Science is dynamic and ever changing. As new research is published, theories get revised, and hypotheses retested. The field of genetic ancestry is no exception: The flurry of published research just in the last five years has been staggering, and we can now piece together the histories of many groups from nearly all parts of the globe. At the same time, a worldwide community of genealogists has seized upon this wealth of published research, combining it with their own genetic data to produce an even richer, more detailed human history.

We want our customers to have the most current information possible, so our scientists and engineers have spent the last several months updating the paternal lineages, or haplogroups, for all of our (male) customers. This has been quite a task, involving many layers of analysis and quality control to meet our standards of precision and accuracy.  The end result is a more detailed understanding of paternal ancestry for our customers.

The New Tree

Customers can find the 23andMe paternal haplogroup tree on the paternal line feature page.  It lays out the specific haplogroups for populations around the world, how they are related to each other, and how all men alive today can trace their paternal ancestry back to one individual who we refer to as the PoP (Poppa of all Poppas).  The organization of this tree is derived from more than 2,000 variable genetic markers, known as SNPs, on the Y chromosome. The particular combination of SNPs a man has determines which haplogroup his Y chromosome belongs to.

Finding the Right Tree

Over time enough additional SNPs are discovered, and there are enough revisions to the organization of other researchers’ Y haplogroup trees, that we must give our own a face lift to keep up. We used a variety of sources as a basis as we developed our new paternal haplogroup tree. We examined the published literature and spoke with experts in the field of Y chromosome genetic ancestry.  Perhaps most importantly, we used the wealth of information gathered from the International Society of Genetic Genealogy (also known as ISOGG).  This non-profit organization is run by genealogy enthusiasts who are passionate about discovering their family history through genetics. These enthusiasts, many of them 23andMe customers, have sifted through mounds of genetic data, both from the published literature and their own genetic profiles. The fruits of their labor are collected and organized in a haplogroup tree that is regularly updated at a high level of detail. ISOGG exists and prospers because so many genealogists are working together for a common goal.

We have worked primarily with the December 2008 ISOGG paternal haplogroup tree as a basis for updating our own.  Even since then, some paternal haplogroups been updated significantly.  So for these rapidly evolving haplogroups, we used the May 2009 ISOGG paternal haplogroup tree as a reference. The end result is a very detailed and up-to-date paternal haplogroup assignment for each of our male customers.

Your Paternal Haplogroup

What does this update mean for our customers?  For many it means a change in their haplogroup assignment. That change may be slight, or it may be more substantial.  For other customers it means no change at all.  When examining your new paternal haplogroup, it is likely you will see one of the following differences:

1) A more specific assignment:  Because the new paternal haplogroup tree examines many more SNPs than the original, we are able to give our customers more precise assignments. As a result, it is possible that your new haplogroup assignment may be longer and more specific than the original.  For example, customers who were assigned haplogroup J2a1 will now be reassigned to haplogroup J2a1a.

2) A more specific and slightly different assignment:  This category of change is by far the most common affecting our customers, because the organization of the haplogroup tree has changed. Therefore someone’s new assignment may look similar to their old one, but it will be longer and/or slightly different. For example, a customer who was assigned to R1b1c may now be reassigned to R1b1b2.

3) A completely new letter assignment: This is the rarest of the changes that will likely occur, and is also due to a reorganization of the paternal haplogroup tree over the past few years. For example a customer currently classified as K2 will now be reassigned to haplogroup T.

It is important to note that your ancestry has not changed, only your haplogroup assignment. But because this update has allowed us to define many more haplogroups than we had originally, we can give even more specific information about our customers’ paternal ancestry.  In the coming weeks, we will be updating the summary pages for our haplogroups with this additional genetic history.

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It has been known for decades that having the gum disease periodontitis increases a person’s risk for heart attack (free registration required), stroke and other forms of cardiovascular disease. Research suggests that the link is due to inflammation in the gums causing an immune reaction throughout the entire body. That can increase blood pressure and encourage the accumulation of atherosclerotic plaques in the arteries.

Now researchers have drawn a genetic link between periodontitis and heart disease as well. It turns out that variations in a region of chromosome 9 that have already been associated with heart disease also influence a person’s chances of developing periodontitis.

The specific genetic marker identified by the study is not part of the 23andMe Personal Genome Service. But another marker that has also been linked to heart disease and lies in the same chromosomal neighborhood is described in the Heart Attack research report.

Arne Schäfer of the Institute for Clinical Molecular Biology in Kiel, Germany presented the research in Vienna, Austria, last week at the annual meeting of the European Society of Human Genetics. He and his colleagues found that people with a marker for increased cardiovascular risk in a stretch of DNA known as 9p21 were more likely to have gum disease as well.

The high-risk version of the marker increased a person’s chances of having generalized aggressive periodontitis by 1.99 times, and localized aggressive periodontitis 1.72 times. Aggressive periodontitis generally strikes early in life and progresses rapidly, leading to tooth loss as early as age 20.

The 9p21 region of chromosome 9 contains several genes involved in suppressing the proliferation of cells. In a recent PLoS Genetics paper the researchers suggest that the variation they studied somehow affects the function of one of these genes.

Rather than superceding previous findings linking the effects of periodontal inflammation itself on heart disease, the researchers said, their study provides valuable additional information that could help unravel the connection between the two conditions.

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Malaria is one of the leading causes of death in the developing world, claiming nearly a million victims each year. The great majority of them are African children below the age of five. The illness is caused by a single-celled parasite called Plasmodium that is transmitted by mosquito bites to humans. In a paper published today in Nature Genetics, a group of African and British doctors and scientists report on their study of the genetic roots of malaria susceptibility. They found no new smoking gun with this effort, but learned much about how to improve African genetic studies in the future.

The researchers gathered the SNP genotypes of 2,500 children, with the consent of their parents, from a small region in The Gambia. About 1,000 of the children had been admitted to the hospital with a case of severe malaria — the other 1,500 were newborns. In a genomewide association study, the researchers checked each of a half-million SNPs (single nucleotide polymorphisms) for sharp differences in genetic composition between the group of children suffering from malaria and the group of newborns, who served as an approximation of a malaria-free group. If one version of an individual SNP was seen at high frequency among the malaria victims, but at low frequency in the newborns, then the difference might be because the SNP tends to cause malaria or is nearby one that does.

Upon scanning their data, the researchers came up more or less empty-handed: by the usual standards of the field, none of the 500,000 SNPs would pass muster.

This deflating result stands at odds with what is known already about the genetics of malaria susceptibility. Most people who have taken a biology class learn that human populations in malarial regions have developed a natural immunity to malaria infection, not through their immune systems, but through a genetic modification of hemoglobin. Hemoglobin is a molecule charged with ferrying oxygen from your lungs (and the lungs of most life forms that have them) to all your cells, an essential task. Biologists have traced hemoglobin-based malaria resistance to a change at a single DNA base pair on chromosome 11 — wouldn’t we expect at least this SNP to light up as significant?

In truth, the failure wasn’t so surprising; it arises from the interplay of genetics with our species’ history. Humans first arose in Africa, so that’s where genetic variation has had the longest time to build up. Modern-day Asian, European, and Native American people descend from people who emigrated from Africa about 50,000 years ago. These migrants carried just a subset of the African gene pool with them, so non-African populations today have much less “well-mixed” genomes than African populations. The present study uses genotyping chips developed for use in European populations, and its failure to find the known hemoglobin SNP (which isn’t even genotyped by the chip) and other known genetic contributors to malaria resistance is essentially due to the fact that you’d need more like two million SNPs than half a million to do the job right.

The solution, you’d think, is just to make a chip with a lot of markers for specific use in Africa, and be done with it. But the authors show that African genomes appear to be mixed so well that no single such chip could be designed. Instead, they propose an alternative approach: use a good but inevitably suboptimal African SNP chip in your full study sample, then obtain full genome sequences from a small number of the members of that sample. Then, using a powerful statistical method called imputation, you use the full sequences of the smaller group to fill in the full genomes of the entire study sample based on their SNP genotypes. This approach, as the authors demonstrate convincingly in the case of hemoglobin-based malaria resistance, would provide a statistically powerful and economically viable means of tracking down the causes of some of the most challenging health problems of our 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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Generally when you think about what separates humans from other species, features like upright walking, large brains and language come to mind.

But diet has actually played an enormous role in human evolution. Today at the annual meeting of the American Association for the Advancement of Science, a panel of anthropologists, geneticists and paleontologists got together to discuss how who we are has been shaped by what we eat.

Perhaps the most surprising conclusion was that — despite what some diet gurus may say — there is no “natural” human diet. Not only can humans thrive on a wide variety of diets, from the highly carnivorous fare of nomadic Siberians to the virtually all-potato menu consumed by native Peruvians, but thanks to evolution our species can change its diet surprisingly readily.

“You can find humans living well and healthily from a tremendous diversity of diets,” said William Leonard, an anthropologist at Northwestern University in Evanston, Ill.

But all cultures have one dietary feature in common, said Harvard University primatologist Richard Wrangham — they cook their food. Wrangham believes the advent of cooking during human prehistory was a major evolutionary milestone, because it essentially pre-digested starches and proteins and softened food, helping increase the amount of energy that could be extracted on it. In fact, he pointed out that people in modern technological societies who take up so-called “raw food” diets usually lose substantial amounts of weight.

Many diet books advise following a high-protein, low-carbohydrate diet in order to emulate the eating habits of pre-agricultural humans. Whatever the benefits of such a diet, however, it is clear that in the 10,000 years since the development of farming our genes have responded to the increasing availability of foods such as rice, grains and milk.

“I would say most people who descend from agricultural populations are actually pretty well adapted to a starch diet, because most of the world eats a lot of rice, a lot of corn and a lot of potatoes, said Anne Stone, a geneticist at Arizona State University.

Stone and her colleagues have studied the gene AMY1, which encodes a salivary protein called amylase that breaks down starch. All people have multiple copies of the AMY1 genes. But those from traditionally agricultural populations, such as the Japanese and Europeans, have many more than those from cultures that have never practiced agriculture.

Customers of 23andMe may be able to see the evolutionary effects of an agricultural heritage in their own genetic data. Before people started herding cattle, goats and sheep, the human biological machinery for digesting milk was turned off not long after infancy — perhaps to prevent older children from getting in destructive fights over breast milk. But with herd animals on the scene, when a genetic modification that kept milk digestion functioning into adulthood arose in Europe around 8,000 years ago, it was so beneficial that it eventually spread throughout the continent.

23andMe customers have one modified version of the lactase gene for each A at the SNP rs4988235.

Similar scenarios happened in several other parts of the world as well, so that now many people of European and some of African ancestry can easily digest large amounts of milk.

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Chia, a former organic chemist who is happy to be out of the lab after a ten-year stint in front of a bench, is the Community Manager at 23andMe. What does this mean, you ask? Well, it’s a cross between a den mother, grassroots PR person, customer service agent, brand evangelist and community advocate. This position grew out of the early days of the internet, when the nominal leaders of a group were known as Sysops or more recently, moderators of a forum. Chia has been a passionate advocate for using the internet to bring people together since the early days of online communities using BBS (Bulletin Board System)in the late 80’s and early 90’s.

You can find Chia on Twitter.

Chia on the 23andMe Service:
“I found out some very interesting information about my ancestry that I never suspected. My maternal haplogroup is not found in Han Chinese, but is instead common in a small minority group called the Daic that lives in southeastern China. Other common places my haplogroup, F, is found are Thailand, Vietnam, Indonesia and neighboring islands. I haven’t had the heart to tell my extended family as they have always been proud to be Han Chinese.”

“I also found out that I’m a slow caffeine metabolizer, which is not surprising. I was banned from having coffee at another start-up I worked at because I would buzz around the office for hours like a hummingbird after one cup. I have figured out that I can’t have caffeinated tea or coffee after 11 am unless I want to be up until 3 am, sorting my sock drawer.”

Chia on Being a 23andMe Employee:
“I’m the first community manager and I feel very lucky to be able to remember my scientific training but at the same time be part of a biotechnology revolution. It’s great to be able to help people understand what 23andMe is!”

Think you’d like to join our team? Check out our jobs page!

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Rachel is the Manager of Communications at 23andMe, i.e. the company gatekeeper. She handles incoming press inquiries, manages the public relations surrounding the launch of new features and partnerships, and talks to reporters and news producers about everything 23andMe. Imagine C.J. on the West Wing, except shorter and with less politics and more genetics. Rachel joined 23andMe in May, escaping a career in corporate litigation for the serenity and rationality of science.

Rachel on the 23andMe Service:

“Because I’m not a scientist, I hadn’t thought much about my family’s genetic relationship prior to using the service. Now that my Mom and I are both customers, it has been interesting to discover where our genetics are similar and how they differ. It turns out I can blame her for my higher than average risk for psoriasis. It was also interesting to find out about our maternal haplogroup, K2a2a, which is common among Ashkenazi Jews. Now, we just need to do a 23andWe study to determine whether there’s a genetic basis for repeatedly asking, ‘Are you going to be warm enough in that?’”

Rachel on Being a 23andMe Employee:

“Because I have to keep up-to-date about on all aspects of the company, I learn something new every day. Everyone here is incredibly intelligent and creative. The scientists and engineering and product teams are always eager to explain a complicated genetics concept or how a new feature works. And, because we continuously are working on features and research projects, there’s always a new story to tell. Needless to say, my job never gets boring.”

Think you’d like to join our team? Check out our jobs page!

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Jonathan was a founding student of CSU Monterey Bay where he studied International Relations, Global Economics and Computer Science. Though he wanted to work in international politics and only studied computer science to keep his two Silicon Valley engineer parents happy and paying for college, eventually genetics won out and he joined the “family business.” Upon graduation he began working in network and physical security, getting paid to break into banks and R&D facilities. Eventually he settled into more of a sysadmin role in security which led him to run a QA Lab at Qualys and then IT for 23andMe.

Jonathan on the 23andMe Service:

“Coming from a diverse family where my cousins include Guamanians, Native Americans and Norsemen, genetics has always been a curiosity of mine. A friend of my father’s worked on the Human Genome Project and I loved to talk with him about the possibilities it offered for the future. One of the things we envisioned was a service like 23andMe.”

“It has been very interesting for me to learn what traits I did inherit from the different branches of my family, particularly with such a mixed heritage turning out to be genetically almost purely Norse. I have started sending kits to my family, starting with my grandmother, to trace this down.”

“I also always wondered how true my mom’s highly scientific supposition of ‘you are just like your father’ whenever she was mad at me growing up was, now I will know!”

Jonathan on Being a 23andMe Employee:

“I got curious about 23andMe when a friend told me about the company. I read all sorts of articles about the groundbreaking work they were doing in trying to make genetics understandable and available to the masses and was fascinated. I cut a sabbatical short and applied to work here a week later.”

“23andMe has a great environment that fosters team work, sharing of ideas, forward movement and learning. I definitely made the right decision in coming here and am excited to be a part of transforming this brand new industry.”

Think you’d like to join our team? Check out the 23andme Jobs page!

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One of the reasons genetics is such a powerful tool for telling us about the past is that mutations that accumulate over the generations can be used as a clock, allowing scientists to calculate when different events occurred in the prehistoric past.

By counting the number of mutations differentiating one person from another, we can determine when in the past they shared a common ancestor. Each mutation is like a genetic tick of the clock, equivalent to a certain period of time. But figuring out how frequently mutations occur, and thus how long each tick of the genetic clock takes, is a major enterprise.

In a new paper appearing this month in Molecular Biology and Evolution, scientists from 23andMe propose that the genetic clock may have started running faster after the Ice Age ended about 15,000 years ago. If so, they may have resolved a discrepancy that has perplexed researchers for a number of years.

DNA mutation rates are estimated in two different ways. Geneticists can either count the number of mutations that occur in one generation (the changes between parents and their children), or they can count the number of differences between human and chimpanzee DNA and calculate a mutation rate based on the number of years since the two species diverged — about 6 million years.

It turns out that mitochondrial DNA mutation rates measured by these two methods described differ almost 10-fold. This difference is seen not only in humans, but also in species such as birds and fish. The discrepancy hints at the possibility that what we are measuring might be more complicated than we previously thought.

Working with Marcus Feldman of Stanford University, 23andMe scientists set out to find a new way of estimating the human DNA mutation rate by comparing the genetic diversity of lineages derived from the first human inhabitants of various continents and islands with archaeological finds that give precise information about when those colonists arrived (such as Polynesia).

We focused our studies on mitochondrial DNA data because there are a large number of mitochondrial sequences available in databases and the mutation rate of this DNA is known to be higher than in the autosomal DNA found in the 23 pairs of chromosomes,

What we found was surprising. Younger lineages (i.e. groups of people that have more recent common ancestors) had higher rates of mutation than older lineages, meaning that the molecular clock is not constant for human mtDNA: it slows down as lineages get older.

But why?

In our study the estimated mutation rates dropped off quickly around the end of the Ice Age — 15,000-20,000 years ago — suggesting that population history may play an important role in explaining the reduction in genetic diversity, and thus the changing pace of the DNA clock.

Prior to 20,000 years ago, humans lived in small hunter-gatherer groups that likely experienced boom and bust cycles: periodic climatic shifts or food shortages probably caused frequent and sudden population collapses. When populations decrease in size, or “bottleneck,” some genetic lineages are lost, which decreases the genetic diversity of the population. Since mutation rates are calculated using genetic diversity, the mutation rate estimates from these older lineages are slower.

After the climate warmed about 15,000 years ago and humans subsequently invented agriculture, populations grew dramatically. This resulted in more stable genetic diversity and faster mutation rate estimates.

More research needs to be done before we can determine whether population history or other factors, such as natural selection changing mutation rates, are primarily responsible for the human molecular clock slowdown. For example, we could simulate genetic diversity changes when a population size decreases and see if this matches the empirical mutation rate estimates.

Using our new data, which trace the slowdown in mutation rate back in time, scientists can identify the number that is most appropriate to use for studies of particular population events.

To date, the timing of most population events in human evolutionary genetics was estimated has used a rate close to the slower one we see for older lineages, before the end of the Ice Age. So our understanding of the genetic history of early human evolution shouldn’t change very much. But the timing of the splits between mitochondrial lineages associated with relatively recent events, such as agricultural expansions, may need revision. Using our newly calibrated mitochondrial mutation rates, researchers will be better able to correlate genetic, archaeological and linguistic data, leading to a more accurate understanding of human prehistory.

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Editor’s Note: This week TIME Magazine is naming the 23andMe Personal Genome Service™ its Invention of the Year, an honor that the publication has previously bestowed on innovations such as the iPhone and YouTube. This post by Director of Products Alex Wong (back row, second from right) offers a glimpse at how 23andMe came to be, and what makes it such a powerful tool for exploring your DNA.

We’re thrilled that our product has been named TIME Magazine’s 2008 Invention of the Year. But what exactly did we invent? To answer that question, let’s to go back to the early days of 23andMe … .

I first met our co-founders Anne and Linda, together with Serge and Brian, our first two employees, in the summer of 2006 at a bakery in downtown Palo Alto, Calif.. As they were explaining the basic concept behind the company, Linda reached into her bag and pulled out a CD with “Aveys” written on it in magic marker.

“What’s that?”, I asked.

Her reply: “It’s my family’s genomes!”

That’s a first, I thought to myself — pulling genomes from a handbag. I was hooked. I knew I wanted to join 23andMe and help make this possible for everyone and their family.

But we had a long way to go. DNA chip technology was still fairly new, something that only researchers had access to. Linda, having worked at a DNA chip company, was able to get her own family genotyped. But unless you had an in at a research lab or one of these companies, getting your own genome just was not possible. Even if you did manage to get the genomes of you and yours on a CD, all you’d find when you looked at it would be a bunch of giant, indecipherable text files filled with “rs” numbers and A’s and B’s. These are the raw data files of SNP information that the DNA chip analysis produces.

How to make sense of all that data? The good news was that years of research, starting with the Human Genome Project and the International HapMap Project, had produced a wealth of publicly available information about human genetics. The bad news was, it was all locked inside databases designed by researchers, for researchers. Want to know what one of your SNPs means? A logical place to start, you would think, would be dbSNP, a massive database of SNPs run by the National Institutes of Health.

Good luck. Assuming you can wade through its dense user interface, make sure you get your alignment, genome build, major and minor alleles, orientation, and stranding right, or you’re liable to get your interpretation backwards and think you’re supposed to have wet earwax when you really have dry! Don’t know what stranding, genome builds, or any of those other things are? Trust me, you’d rather not.

Not only did these government and academic databases sport slow and unfriendly user interfaces, but some of them also had data quality and consistency problems and few of them were linked together.

So it was going to require more than just building a website to make all the fruits of ongoing genetic research accessible, useful, and compelling to regular people like you and me. We had to create a whole architecture and process for cleaning up, aggregating and integrating all of this human genetic information, combining it with an individual’s own genotype data, running comparisons and algorithms on it, blending it with great educational content, and serving it back to our customers through a friendly user interface — all in under 500 milliseconds, which is how long you have before people start to complain that your website is slow.

On top of that, we wanted personal genetics to be social, so our customers could see their genetic data in context and learn about what makes us all different and similar at the same time. That meant building in the ability for customers to share their data with family or friends without sacrificing privacy or security.

It’s taken the combined talents of all the different kinds of people we have at our company, from bioinformaticians, to engineers, to writers, to UI designers, but we’re all so excited about having made it possible in 2008 for anyone with $399 to explore their own genome.

Of course, if you’d like to rock it 2006-style, you can still get your own gigantic text file full of SNPs using our Download Your Raw Data feature. You can even burn it onto a CD and stick it in your handbag!

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