 years ago. Conventional wisdom states that the Celtic Fringe only evolved after the Celts were pushed back following the invasion of the Romans and Anglo-Saxons.

How does Searle explain this discrepancy? He and his team argue that the Celtic Fringe is not actually Celtic in origin. Rather, its presence predates the arrival of the Celts and their arrival only ‘reinforced’ a pre-existing division that was already there.

In that case, it would have been the Celts themselves whose arrival pushed earlier inhabitants to the isolated corners of the British Isles. Subsequent migrations would have pushed the Celts into these same corners, which is why the language and culture of these regions are inherently Celtic. And that would also explain why the languages, culture, and history of the pre-Celtic people of Britain have mostly been lost to time.

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For as long as humans have lived in complex communities, cities and civilizations, they have divided and classified their societies. Those divisions have been based on age, gender, appearance or – in many cases – occupation. In many traditional societies artisans would share the same social status; as would soldiers, priests and workers in any number of other occupations.

In antiquity, the status of a family rarely changed. If you were a farmer, your sons would be farmers, and so on. While today social status barriers are crumbling in many societies, in others they remain largely unchanged.

India’s complex social stratification, known as the caste system, has been one of the traditional cornerstones of society. Though urban Indians are shedding the caste labels of their parents and grandparents, many rural Indians – who make up 72% of the entire population – hold steadfast to the system. In small villages and towns, the Brahmin caste – consisting of scholars and priests – is still revered as one of the highest social strata. And members of the Dalit caste – formerly known as “Untouchables” – are still viewed as unclean and remain separated from others.

The rigidity of the system still present in rural India has made many wonder exactly how long castes have existed. Historical records are unclear, as early Hindu scriptures like the Bhagavad Gita are somewhat ambiguous when it comes to the topic. Some historians even propose that the caste system as we know it today is largely a construct of the English Colonial Era, arguing that the development of such a system could have been deemed necessary to instill order.

Genetic analysis has also proven inconclusive, as analysis of small segments of the human genome has yielded different results. But a new study by geneticist David Reich and colleagues, published in the September 24 issue of Nature, takes a new approach to understanding the genetic history of India.

The core difference between Reich’s genetic analysis and previous studies is in the sheer amount of genetic material analyzed. Reich’s team examined more than 550,000 points across all segments of the human genome. In doing so, they hoped to obtain a more complete picture of Indian genetic history.

The research team analyzed the DNA of 132 individuals from India and neighboring regions, dividing them into 25 distinct groups based on geography, caste and language. They calculated how genetically ‘closed’ each of these groups were. In the caste system it is rare to marry someone from another class, making caste societies very closed, or ‘endogamous.’ If this endogamy continues over many generations, it will leave a behind a genetic signature for scientists to discover.

Reich and his team found such a signature, indicating a long history of endogamy in several of the groups. In fact, the research team calculated that the DNA of six of the groups can be traced back to just a few individuals who lived anywhere from 30 to more than 100 generations ago. Assuming a generation time of 25 years, that establishes the existence of the caste system in the range of 750 to more than 2,500 years ago — long before the British colonial era.

In a second analysis, Reich and his team examined how ancient migrations could have influenced the formation of castes. First the researchers divided the Indian groups into language families: Indo-European and Dravidian. Dravidian tongues, like Tamil and Malayalam, are mainly spoken in southern India and are believed to be a remnant of languages spoken by some of the earliest inhabitants of the region. Indo-European languages, like Punjabi and Urdu, are more common in the north. They are believed to have arrived with a migration of farmers from southwestern Asia or the Near East about 9,000 years ago.

Reich and his colleagues then compared the genetics of each of the Dravidian and Indo-European groups to a sample of European DNA. The team reasoned that, if Indo-European groups were really descended from the farmers, they would show more genetic similarity to the Europeans than the Dravidians.

Not surprisingly, the authors’ hypothesis held true. The Indo-European speakers, like the Kashmiri Pandit and Vaish, were more genetically similar to Europeans. And because the majority of the upper castes speak Indo-European languages, while the lower ones tend to be Dravidian speakers, there could be a relationship between the arrival of Indo-European people and the formation of caste structure. Further evidence that an ancient caste system has permeated through India for thousands of years.

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Each one of us carries in our cells the vital genetic data, compliments of our parents, that code for many of our traits and attributes.  Whether it’s our eye color, height or the ability to consume dairy products, the variations in our genes contribute to making us ‘one of a kind’.  Unfortunately, these variations can also lead to the onset of disorders that aren’t so unique.

Technology now allows scientists to tap into our DNA as they attempt to unlock the underlying genetic causes of diseases that afflict so many of us.  These studies, often called Genome-Wide Association Studies (GWAS) because of their comprehensive design, are producing some very compelling results. Under the present research model, individuals who are asked to consent to participating in these studies typically donate a blood or saliva sample and provide access to information about their particular disease (or drug response, in the case of pharmacogenetic studies) through their health records or through diagnostic interviews.  Scientists then look for genetic correlations that can help direct the development of diagnostics and therapeutics.

This model is fairly steeped in tradition and protocol.  Once your sample and information are collected, researchers go out of their way to break the link back to you, with the mindset that it’s a necessary measure to protect your privacy — and, frankly, minimize their liability to deliver and explain the data. The genetic information derived from your DNA is often “de-identified” or “anonymized” so that it can’t be traced back to you.  As a “human subject” in a study such as this, you are not offered access to this very personal data.  Yet it could be very important for you to know. Now that we have more knowledge about how our genes impact our lives, thanks to these very studies, shouldn’t you be given access to the data if you want it? Even if there’s little you can do to alter the course of your genetic predispositions — which are often not definitive — we’re seeing overwhelming evidence that a lot of people would like this information.

At 23andMe, we believe it’s time for a research revolution, where the people involved — let’s no longer call them human subjects — can play a more active role and contribute more directly to studies of most interest to them and their families.  And if any individual would like access to his or her data, he or she should be granted that request.

In this spirit, 23andMe is proud to support www.HealthDataRights.org and the Declaration of Health Data Rights.  We believe genetic data are an integral part of your health information, and you should have access if you so choose.

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I spent the better part of my undergraduate career lugging around massive biology textbooks.  General biology, genetics, embryology: It didn’t matter, they all weighed a ton. I pored over endless chapters of text, highlighting the important sentences, always wishing for more photos, more diagrams, more graphs. A single well-made diagram or image was easier to understand than the preceding 10 paragraphs about the same topic.  I always wished that my textbooks were a little more visual and a little less wordy.  An added benefit, I thought, would be that I could shave a few pounds from my backpack.

My college days are long over. But my wish may have finally come true, in the form of a new graphic guide to genetics entitled The Stuff of Life: A Graphic Guide to Genetics and DNA, by Mark Schultz.  Published in December, it takes a more visual approach to presenting the most current knowledge on a particular branch of the biological sciences close to my heart: genetics.

The Stuff of Life is centered around a group of aliens who are trying to understand the genetics of all life on earth. These aliens are both rather ugly (the illustrator has drawn them to resemble sea cucumbers) and rather arrogant. They can’t seem to understand why a lowly, hairy primate has come to dominate the planet and make such amazing advances in science and technology. In the style of a comic book, with various windows and balloons leading us from the origins of the earth 4.6 billion years ago to modern day applications of genetics and DNA, it falls flat in oddly juxtaposing complex information and somewhat juvenile humor.

For anyone who hasn’t taken a college (or advanced high school level) biology class, the information presented will seem overwhelming at best, and confusing at worst. For those who are well versed in the biological sciences, the information may be understandable but the humor will seem trite and silly.  After the first few chapters of the cucumberesque aliens repeatedly exclaiming that they can’t believe humans have managed to understand how genes are passed down from parents to children, that they can’t believe humans have been able to sequence DNA, understand the genetics of cancer, and create genetically modified organisms, I began to dread their appearances. I stopped reading the sections focused on them, instead skipping to the parts that contained actual information. Once I did I began to enjoy the book much more.

The organization of the book is similar to a standard introductory genetics textbook.  It begins with a description of the structure of the cell, DNA, and how the genes housed within our DNA can determine thousands of physical traits.  Schultz then moves quickly forward, presenting important genetics concepts such as inheritance, dominant vs. recessive alleles, and why my cat has two different colors of fur.  Finally, he spends the last one-third of the book examining modern-day applications to the study of genetics.

The strategy works well by allowing the reader to understand the practical value of understanding the basic genetics concepts that were brought up in earlier chapters.  Indeed, having more applications-centric lectures during college might have silenced the students who never understood why this field is so important.  Undoubtedly, this section was written with the more general reader in mind.  It is easily the best section of the entire book.

Though the constant banter from the sea cucumber-like aliens should not interest anyone over the age of 10, this book would be of use to those currently taking an introductory course in biology, as it might help solidify more difficult concepts that might prove difficult to students.  For educators, this book could prove useful in providing fresh ideas on how to present some of the most important genetics concepts.

The uneven feeling I got from reading The Stuff of Life is something that must constantly be a fear for anyone who is trying to make science fun and accessible to the general populace.  Presenting such important topics as genetics and DNA that are easy for anyone to understand, scientifically accurate, AND enjoyable, is no easy feat.  And, while The Stuff of Life may have stumbled in some aspects, it is most certainly a noble effort, and may lighten the load in biology majors’ backpacks in the coming months.  I sincerely hope that Schultz continues with more volumes, though I could do without those sea cucumbers next time.

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The way our Personal Genome Service™ works is pretty straightforward, at least from a customer’s point of view. We send you a saliva collection kit, which is at its heart a plastic tube. You spit in the tube and send it to our laboratory, which extracts DNA from your saliva, analyzes it and deposits the resulting genetic data in your account.

Though the process usually goes off without a hitch, each sample has to clear a number of quality control hurdles in order to be processed. If it doesn’t, a customer’s data may take a little longer than expected.

Sample problems can almost always be corrected one way or another. It is only in very rare cases that a person’s saliva contains so little DNA that repeated efforts to analyze it fail (In those situations, we do provide a refund!).

For those of you who really want to know all the messy details, below is a detailed account of what can go wrong with a sample, and what we do if it does:

Step One: The Visual Exam

Samples arrive at our lab every day. The first thing technicians do with each new sample is scan the barcode on it, because that’s the only identifying information the laboratory has. For privacy reasons, the customer’s name and other account information never passes beyond the 23andMe firewall.

As soon as the samples have been scanned, they undergo their first test — a visual inspection to make sure they contain fluid up to the “fill line” on the side of the tube. Occasionally samples do not pass, either because they leaked in transit or the preservative solution (buffer) isn’t released into the tube when the customer snaps the oblong cap onto the collection funnel. Either way, if a sample tube doesn’t contain enough liquid we immediately contact the customer and ship a free replacement kit so he or she can spit again.

Step Two: DNA Extraction

If a sample passes visual inspection, it’s time for DNA extraction. The process our laboratory uses to isolate and purify the DNA in your saliva is simply an automated version of the same one you can do at home that allows technicians to process batches of 96 samples. Technicians remove a portion of the saliva from each tube, then put the rest of the sample aside so they can try again in case their first attempt fails. If a second attempt to extract DNA from a particular sample fails as well, we send a second kit to the customer who provided it (free of charge) so that person can provide a fresh (and hopefully DNA-rich) one.

A sample may lack enough DNA for extraction if the preservative solution is not released when the customer snaps the cap onto the funnel during the collection process. A sample could also contain an insufficient amount of DNA simply because there are not enough cells floating around in it. Some people seem to have less DNA in their spit, though almost everyone has enough for the purposes of our analysis.

Step Three: Genotyping

Samples that yield sufficient quantities of DNA are submitted for genotyping,  which scans the genetic material at the approximately 580,000 markers (SNPs) included in our service. This process is also performed in batches of 96 samples. And once again, we monitor the process to make sure it is going as expected. If it isn’t, we try again. In this case a sample is re-run if the analysis process cannot determine its genotype at a minimum of 98.5% of the locations we probe (roughly 570,000 out of the 580,000). If the second attempt fails as well … we ship the customer another sample collection kit for free.

Once a sample has been successfully analyzed, the laboratory sends the resulting data to 23andMe along with the barcode that came with the sample. That allows our database to deposit the information in the proper account and send an automated email notification to the customer who holds it.

With all the things that can go wrong, the sample analysis process may seem a little precarious. But it’s actually quite robust — the vast majority of samples sail right through without a hitch. If things do go smoothly, we can generally return data within eight to 10 weeks of the date a sample is sent to the lab.

My name is Varsha Baichwal and I work here at 23andMe as Director of Operations. You can share your genome with me if you wish – my 23andMe ID is “varsha”.

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Biology has changed a lot over the past 150 years. Scientists have discovered entirely new forms of life, deciphered the molecular code of heredity and observed the machinery of life on the smallest dimensions. And through it all, one scientific theory has stood the test of time.

New discoveries in genomics, medicine, developmental biology, and countless other fields could have derailed the the theory of evolution. But the core principles of evolutionary theory, proposed by Charles Darwin 150 years ago, have remained among the strongest explanations of the natural world ever published.

In honor of Darwin Day 2009, which celebrates the 200th anniversary of Charles Darwin’s birth and the 150th anniversary of the publication of his seminal work, On the Origin of Species, we’d like to take a look at how evolution has itself ‘evolved’ over the decades — how new advances in science and technology have both reinforced Darwin’s original idea and given us insight into the inner workings of the theory that explains so much about the world in which we live.

In 1859, the phrase ‘evolution by natural selection’ was already beginning to make the rounds among the scientific elite in Europe and in America.  This was the year Darwin published On the Origin of Species, and his ideas about how species change over time were causing heated debate among the experts.  But Darwin didn’t invent the idea of ‘evolution’ (that is, the idea that species change over time).  What he brought to the table was an explanation of how species change, a process Darwin called ‘natural selection.’  On his famous journey to the Galapagos Islands 25 years earlier, Darwin had witnessed unique variation in hundreds of species.  As he pored over his notes for the next two decades, Darwin pieced together the notion that species must adapt to environmental pressures (like changes in climate or a volcanic eruption), in order to survive.  If they did not adapt to these pressures, then they may not survive.  It was natural selection, Darwin argued, that was the basis for the vast differences we see in plant and animal species across the globe.

But there was a lot that Darwin did not know when he published his ideas of evolution.  He did not know, for instance, how changes in a species’ appearance (a longer beak, a bigger shell, or a thicker coat of fur) are passed down from generation to generation.  The idea of discrete units — ‘genes’ that are passed down from parents to children — had not even occurred to Darwin, nor to most of the other scientists of the time.  Even when, in 1866, an Austrian monk named Gregor Mendel reported his ideas on patterns of inheritance in pea plants in the obscure Proceedings of the Natural History Society of Brünn, few took notice.

In fact, the word ‘genetics’ wasn’t coined until 1905, by biologist William Bateson. Bateson, who is sometimes credited with ‘rediscovering’ the lost works of Mendel, helped to usher in a new wave of research and discovery — this time looking at how species differ from each other at the molecular, or genetic, level.  Bateson’s push for the use of genetics in evolutionary research reached fruition in 1952, when Cambridge scientists James Watson and Francis Crick decoded the structure of DNA. Soon others discovered how specific genes are passed down from generation to generation, and how changes in our genetic code are connected to changes in species.  As each new genetic discovery allowed us to better understand the natural world at a microsopic level, Darwin’s theory of evolution by natural selection was continually reinforced.

The evolution of our species, Homo sapiens, forms the basis for virtually everything we can learn from 23andMe’s Personal Genome Service^TM.  The signature of millions of years of evolution is present in every person’s genome, and often in our physiology, rendering some of us resistant to malaria, others unable to digest milk, and even causing some to have lower risks of cancer or other diseases.  As advances in science and technology continue to bring us more information hidden within our genes, we can be thankful that 150 years ago, an amateur naturalist from Shrewsbury, England, boarded a ship bound for South America and began piecing together the evolutionary story of not just our species but of all life on earth.

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Because their ancestors often were slaves during the 18th and 19th centuries, and therefore usually lacked birth or death certificates, it is very difficult for African American genealogists to trace their ancestors further than a few generations. Even when they can trace their ancestry to the slavery era, it is virtually impossible to find exactly where their ancestors originated because slave ships did not keep passenger lists of the people they captured from Africa.

As a consequence, many have been turning to genetics as a tool to help trace their African ancestry. But how reliably can genetics trace a person’s ancestry back to a specific African location or ethnic group? Using genetics this way is quite complex; even the most advanced analysis can’t provide all the answers.

Relying on genetic data for genealogical purposes can be problematic, especially if your expectations are too great. For example, Henry Louis Gates, Jr., the Director of the W.E.B. Du Bois Institute for African and African American Research at Harvard, had his Y-chromosome genotyped by two different companies. The first told him that his ancestors likely traced back to Nubia or Egypt, while the second test more accurately placed his paternal ancestry in Europe. As an African American, Gates believes that the first company may have simply ‘told him what he wanted to hear’: that all of his ancestry traced back to Africa. But, as is often the case, one’s genetic ancestry can be more complex than meets the eye.

One problem is that genetic analyses predominantly trace deep ancestry. Because genetic information does not change significantly within one or two generations, genetics generally shows where a person’s ancestors lived thousands of years ago. This is hardly useful to genealogists who are looking for information about ancestors who lived only a few hundred years ago.

That isn’t to say we can’t learn anything useful about the deep ancestry of many African Americans – in fact, studies of genetic ancestry have yielded much information about prehistoric population movements across the continent. For example, there are clear genetic ‘footprints’ in modern Africans — and African Americans — indicating massive expansions of Bantu-speaking peoples from West Africa into the eastern and southern part of the continent over 4,000 years ago. This has helped archaeologists understand the extent to which not only the Bantu culture and language, but the people themselves, spread throughout the continent.

Most African Americans have the signature of this Bantu migration in their genes because they are descended from populations that were affected by it. But many, including Gates, have the genetic signature of another widespread group: Europeans. Indeed, European ancestry is not uncommon among African Americans, whose ancestors can include white slave owners who fathered children with their slaves. The use of genetic data can be useful in confirming anecdotal evidence of a non-African ancestor in an African American’s family tree.

Many African American genealogists want greater detail and resolution from their genetic information, even a link to a specific nation or tribe. But in many cases this is simply not possible. The population history of Africa – especially sub-Saharan Africa – is older and more genetically complex than that of any other region of the world. Homo sapiens evolved in East Africa more than 150,000 years ago, and has been living throughout Africa continuously since that time. There have been countless migrations, dispersals, and expansions of African peoples to all parts of the continent – in addition to the Bantu expansions. As a result, the genetic diversity of present-day Africans is incredibly complex.

In many cases, scientists are unable to associate a specific genetic classification with a specific tribe or ethnic group. There are of course a few exceptions – isolated hunter-gather groups like the !Kung of the Kalahari Desert and the Pygmies of the Central African Rainforest have lower levels of genetic diversity as a result of their relative isolation. But in West Africa, where the majority of slaves were captured, there is significant genetic diversity both within countries and within tribal or ethnic affiliations. The high level of diversity means that scientists have a difficult time pinpointing where a particular person’s genetic roots trace beyond a more general geographical region (i.e. West Africa). For example, the paternal haplogroup E3a, found in more than half of African American men, is just as common in Africa itself – and spread throughout the continent. So, for an African American male who’s paternal ancestry falls within the E3a haplogroup, it could be virtually impossible to narrow down the place of origin of his African ancestors.

Still, when traditional tools are unavailable or incomplete genetics can reveal useful genealogical information, whether a person’s roots trace back to Africa, Europe, or someplace else entirely.

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The American Society for Human Genetics (ASHG) has released a statement outlining a set of recommendations for genetic ancestry testing.

At a press briefing on Thursday, members of the ASHG Ancestry Testing Task Force Committee discussed two main themes: the need for clear communication about the limitations of genetic ancestry testing, and the need for researchers and companies doing this type of testing to engage with the social sciences to put results in context.

Michael Bamshad of the University of Washington School of Medicine discussed at length the need for people to understand that ancestry assignments based on genetics are inherently uncertain and can be affected by several factors, including the reference populations used in the analysis, the type and number of genetic markers analyzed, and the statistical methods employed.

ASHG president Aravinda Chakravarti further emphasized that questions about the “accuracy” of genetic ancestry testing are aimed at the interpretation of the genetic data, not at the actual DNA analysis.

Task force co-chair Charmaine Royal of the Duke University Institute for Genome Sciences and Policy addressed the committee’s concerns about the psychological impacts of genetic ancestry testing, especially as related to issues of identity.

23andMe Senior Director of Research Dr. Joanna Mountain had a chance to talk with some of the members of the ASHG Ancestry Testing Task force about their statement.

“Members of the panel emphasized to me that their primary goal was to raise a set of concerns around identification of ancestry through genetics,” said Mountain.

“Because several of us at 23andMe were previously aware of these concerns, we developed our ancestry features with those concerns in mind. For instance, we consider a large number of markers for all the chromosomes of the human genome, including the mitochondrial genome. We also avoid being overly precise in reporting an individual’s ancestry. And we are currently creating educational tools to help our customers understand how genetic information can be informative about ancestry.”

The speakers stressed several times that their statement was not aimed just at consumer companies offering genetic ancestry testing, but also at academic researchers in the field.

Unfortunately, Mountain said, the ASHG guidelines leave out some of the potential benefits of ancestry genetic testing.

“For instance, ASHG President-Elect Ed McCabe encouraged the audience to ask their family elders about family history over Thanksgiving, as an alternative to learning about ancestry through genetics. But individuals who have signed up for 23andMe’s service may find themselves far more motivated to discuss family history than they would before seeing their genetic data.”

For a more thorough analysis from a genetic genealogist’s point of view, click here.

McCabe said the statement released this week is a preliminary document. The committee expects to issue a more detailed report in Spring 2009.

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As talks began Saturday at Cold Spring Harbor’s first “Personal Genomes” conference, the first half of which I blogged on here, several leading explorers of the strange new world of “structural variation” in the human genome, such as Evan Eichler and Mike Snyder, shared some of their latest findings.

You can observe the most common kind of structural variation by lining up two corresponding chromosomes; if you notice that one of them is missing a stretch of DNA letters that is present in the other, that’s a deletion (or an insertion from the other chromosome’s viewpoint). Geneticists call these types of variations insertion/deletions, or indels for short.

The main way these variations seem to happen is during the production of sperm and eggs, when an individual’s homologous chromosomes recombine with one another. Usually, chromosome pairs line up perfectly for recombination, but when they don’t, you end up with chromosomes that have a little more or a little less DNA than the originals.

Problems can arise when the stretch of DNA lost in the shuffle was part of an essential gene. Recent work has shown that one form of autism is caused by a deletion, and the same is true for forms of schizophrenia and cystic fibrosis.

Both basic research and clinically-motivated research were presented Saturday. Eichler, of the University of Washington, and Snyder, of Yale, are among those making detailed maps of structural variation in the human genome. The consensus is emerging that there is a *lot* of it. Snyder showed that, at least in the handful of individual genomes he’s looked at so far, any two individuals differ by more than one thousand indels of at least 3,000 DNA letters. Eichler made a similar observation with respect to his comparison between a sample individual’s sequence and the reference human genome, and commented that this means there are at least 3 million DNA letters (3,000 times 1,000) in the sample individual’s sequence not present in the reference genome. That’s on top of the 3 million one-letter SNP variants between any two humans. So it looks like genetic variation is the rule and not the exception, and the very notion of a “reference” sequence may need to stretch a bit in order to stay consistent with the data.

Derek Chiang of the Broad gave a fascinating talk about progress in trying to understand how structural variation can cause medical problems. Chiang, of the Broad Institute of MIT/Harvard, has developed sophisticated software to find structural variants associated with cancerous tissue based on microarray data. His efforts have already yielded a new oncogene for lung cancer. Chiang also described a clever algorithm for finding structural variants from next-generation sequence data that appears to work quite well by comparison to methods based on microarray data. Like the work Elaine Mardis presented Friday, Chiang’s talk suggests a future in which cancerous tumors could easily be distinguished from normal tissue using genetic scans.

The task of understanding what these differences *do* is another, very difficult, question entirely. And being able in turn to develop a therapy tailored to that specific change is yet another challenge.

Sunday’s talks took us into the world of *next next* generation sequencing, as though the prospect of plain old next generation sequencing weren’t already shaking up the field enough. Steve Turner gave a talk on Pacific Biosciences‘ sequencing technology that kept the audience rapt. The technology is ingenious, and solves a number of problems that have bedeviled sequencing since its inception. I will punt on explaining the basics of the technology, since it’s so well-explained on their website.

Turner offered an update that doesn’t appear on the website yet; the technology depends critically on the use of an enzyme, called DNA polymerase, that is responsible for copying DNA. Their team has modified the DNA polymerase used in the machine from the version that exists naturally in humans using a technique called experimental evolution. They generated a collection of mutant polymerases that each differ from the original at random. Then they tried each variant in their machine, retained the ones that do best, and repeated the process. It’s fair to say that horticulture and animal husbandry are slower, less direct forms of experimental evolution. After several generations, they ended up with a polymerase that was better suited to the environment of their machine than natural human polymerase is.

The meeting ended Sunday as Maynard Olson of the University of Washington, an eminent geneticist and one of the architects of the Human Genome Project, closed the conference with a witty and thoughtful summary of the proceedings. Olson suggested that true personalized medicine could be a long time coming, and expressed skepticism that it would arrive at all. One generalization from the talks, he said, was that it appears increasingly that the genetic mutations that impact health are rare, and it may be the case that many diseases can be caused in a large number of ways. The difficulty of working out what each version means could make it hard to work out therapies for so many different possibilities. He predicted a near-term future of unpredictability, especially in guessing which sequencing technologies will come to be adopted the genetics community. He closed by reciting the lyrics to Bob Dylan’s “The Times They Are A-Changin’,” which seemed fitting to me.

Photo: Henryk Kotowski

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