The Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH) is an exceptional study that has the potential to transform medicine.  As someone who proudly spent over 25 years as a patient with Kaiser, I would be excited to see my family’s medical records used for such a worthy cause.  I was disappointed, however, to learn that Kaiser will not be giving participating individuals the option to get access to the genetic data Kaiser generates in the study, as I said in my recent TEDMED talk.  Yesterday, Cathy Schaefer, executive director of the RPGEH, commented on the Robert Wood Johnson Foundation blog that the research data will not be returned “because genetic information obtained through today’s genome-wide studies has not been designed to be useful to individuals; it is designed for use in research” (also noted by Genomics Law Report and Genetic Future).

I strongly disagree that one’s genome is currently only useful in research and not for individual use.   There are a number of highly useful genetic results that may be generated.  Individuals may learn that they are carriers for Mendelian disorders such as cystic fibrosis or sickle cell anemia.  The genetic data might reveal that an individual is at higher risk for certain diseases such as age-related macular degeneration, blood clots, Parkinson’s disease or breast cancer.  Last, the genetic data may tell an individual whether or not they are likely to respond to certain drugs, like Plavix and Coumadin.  Is it right for Kaiser to tell me what information I can or cannot have about my own body and my own genes?

I co-founded 23andMe, a personal genetics company, to enable individuals to access their genetic information—what we believe to be a fundamental right.  We also believe this right should extend to research participants.  Though the RPGEH plans to inform individuals if researchers discover something that “may be important to their health”, this is not the same as an individual having their complete data in hand, and it is unlikely that researchers would continue to update 100,000 participants as genetic research progresses.

Even if genetic research is at an early stage today, having one’s genetic data will be of increasing utility as research progresses.  Individuals have a vested interest in understanding what their genetic data mean in the context of new studies.  They may examine their data through 23andMe, other companies, or open-source services such as SNPedia.  The choices about what to do with that information are then with the individual, where they should be.

My husband, Sergey, learned through the 23andMe test that he is at substantially higher risk for Parkinson’s disease. That information has had a significant impact on our lives.  We eat better and we exercise more.  We are motivated to follow, participate in, and fund Parkinson’s research.  This information is important for understanding our general health and for helping us plan our lives.  Some in the medical world do not believe we should have this information.  In fact, when the Parkinson’s variant was discovered, we were dissuaded from being tested because “there is nothing to do.”  But there are things one can do, and that choice should be ours.

A growing body of evidence suggests that individuals do not suffer adverse effects from knowledge of their genetic data, and that public opinion leans strongly toward offering the return of results to research participants.  For example, in a study of focus groups, the Genetics & Public Policy Center found that “focus group participants voiced a strong desire to be able to access individual research results.”  And far from frightening people, returning genetic results could provide an incentive for future recruitment into these important studies.  Whole-genome information would also be useful to the growing number of people interested in genealogy.

We also believe that researchers cannot know—and therefore should not dictate—what is or isn’t useful to individuals.  Even for “non-actionable” variants with severe consequences such as the ApoE e4 association with Alzheimer’s disease, research from the REVEAL studies at Boston University showed individuals may find personal utility in having their data.  For example, they may choose to prepare their family, buy long-term care insurance, or participate in research—these are choices individuals and families have a right to make with knowledge about their own health.

Kaiser is breaking new ground with the RPGEH study but we believe they are missing a key component.  Kaiser should afford the participants the respect they deserve by allowing them to decide for themselves whether they want to see their own genome.

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We may be another step closer to discovering what makes us human.

A new study published online this week in Genome Research has pinpointed three genes in humans that may genetically differentiate us from chimps and other primates. Genetically we are very similar to chimps, so most of the differences researchers have observed to date regard physical appearance and behaviors.

The new study found several genes that were once silent and nonfunctional in our primate ancestors, and seem to have awakened around the time that humans formed a new evolutionary branch.

Researchers at the University of Dublin compared sections of the human genome with those of chimps and other primates to find active genes that are absent from the chimp genome. They found three human genes, CLLU1, C22orf45 and DNAHI0OS, that were present but inactive in non-human primates.

At the location of each of the three human genes, a disabling sequence of DNA was found in the genomes of the chimp, macaque, gorilla, gibbon and partially in the orangutan. The study suggests that the awakened human genes not only shed their disabling components, but gained “enabling” sequences that helped them do the work of forming proteins in the body.

Previous research found that genes arising from inactive DNA were present in flies and yeast. The study suggests there may be a total of 18 awakened genes in humans, but researchers were limited to analyzing only a part of the 24,000-gene human genome.

The functions of these novel genes are not yet known, but it is tempting to infer that these genes, specific to humans, are responsible for the attributes that differentiate us from other primates.

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There are many examples around the world of two distinct ethnic groups living side by side.

Sometimes these groups co-exist peacefully. Other times they do not.

Often two groups’ differences – along with circumstantial factors – lead to tension between them and sometimes violence. The Hutus and Tutsis of Rwanda, the Sunnis and Shiites of Iraq, and the Croats and Serbs of former Yugoslavia all illustrate how cultural distinctions – like language and religion – can contribute to tensions and conflict around the globe.

But do these cultural and ethnic distinctions translate to biological distinctions as well? Exactly how biologically distinct are two ethnic groups living side by side? Anthropologist Evelyn Heyer and an international team of researchers set out to answer these and many other questions by studying the adjacent – and culturally very different – Tajik and Turkic speakers along the Silk Road of Central Asia. Their results are published in this week’s BMC Genetics.

The authors focused on the Tajik and Turkic speakers because those groups offered a unique perspective on how two groups living in such close proximity can be so different from each other.

The Turks are largely nomadic herders. They speak Indo-Iranian languages like Azerbaijani, Turkish, and Altay. Their society is organized into clans, or “descent groups,” whose membership is passed down from father to children.

The Tajiks are, conversely, agriculturalists. They speak various dialects of the the Tajik, or Tajik Persian, language that may have arrived with Muslim invaders 1,000 years ago. Their society is largely patrilocal – meaning that when couples marry they put up residence near the husband’s family; and first cousin marriages are encouraged.

The two societies are supposedly closed, and members of both groups are said to rarely leave their clan or village. This cultural isolation made them perfect candidates for Heyer and her team to study.

So the researchers collected both maternally inherited mitochondrial DNA and paternally inherited Y chromosome DNA from more than 1,000 individuals spanning 24 Turkic and Tajik populations.

What they found was that these two ethnic groups weren’t so different after all.

Genetically, the Tajiks and the Turks were virtually indistinguishable. The authors found the overall level of genetic diversity between the two groups to be less than 1% overall — so small that there was a greater amount of diversity within each group than between the two.

Their analysis also shed some light on the origins of these these two ethnic groups. The modern-day people of Central Asia maintain their own origin stories that are unique to their particular group. In part, it is these unique origin stories that distinguish them from one another. But Heyer’s analysis proves that these groups actually share the same roots; they are simply a hodgepodge of the clans, tribes, and villages that have called Central Asia their home for thousands of years. Over many generations they banded together to form larger groups until they consolidated into just two major divisions: the Tajiks and the Turks.

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On August 20, 79 AD, a series of small tremors and earthquakes began to shake the two ancient Roman cities of Pompeii and Herculaneum.  Lying in the shadow of Mount Vesuvius — about 150 miles south of the Roman capital — the two cities were often hit by tremors and earthquakes, so most residents were unperturbed.  After all, the tremors were relatively mild, especially compared to a severe earthquake that had hit both towns 17 years earlier.

They did not know, however, that this new string of tremors was in fact due to increasing pressure inside Mount Vesuvius; they did not know that Mount Vesuvius was in fact an active volcano; and they did not know that it was about to erupt.

Just four days later, on August 24, Vesuvius did just that.  The cities of Pompeii and Herculaneum were taken completely off guard.  So much so, in fact, that many residents were unable to escape the rain of pumice and ash that fell to dozens of meters high, burying people inside their homes.  Even those who did survive the ash were unable to outrun the pyroclastic flow, a wave of white-hot cinders that tumbled down Mt. Vesuvius at over 100 mph.  In just a few days, these cities became buried, and soon were forgotten.

Pompeii and Herculaneum remained buried for the next 1,600 years, when military engineers digging a new course for the River Samo uncovered what looked to be an underground city.  They had found the remains of the buildings, houses and plazas that made up these two ancient Roman cities.  And – perhaps more importantly – they found the remains of the inhabitants, often almost perfectly preserved.

This was especially true for the remains of 13 individuals, hidden inside a villa belonging to a Pompeii resident named Caius Iulius Polybius.  Inside the villa, two individuals were still holding hands; another was clutching her stomach, the remains of her unborn child still inside. Archaeologists have spent many decades trying to uncover as much as possible about these and the other thousands of individuals found buried in Pompeii and Herculaneum.  Now geneticists have entered the fray, using sophisticated techniques to extract and analyze the DNA of these 13 individuals with the goal of understanding the relationships between them.  The results of this analysis are published in the July issue of the the Annals of Human Genetics.

The research team, led by Giovanni de Bernado from the University of Naples, extracted the mitochondrial DNA (mtDNA) from all 13 individuals.  The mtDNA is passed down, almost always unchanged, from a mother to her children. So researchers can conclude that individuals in a grave or archaeological site who share similar or identical mtDNA profiles – known as haplogroups – are likely related to each other along the maternal line. The mtDNA is also useful in archaeology because it is more likely to remain preserved long after an individual dies.

But there can be problems with preservation when analyzing mtDNA, and that is exactly what happened with a few of the remains.  Di Bernado and his team were unable to extract mtDNA from three of the individuals.  But for the others, they were successful.  In fact, six of the individuals yielded an identical maternal haplogroup assignment:  T2b.  T2b exists in about 4-5% of modern Italians, making it one of the rarer haplogroups in the region.  So for it to exist at such high levels within a single household almost certainly proves some kind of familial relationship between the inhabitants of this house.

Who were the individuals bearing the T2b haplogroup?  Four children ranging in age from three to 14, a young woman of about 18 years, and a man of about 30 years. Di Bernado argues that the four children were probably siblings (or at least cousins), that the 18 year-old woman could perhaps be an older sister or aunt, and the man is likely to be a maternal uncle.  Unfortunately, one of the female remains – who would be an ideal candidate as the childrens’ mother, yielded no reliable mtDNA type.  The remaining individuals bore different haplogroups, and may have represented the father or paternal grandparents.  There is also the possibility that one of the adult women was a mistress of the head of the household, something not uncommon in ancient Rome.

For many years, the identities of the Pompeian and Herculanean victims’ remains, entombed in ash and cinders, have both haunted and intrigued scientists.  Now, with efforts such as the ones performed here by Di Bernado and colleagues, we are learning more about who they were in life, and not just about their final moments.

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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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Only 250 miles separates the island of Madagascar from the southeast coast of Africa.  The short distance between the two land masses traditionally led the outside world to assume that the native inhabitants of Madagascar – known as the Malagasy – originally came from the west, probably from the present day southeast African nation of Mozambique.  Yet upon closer examination of the Malagasy’s language and their physical features, many scholars began to question this notion.  The Malagasy of the central plateau of Madagascar, known as the Highlanders, had light skin and facial features more akin to Southeast Asia or Indonesia.  They also practiced a rice culture that was not unlike the rice cultures of Asia.  And yet the coastal Malagasy, known as the Côtiers, seemed just the opposite.  They had darker skin and curly hair that was more similar to modern day Africans.

But both the Highlanders and the Côtiers speak the same language, which shares 90% of its vocabulary with a language spoken today in Southeast Borneo, and which has been officially classified as a branch of the Austronesian language family called West Malayo-Polynesian.  So how could a significant portion of Malagasy seem to share more in common with a region 5,000 miles away than they do with mainland Africa?  Trying to find the answers to these questions has vexed archaeologists, historians and linguists for generations.  Over the past several years, geneticists have entered the fray to try and unravel the mysterious origins of the Malagasy.  Their most recent effort appears this week in Molecular Biology and Evolution.

This study, led by Sergio Tofanelli of the University of Pisa, built upon a 2005 study by Matt Hurles and colleagues that was the first genetic exploration of the Malagasy people.  But Tofanelli and his colleagues wanted to dig even deeper into the genetic history of the Malagasy.  So they took the data analyzed by Hurles in addition to new DNA samples that were collected from people across the island of Madagascar.

They focused on two regions of the human genome often used in genetic ancestry studies:  the mitochondrial DNA (mtDNA) and the Y chromosome.  Because the mtDNA is used to trace maternal ancestry, and the Y chromosome to trace paternal ancestry, analyzing both in the same study can give a more complete picture of a group’s genetic history.

Tofanelli and his research team examined the mtDNA and Y chromosomes of Malagasy individuals scattered across the island, from both the Highlander and Côtiers groups.  They were searching for any clues that would give an exhaustive understanding of how and when the island of Madagascar was first settled, and by whom.

The researchers’ analysis revealed a mixture of both African and Asian genetic ancestry, in both the Highlanders and the Côtiers, which is perhaps contrary to the two groups’ physical apperance.  So what does this mean?  That even the Côtiers people, who often look more African in appearance, have an ancestry that traced back to Asia, specifically Borneo.  These results fit well with Hurles’ study and with what linguists have been saying for years; that the Malagasy language – while clearly tracing back to Borneo – also has some African elements that are significant.

The results from these analyses then begged the next question — how and when did the earliest inhabitants of Madgascar arrive on the island?  Was it in two separate migrations – one from the east and one from the west – or did the Asian/African genetic make-up of the Malagasy exist prior to their first steps on Madagascar?  It is easy to assume that any intermarriage between Africans and Southeast Asians happened after each arrived on the island.  In fact, Tofanelli describes the genetic make-up of the Malagasy as a consequence of “the encounter of people surfing the extreme edges of two of the broadest historical waves of expansion” in human history.  He is referring to the sub-Saharan African Bantu expansions that began 5,000 years ago and swept across Africa from Cameroon to Mozambique and southern Africa, and the Austronesian expansions about 4,000 years ago when seafarers journeyed from Taiwan to Borneo and beyond.

But Tofanelli proposes an alternative hypothesis as well.  He argues for a long history of contact between Bantu-speaking Africans and seafarers from Borneo dating back thousands of years.  As evidence he cites banana cultivation in Cameroon and Uganda that can be traced back to Southeast Asia, as well as the introduction of humped cattle into Africa from Asia.  If the Southeast Asians and eastern Africans shared farming techniques, it stands to reason that they may have shared genes as well.  Thus the people of Madagascar may have not simply been Africans and Southeast Asians arriving on the island from opposite directions, but rather they represent a more complex genetic history of proto-Malagasy arriving on Madagascar about 2,300 years ago, already containing a mixture of Asian and African ancestry.

This hypothesis most certainly needs additional evidence and data before it can be supported, but it brings a new level of understanding to the mysterious origins of the Malagasy.

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

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

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

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

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

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

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

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

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

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

Related posts in the Spittoon:

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

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

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

SNPwatch: Genetic Variants Affect Weight Loss Drug Effectiveness

SNPwatch: Genetic Link Between Obesity and Colorectal Cancer

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

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

SNPwatch: MC4R Gene Associated With Body Mass

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Great apes really do giggle when tickled, new research says – just like you and me.

Researchers from the University of Hannover in Germany recorded the tickle-induced vocalizations from three human infants and 21 infant and juvenile orangutans, gorillas, chimpanzees and bonobos and analyzed this acoustic data to find similarities and differences among the five species.  Their results, published online today in the journal Current Biology, show that not only are the hoots, hollers and snorts of the great apes really laughter, but the evolutionary relationships between the sounds match up with the known evolutionary relationships between the species based on genetics.

“At a minimum, one can conclude that it is appropriate to consider ‘laughter’ to be a cross-species phenomenon, and that it is therefore not anthropomorphic to use this term for tickling-induced vocalizations produced by the great apes,” the authors write.

But the researchers’ findings also indicate something more profound: rather than being a uniquely human invention, tickle-induced chuckles can be traced back 10 to 16 million years to our last common ancestor with the great apes. Analysis of the chortles of a lesser ape, the siamang, suggests that laughter may be even older.

The tree based on laughter matches the genetic tree.

Despite the all the similarities the researchers found between humans and the great apes, the fact remains that human giggles are distinct – we mostly laugh while exhaling and our vocal chords vibrate to make the “ha ha ha” sounds, while ape snickers are more of the in-and-out panting variety.  The question for future research to answer is why particularly human features emerged and what functions they may have served as laughter became a large part of human social interaction.

Insanely cute video of giggling chimps here.

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Type 1 diabetes is on the rise in European children, says a new report.

Researchers studied type 1 diabetes data collected between 1989 and 2003 at 20 centers in 17 European countries. Their results, published online yesterday in the Lancet, show that more children, especially younger children, are being diagnosed with the disease each year.  Based on the trends they saw, the scientists calculate that there were 94,000 kids under the age of 15 with type 1 diabetes in Europe in 2005, and that by 2020 that number will soar to 160,000.

While researchers aren’t exactly sure why this is, they do know that it’s not due to changes in the prevalence of susceptibility genes.  Genes just don’t change that quickly.

An almost 70% increase in disease prevalence in one generation must be due to changes in non-genetic factors. Most random genetic changes in a population come and go pretty quickly, especially mutations that reduce fitness.  And if a new mutation does manage to stick, it would take millions of years, not tens of years, to see its effects.  Even for mutations that provide a benefit, like the one that led to the lactose tolerance seen in many people with European ancestry today, it takes a few hundred years to build-up to high enough levels in the population to cause an observable change in a trait.

An increase in disease incidence due to changes in non-genetic factors, whether they are environmental or cultural, has been seen for many diseases.  It’s especially apparent when groups migrate from low- to high-risk countries for a particular condition.  Just this month a study showed that Asian Americans who are more “westernized” have adopted the sunbathing ways of their families’ new homes, which the authors suggest may be the cause of increasing rates of skin cancer in this group.

But the effects of lifestyle changes can also be seen in shifts in disease rates within a population. The prevalence of obesity in United States adults, for example, jumped from 15% in the late 1970’s to nearly 35% today thanks to the trend toward eating more and exercising less.  And because of the increase in obesity, rates of type 2 diabetes are also up.

Many scientists attribute the increase in incidence of several immune system-related disease to what on the surface seems like a good thing about modern lifestyles: fewer infections.  The so-called “hygiene hypothesis” suggests that without the types of infections our species evolved to deal with (many of which are still prevalent in developing nations), our immune systems don’t get the right training.  The lack of challenges to the immune system has been linked to increased rates of allergic diseases like asthma and eczema and autoimmune diseases like Crohn’s and multiple sclerosis.

For some diseases, the reason behind their apparent increases has more to do with increased detection than changes in environment. Up until a few years ago, for example, it was thought that only about one in every 3,000 people in the United States had celiac disease.  But now, thanks to better guidelines on how to diagnose the disease, physicians are finding that about one in every 133 is affected.

On the other hand, some conditions may appear to be increasing because disease awareness is a hammer that makes a lot of people feel like nails.  It has been put forward that restless legs syndrome, for example, is far less prevalent than some estimates suggest and that increases in diagnoses can be traced to “disease mongering” by pharmaceutical companies.

The authors of the Lancet study suggest that the changes in type 1 diabetes rates they are seeing are due to something about modernization.  They point to the fact that the biggest increases were seen in eastern European countries, which have seen the most rapid changes in lifestyle in the last few decades.  But whatever the culprit is, it is obviously not affecting all children.  And that’s where genetic susceptibility comes in.  DNA variations that increase risk may not be changing in prevalence, but type 1 diabetes, like almost every other common disease, is the result of a complex interplay of genes and environment.

(23andMe customers can see how their genes influence their risk of type 1 diabetes in Clinical Reports.)

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The Royal House of Habsburg, one of the most powerful dynasties of Medieval and Renaissance Europe, reigned over much of Europe for centuries. Beginning in the early 12th century they quickly expanded their realm through a series of strategically executed marriages, from the mountains of Switzerland to a territory that included swaths of Austria, Hungary, Italy, France and Spain. The Spanish branch of the Habsburg dynasty helped create an empire that reached its apex in the 16th and 17th centuries, controlling land from the Phillippines to the Americas.

Yet the Habsburgs are known not only for controlling huge tracts of Europe, but also for maintaining control by rarely marrying outside the dynasty.  By the end of the 17th century, the results of their marital practices had become apparent in the form of a distinctive protruding lip, a high rate of infant mortality and a host of other health problems. Could the same marital practices that helped bring the Habsburg dynasty to power also have led to its demise?

In the April 15 issue of PLoS One, scientists from Spain’s University of Santiago de Compostela argue that inbreeding so incapacitated the Habsburgs over the centuries that by the death of King Charles II of Spain in 1700, they were virtually unable to reproduce.

From 1516 to 1700, it has been estimated that over 80% of marriages within the Spanish branch of the Habsburg dynasty were consanguineous; that is, they were marriages between close blood relatives. Most often, these unions took the form of marriages between first cousins, double-first cousins, and uncles/nieces.  Conceivably as a direct result of these marriages between relatives, infant and child mortality rose to 50% among Spanish Habsburgs, much higher than the average for the period.

But the final Habspurg king of Spain, Charles II, was perhaps the most unfortunate result of these unions.  Also know as “El Hechizado” (”The Hexed”), Charles was severely deformed.  The so-called “Habsburg Lip”, a form of mandibular prognathism often seen among members of the Habsburg Dynasty, was so pronounced in Charles’ case that it was difficult for him to speak.  An enlarged tongue, gastrointestinal problems, mental retardation, and possible growth problems meant that Charles was raised almost as an infant until the age of 10.  Even as he grew older, he was never able to govern effectively.  His rule saw the rapid decline of the Empire, only exacerbated by his death in 1700.

But for all the speculation and anecdotal evidence of the negative impact of inbreeding on the House of Habsburg, there has been little scientific research as to whether inbreeding actually played a factor in its extinction.  The authors of this study sought to achieve this goal by examining genealogical information, in the form of family pedigrees, for the eight royal families connected with the Habsburg dynasty.

All told they analyzed family pedigrees of over 3,000 individuals spanning 16 generations. They then used this information to calculate the inbreeding coefficient for each family member. The inbreeding coefficient is simply a measure of the chance that someone will receive an identical set of genes from both parents.

Unsurprisingly, the authors found elevated inbreeding coefficients that for many Habsburgs.  In fact, the levels increase consistently from the earliest Spanish Habsburgs, like King Philip I (1478-1506), to Charles II, the last Spanish Habsburg king.  Even more interestingly, some of the Habsburgs – notably Charles II – had an inbreeding coefficient nearly twice what one would expect given the level of relatedness between his mother and father.  In other words, even though Charles’ parents were related to each other as uncle and niece, his inbreeding coefficient fell at the same level as someone whose parents were brother and sister.

These unexpectedly high levels indicate that consanguineous marriages, like that of Charles’ parents, had probably been happening along the Habsburg line for hundreds of years. This practice came to a head with the birth of Charles, whose inbreeding coefficient was the highest of all the Spanish Habsburgs, and whose physical deformities were the most severe.

Further, the authors argue that Charles’ ill health was a direct result of centuries of consanguineous unions.  Specifically, they point to a growth hormone deficiency and severe renal tubular acidosis, which may have accounted for his short stature and his many physical deformities and ailments.  While these diseases are quite rare in the general population, the fact that so many of Charles’ ancestors were related to each other would have increased his chances of inheriting the genes associated with them.  Whether Charles did in fact suffer from these specific diseases is still open to interpretation, though it is clear that his physical and mental difficulties prevented him from fathering any heirs to the throne. The Habsburg dynasty in Spain ended when Charles passed away in 1700, a few days shy of his 39th birthday.

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