Last week in the Blog we reported on a new study that identified an interesting genetic trade-off – a genetic variant known that has one effect on a person&#8217;s vulnerability to malaria, and the opposite on susceptibility to HIV infection. The &#8220;Duffy negative&#8221; version of the gene, which is common among Africans and African Americans, appears to protect a person against malaria but increases vulnerability to infection by HIV. As it turns out, Duffy is not the only example of a genetic trade-off in humans.   There are many instances of genetic variation throughout the human genome that offer both genetic advantages and disadvantages to their carriers.  
<h6> Sickle Cell Anemia vs. Malaria</h6>
<a href="https://www.23andme.com/topics/carrier/sickle-cell-anemia">Sickle cell anemia</a> is caused by a genetic mutation that alters the shape of an individual’s red blood cells.   This mutation, called Hbs, causes red blood cells to take on a sickle-shape, as opposed to the normal round shape.   The sickle-shaped cells then get stuck in the veins and arteries, causing tremendous pain and discomfort.   Sickle cell anemia is recessively inherited, meaning that someone must inherit the Hbs mutation from both parents in order to have the disease. Malaria is a disease that kills between 1 and 3 million people worldwide each year, mainly in the tropics.   After scientists noticed similarities between the geographic distribution of sickle cell anemia and malaria, they began to wonder if there was some sort of connection between the two.
Experiments soon confirmed that sickle cell anemia is a sort of genetic Faustian bargain. Recall that individuals with two copies of Hbs suffer from sickle cell anemia, but people with only one copy of the mutation do not.   They do however, display a resistance to malaria compared with people who have no copies of Hbs.   Occasionally, a pair of malaria-resistant parents will both pass Hbs – and thus sickle cell anemia – to their child. But overall, having only one copy improved the survival rate in human history so much that the Hbs mutation continues to exist in in spite of the disease burden it causes.
<h6>Hereditary Hemochromatosis vs. Iron Deficiency</h6>
Hereditary hemochromatosis (HH) is a genetic condition in which the body absorbs too much iron from the diet.   This leads to the toxic build-up of iron in the tissues of major organs such as the liver and heart.   Without treatment, HH can lead to organ failure. Genetic studies have found that HH, like sickle-cell, is a recessive trait. It appears to have evolved about 1,400 years ago, probably in western Europe, at a time when people ate mostly cereal grains – which are very low in iron. Because having some amount of iron in the diet is essential to maintain normal body functions, this was a serious problem.   During this time period, the ability to store extra iron in the body would have been helpful.   Individuals with HH could take iron from foods when it was available, and then store it in the organ tissues, dipping into those reserves when the supply of iron-rich foods was low.   Today, however, iron is much more abundant. It is an excess of iron, not a lack of it, that threatens the health of people with HH.
<h6>The Paleolithic Diet vs. Obesity</h6>
Why is it that humans crave the very foods that are unhealthy?   Why do we prefer donuts and candy to celery and spinach?   Like hereditary hemochromatosis, the source of this cruel irony lies in the history of our species. The human brain is a very expensive organ to maintain.   It requires a lot of energy to keep all the synapses working correctly, and simply feasting on celery would not do the trick.   Hundreds of thousands of years ago, our ancestors began eating meat as a way to get the required energy their brains needed.   Meat is high in the energy that humans needed to survive, and also in long-chain polyunsaturated fats, which are essential to maintenance of brain tissue.   Bone marrow, the fatty substance inside long bones, is also high in fat and calories, and was thus another prized item in our ancestors’ early diet.   Because foods high in fat and calories were so important to our ancestors, they would have searched them out and evolved a natural preference for them.   Their bodies would have evolved to store any excess fat, in case there were was a long hiatus until the next piece of meat or bone marrow came their way.   This ‘thrifty’ metabolic approach to fat has persisted to the present day, despite drastic changes in the way we feed ourselves.   Now, instead of searching constantly for food we have seemingly unlimited access to Twinkies, beer and other high-calorie delights.   But our bodies are still storing the excess fat. The genetics of obesity are complicated, and by no means can they be fully explained by our ancestors’ diet. But the dramatic change in the human diet since the Stone Age does help explain our cravings from an evolutionary perspective. Variations in the human genome are full of examples such as these: genetic mutations that are beneficial in some ways but harmful in others, or that used to be beneficial, but now result in an increased waistline.   Understanding these genetic ‘trade-offs’ is helpful to understanding the history of the human genome, and could be helpful in tackling conditions such as sickle-cell anemia, hereditary hemochromatosis, obesity and many others.

23andMe Blog

23andMe Blog Team

The Ultimate Trade-off:  Genes, Environment, and Why We Crave Twinkies

In a recent paper, Southern California researchers <a href="http://ucsdnews.ucsd.edu/newsrel/soc/06-08GenesAndPolitics.asp" target="_blank" rel="noopener noreferrer">announced</a> that political involvement has a genetic component.<img loading="lazy" decoding="async" src="https://blog-api.23andme.com/wp-content/uploads/2008/07/twins-300x199.jpg" alt="" class="alignright size-medium wp-image-392" width="300" height="199" srcset="https://blogcms.23andme.com/wp-content/uploads/2008/07/twins-300x199.jpg 300w, https://blogcms.23andme.com/wp-content/uploads/2008/07/twins.jpg 425w" sizes="auto, (max-width: 300px) 100vw, 300px" />
Though they stopped short of identifying a gene or genes at work, the researchers concluded that the decision to go out and vote was genetically determined by up to 50 percent. Genes, they also noted, were partially involved in other activities such as attending rallies, donating to a campaign, and even running for office.
UC San Diego professor James Fowler and his colleagues published their results in The American Political Science Review — not your typical genetics journal. They studied 396 same-sex twins, culled from a list of nearly four million registered voters in Los Angeles County, who had voted in eight state elections between 2000 and 2005. They then replicated their results using an independent twin population taken from the National Longitudinal Study of Adolescent Health.  
<h6 class="MsoNormal">Twin Study</h6>
Aside from finding identical twins more likely to vote the same way than fraternal twins, their data also suggested that genetics accounts for 53 percent of variance in going out to vote.
Fowler and his colleagues aren’t the only ones who use twin studies for their research. In a way, twins can provide researchers with perfectly matched test subjects and controls. Because identical twins have the same genetic information, for example, scientists can do one-on-one comparisons to find out why one is left-handed and the other right-handed, or why one has cancer but the other doesn’t. Such twin studies allow researchers to estimate how much of behavior is due to genes and how much can be attributed to environmental factors. They can also make such comparisons over larger groups of twins to look for a gene or genes that could explain these common traits.

Twin studies have indicated a genetic component underlying an amazing variety of traits, including:

<ul style="margin-top: 0in;" type="disc">
<li class="MsoNormal"><a href="http://www.sciencedaily.com/releases/2007/11/071114183244.htm" target="_blank" rel="noopener noreferrer">age-related hearing loss</a>;</li>
<li class="MsoNormal"><a href="https://www.ncbi.nlm.nih.gov/pubmed/18257946?ordinalpos=1&#038;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener noreferrer">neophobia</a>, or aversion to new food;</li>
<li class="MsoNormal"><a href="http://www.sciencedaily.com/releases/2008/04/080408160636.htm" target="_blank" rel="noopener noreferrer">back pain</a>;</li>
<li class="MsoNormal"><a href="https://www.ncbi.nlm.nih.gov/pubmed/17804594?ordinalpos=20&#038;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener noreferrer">chronic fatigue syndrome</a>;</li>
<li class="MsoNormal"><a href="https://www.ncbi.nlm.nih.gov/pubmed/17438154?ordinalpos=3&#038;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener noreferrer">heart disease</a>;</li>
<li class="MsoNormal"><a href="https://www.ncbi.nlm.nih.gov/sites/entrez" target="_blank" rel="noopener noreferrer">nearsightedness</a>;</li>
<li class="MsoNormal"><a href="https://www.ncbi.nlm.nih.gov/pubmed/18412099?ordinalpos=27&#038;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener noreferrer">obsessive-compulsive disorder</a>;</li>
<li class="MsoNormal"><a href="https://www.ncbi.nlm.nih.gov/pubmed/15651931?ordinalpos=129&#038;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener noreferrer">the size of one’s brain</a>; and,</li>
<li class="MsoNormal"><a href="https://www.ncbi.nlm.nih.gov/pubmed/18315789?ordinalpos=1&#038;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener noreferrer">happiness</a>.</li>
</ul>

<h6>Not So Fast</h6>
But not all researchers are impressed.

&#8220;We suggest that no scientific purpose is served by the flood of heritability estimates generated by these studies,&#8221; psychologist Leon J. Kamin and economist Arthur S. Goldberger wrote in a 2002 paper.

Kamin and Goldberger looked at two population samples used as the basis for several twin studies. One twin population known as MISTRA (Minnesota Study of Twins Reared Apart) is composed of identical twins separated early in life. Researchers wishing to study behavioral differences who used this group might think that any similarities between the twins would be genetic (attributed to nature) and any differences would then be due to environmental influences (nurture). However, Kamin and Goldberger found some cases where statements the twins had given indicated they might have compared notes prior to being interviewed. Such interactions, they argued, could skew the results in studies using MISTRA twins.

<h6 class="MsoNormal">Other Studies</h6>
A second twin population is known as SATSA (Swedish Adoption/Twin Study of Aging). This sample is composed of four groups of twins: identical twins separated in childhood; identical twins reared together; fraternal twins separated before the age of 11; and fraternal twins reared together.

Kamin and Goldberger questioned the definition of separation as in some cases the twins were raised within the same extended family though they didn’t live in the same house. The environmental influences would be too similar, they argued, and that again could skew any conclusions reached by those conducting studies using these twin populations.

One twin study where researchers seem to have been able to successfully separate and track twins and multiples for years was conducted between 1953 and 1997. Known as the Child Development Center’s Study of Twins Reared Apart, the data are part of the records donated by lead researcher Peter Neubauer to Yale University, with the stipulation that the information remain sealed until 2066. For those unwilling to wait, some tidbits may be gleaned from a book by two of the study’s unknowing participants, Elyse Schein and Paula Bernstein, in their book <a href="https://www.amazon.com/Identical-Strangers-Memoir-Separated-Reunited/dp/1400064961/ref=pd_bbs_sr_1?ie=UTF8&#038;s=books&#038;qid=1215550534&#038;sr=1-1" target="_blank" rel="noopener noreferrer">Identical Strangers</a>, as well as in Neubauer’s own book, <a href="https://www.amazon.com/Natures-Thumbprint-Peter-B-Neubauer/dp/0231104413/ref=sr_11_1?ie=UTF8&#038;qid=1215548664&#038;sr=11-1" target="_blank" rel="noopener noreferrer">Nature’s Thumbprint</a>.

The true value of two-for-one deals

<img loading="lazy" decoding="async" class="alignright alignnone size-medium wp-image-375" style="float: right;" title="bluescale" src="https://blog-api.23andme.com/wp-content/uploads/2008/07/bluescale-300x222.jpg" alt="" width="300" height="222" />European researchers have identified variations in the PCSK1 gene that could influence obesity risk in both adults and children. The <a href="https://dx.doi.org/10.1038/ng.1077" target="_blank" rel="noopener noreferrer">results</a>, published online in Nature Genetics, are based on data collected from nearly 14,000 people in five European countries.
The team was led by David Meyre and Philippe Froguel of the Pasteur Institute in France, who have been studying the genetics of diabetes and obesity.
The researchers were inspired by the <a href="https://www.ncbi.nlm.nih.gov/pubmed/9207799?ordinalpos=4&#038;itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum" target="_blank" rel="noopener noreferrer">earlier</a> research of British colleagues, who discovered a rare mutation in the <a href="http://obesitygene.pbrc.edu/cgi-bin/ace/gene/acedb?name=PCSK1" target="_blank" rel="noopener noreferrer">PCSK1</a> gene about a decade ago. That mutation causes obesity by preventing the production of an enzyme involved in metabolism. 
 
For this study, Meyre, Froguel and their colleagues started by examining genetic data from 1,045 obese and 1,265 non-obese French adults. They found six variants — or SNPs — in PCSK1 that showed a strong association with obesity. The researchers narrowed their list to just two SNPs that cause protein sequence changes: rs6232 and rs6234/rs6235. Because the latter two SNPs are linked, they were treated as one variation by the researchers. (23andMe customers should note that while our service does not currently offer information on rs6234 or rs6235, SNP rs10515237 can be used as a direct substitute for this variation.)
An association between obesity and the PCSK1 variants was also observed when the researchers sampled Danish adults, Swiss adults, French children and Swedish families. A sample of children from Germany found an association with SNP rs6232, but not rs6234/rs6235.
After compiling all their data, the researchers found that each copy of the riskier C version of rs6232 increased a person’s odds for obesity 1.34 times over the TT genotype. Each copy of the riskier G version of rs10515237 — which 23andMe uses instead of rs6234/rs6235 — increased odds for obesity 1.22 times over the AA genotype. 
In laboratory experiments, the researchers found that while the obesity-associated variants of PCSK1 found in this study do not interfere with production of the enzyme, rs6232 did reduce the enzymatic activity of the PCSK1 protein by 10%. Research in mice has shown that a change in the mouse PCSK1 gene very similar to the C version of rs6232 in humans <a href="http://hmg.oxfordjournals.org/cgi/content/abstract/15/11/1884" target="_blank" rel="noopener noreferrer">results</a> in increased fat accumulation and obesity.
In the following table, “Effect” is the increase in odds of developing obesity conferred by each copy of the riskier version of a SNP. SNPs where we are providing a proxy for the ones originally reported in the paper are marked with an asterisk. This information applies only to people with European ancestry.
&nbsp;

Researchers Find Genetic Variants That May Influence the Risk For Obesity

The question: What does DNA look like?
While many of the 23andMe scientists have purified DNA more times than we’d like to remember, there are a fair number of people here (on the science team and on the engineering and business teams) who’ve never spent any time at the lab bench. We love all things DNA around here, so we recently set out to make sure everyone at 23andMe has gotten up close and personal with some Gs, Cs, Ts, and As.
We didn’t use human DNA — instead we isolated the genetic material of strawberries (click here for instructions). It’s pretty simple: smash up some strawberries with some soap and salt, add some rubbing alcohol, and voila! DNA!
As you can see in the pictures and video below, it’s an activity that is fun for all ages!
[minislides]
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The Answer: Snot

<img loading="lazy" decoding="async" class="alignright alignnone size-full wp-image-308" style="float: right;" title="omim1" src="https://blog-api.23andme.com/wp-content/uploads/2008/06/omim1.jpg" alt="" width="347" height="254" srcset="https://blogcms.23andme.com/wp-content/uploads/2008/06/omim1.jpg 632w, https://blogcms.23andme.com/wp-content/uploads/2008/06/omim1-300x220.jpg 300w" sizes="auto, (max-width: 347px) 100vw, 347px" />
You may have already read about 23andWe and the ”<a href="https://blog.23andme.com/2008/01/21/the-power-of-we/" target="_blank" rel="noopener noreferrer">Power of We</a>” in earlier blog posts.
As the research arm of 23andMe, we&#8217;re hoping 23andWe can produce valuable discoveries about the genetic roots of diseases, conditions, and traits that are little-studied due to funding limitations, logistical obstacles or simple lack of interest among scientists. 23andMe&#8217;s payoff could prove enormous by offering insights that may eventually lead to risk predictions, diagnostics, treatments or even cures for diseases.
At 23andMe, we are all about grand ideas with big potential, and we are committed to realizing our vision, but how do you even start such a big project? You begin at the beginning, of course.
<h6>Where do you begin?</h6>
When we first started thinking about the traits we wanted to study in 23andWe, we faced a big problem. Out of all the possible traits out there, which ones should, we study first?
It’s both an overwhelming and wonderful problem to have, and one, I think, is pretty unique in the scientific community.
Most academic human genetics labs don’t have the luxury of splitting their research resources amongst many different problems. Subject recruitment, genotyping, and analysis are so difficult and expensive for even one trait that it’s usually feasible for only the largest and most well-funded centers to do this type of work. Limited funding usually also means that only the traits and diseases that are considered really serious get studied.
<h6>Unique Opportunity</h6>
In 23andWe, we saw a unique opportunity to tackle interesting and important questions about biology and disease that have so far been largely left unanswered.
Focusing on what has traditionally been understudied helped narrow down our field of research questions a little bit, but not that much. Frankly, not that many traits and diseases have been studied very well. So we had to apply a few more filters.
We wanted to pick topics that 
&#8211; Are relatively simple, because we have to walk before we can run. 
&#8211; Are easy to capture accurately over the Internet (which for now will involve online surveys). 
&#8211; Will apply to a wide swath of the population. 
&#8211; Already have some evidence in the literature for having a genetic basis
<h6>Tongue Curl</h6>
I can’t tell you how many <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed" target="_blank" rel="noopener noreferrer">PubMed</a> (a biomedical literature search engine sponsored by the National Institutes of Health) searches we’ve done, nor how many 40-, 60-, and 80-year old papers we had to dig up to find some of the information we needed.
It’s been a fascinating project to work on. Did you know that people have been studying the inheritance of <a href="https://www.flickr.com/groups/97912899@N00/" target="_blank" rel="noopener noreferrer">tongue curling</a> for close to <a href="https://www.ncbi.nlm.nih.gov/pubmed/16588317?dopt=Abstract)" target="_blank" rel="noopener noreferrer">70 years</a> ? Turns out it’s not the simple <a href="https://en.wikipedia.org/wiki/Mendelian_inheritance" target="_blank" rel="noopener noreferrer">Mendelian</a> trait your high school biology <a href="http://udel.edu/~mcdonald/mythtongueroll.html" target="_blank" rel="noopener noreferrer">teacher told you</a> it was. Instead, tongue curling ability is probably determined by a mix of genetic and environmental factors.
<h6>Serious Conditions</h6>
It’s not all about tongue curling though. We’ve also been delving into the literature on many more serious health issues that affect large segments of the population but have not yet received as much attention as they deserve. These topics range from dyslexia to endometriosis, to migraine. We plan to collaborate with experts in the scientific and medical communities to push forward the limits of our knowledge on these important topics, with the long-term goal of helping to improve the quality of people’s lives.
In the coming months, you’ll start seeing the fruits of our labor as we roll out our first 23andWe projects. Of course, this is just the beginning. We’re going to spend countless more hours scanning our PubMed search results and fighting with the scientific journals’ user-unfriendly websites. And our thought processes, methods, and goals will continue to evolve as we gain experience and accumulate data. But it’s all worth it because the rewards are potentially great.
Stay posted…

Tackling Tongue-Curling: The Challenge of 23andWe

A large international collaboration of researchers has tripled the number of SNPs associated with Crohn’s disease, an inflammatory bowel disease that affects about 500,000 Americans. Their results were published online Sunday in <a href="https://dx.doi.org/10.1038/ng.175" target="_blank" rel="noopener noreferrer">Nature Genetics</a>.
<img loading="lazy" decoding="async" class="alignright alignnone size-full wp-image-311" style="float: right;" title="illu_small_intestine" src="https://blog-api.23andme.com/wp-content/uploads/2008/06/illu_small_intestine.jpg" alt="" width="300" height="209" />
Data from more than 16,000 people with European ancestry — 8,059 from a combination of three previously published reports, a new set of 2,325 patients and 1,809 control subjects, and a group of 1,339 families — identified 21 new SNPs associated with Crohn’s disease and confirmed 11 previously implicated SNPs.

Although many of the SNPs described in the report only slightly impact the risk of developing Crohn’s, the findings could be important in helping researchers understand the basic biology of the disease.
“Studies such as this are not about developing diagnostic tests, but about identifying targets for new drug therapies. Crohn’s disease can be a very serious condition, often requiring surgery, and the sooner we can understand the underlying causes, the sooner we will be able to devise new treatments to help our patients,” said study author Dr. Miles Parkes.
Some of the newly identified SNPs are in (or near) genes linked to diseases other than Crohn’s, including type 1 diabetes, arthritis, psoriasis, and asthma. This highlights “the important relationships between different diseases and, as such, may offer valuable insights into the pathways that lead to common symptoms such as inflammation,” said Dr. Mark Walport, director of the <a href="http://www.wellcome.ac.uk/" target="_blank" rel="noopener noreferrer">Wellcome Trust</a>, one of the funding agencies that supported the study.
The researchers suspect there are many more genetic associations left to find for Crohn’s disease.
“These [SNPs] explain only about a fifth of the genetic risk, which implies that there may be hundreds of genes implicated in the disease, each increasing susceptibility by a small amount,” said the study’s lead author, Jeffrey Barrett.
Out of a possible total of 46, 80% of people will have between 17 and 25 copies of the riskier versions of these SNPs. Because there are so many of these SNPs — and because the riskier versions are often more common than their less risky counterparts — even people at the high end of the distribution are not much more likely than average to develop Crohn’s disease.

Number of SNPs Associated with Crohn’s Disease Triples

Many cancer patients who receive high doses of chemotherapy or radiation undergo a bone marrow transplant to replace blood cell-generating tissues that are killed as part of their treatment. But after a transplant these patients face a new challenge — opportunistic infections that take advantage of their weakened immune systems.
<img loading="lazy" decoding="async" class="right" title="aspergillus" src="https://blog-api.23andme.com/wp-content/uploads/2008/06/aspergillus.gif" alt="Aspergillus" width="208" height="207" />Aspergillus fumigatus
One common and life-threatening infection among bone marrow transplant patients is invasive aspergillosis (IA), which is caused by the fungus Aspergillus fumigatus. About 10% of bone marrow transplant recipients are affected by invasive aspergillosis (IA). An estimated 30% of those affected will die within three months.
A study published in the June issue of <a href="http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000101">PLoS Genetics</a> shows that a SNP in the gene encoding a protein called plasminogen significantly affects the risk of developing IA after a bone marrow transplant. Compared to transplant patients with the GG genotype at rs4252125, the risk of developing IA was increased 3.0 fold in people with the AG genotype, and 5.6 fold for people with the AA genotype.

Zaas et al began their study of IA in bone marrow transplant patients by looking for clues in several genetically distinct strains of mice. The researchers mimicked a bone marrow transplant in the mice by giving them drugs that suppressed their immune systems. They then exposed the animals to the Aspergillus fungus.
The researchers found that some mouse strains survived Aspergillus infection, while others did not. A SNP in the plasminogen gene correlated with Aspergillus susceptibility, and the researchers considered it a likely candidate because other scientists had recently indicated that proteins in the same biological pathway as plasminogen are important for fighting off infectious pathogens.
Armed with this clue from mice, Zaas et al turned their attention to humans. They followed a group of 230 immunosuppressed bone marrow transplant recipients for one year. Just as they had seen in the mice, the researchers found that IA was associated with a SNP (rs4252125) in the plasminogen gene.
Oddly, the association between rs4252125 and IA applies only 40 days or more post-transplant. The authors aren’t exactly sure why this is the case. It could be due to the low proportion of patients who are infected with Aspergillus in the first 40 days after their transplants. It could also be that until 40 days, when the transplanted bone marrow really starts to take hold, other risk factors swamp out the effect of rs4252125.
Laboratory tests showed that the plasminogen protein encoded by rs4252125, which is made in the liver, binds to Aspergillus fungus. And computer models indicate that the SNPs found in both mice and humans change the protein in a way that alters binding to the fungus, giving a possible explanation for why the SNP affects susceptibility to IA.
Though more research and evaluation is required before clinical applications can be developed based on this research, the authors write in the conclusion of their report that their results have “important implications for pre and post transplant care, and may also have implications for the management of other immune-compromised patients. For example, genetic testing could identify high risk individuals who may benefit from use of broad-spectrum antifungal agents or enhanced monitoring for infection.”

Genetics and Risk for Infection After Bone Marrow Transplant

<img loading="lazy" decoding="async" class="alignright size-full wp-image-288" style="float: right;" title="ruraliceland" src="https://blog-api.23andme.com/wp-content/uploads/2008/06/ruraliceland.jpg" alt="" width="350" height="231" srcset="https://blogcms.23andme.com/wp-content/uploads/2008/06/ruraliceland.jpg 350w, https://blogcms.23andme.com/wp-content/uploads/2008/06/ruraliceland-300x198.jpg 300w" sizes="auto, (max-width: 350px) 100vw, 350px" />For the past 100 years, there has been a mysterious disease afflicting Icelanders. Called Hereditary Cystatin C Amyloid Angiopathy (or HCCAA), it causes severe brain hemorrhages and dementia in young adults. For those individuals who have the disease, life expectancy is usually no higher than 30 years. Scientists have determined that this disease is caused by a single mutation in the cystatin C gene. But until now, they had not yet discovered how this mutation arose, why it afflicts only Icelanders, and why it suddenly appeared within the last 150 years. A new collaboration between American and Icelandic scientists has helped to answer these puzzling questions about the origins of HCCAA by using Iceland’s Genealogical Database, which includes more than 80% of all Icelandic people who have ever lived. It also sheds light on the last 200 years of Iceland’s population history, and offers clues to understanding the interplay between genes and environment.  The researchers’ original goal — to use genetic and genealogical information to trace the common ancestor of every Icelander with HCCAA — proved unfeasible due to lack of data. But researchers did find a man born in 1684 north of Iceland’s capital, Reykjavik, who was an ancestor to most carriers of the disease. Because the lineages of so many people with HCCAA converged on that person, it can be inferred that he also carried the deadly mutation in the cystatin C gene. Yet census records show he did not have a shortened life span. In fact, through the 18th century the average life span for a person with the HCCAA mutation was in the neighborhood of 65 years, about average for the period. In addition, there are no historical records of Icelanders suffering from this disease throughout the 17th and 18th centuries. So if the mutation existed in 1684, why did no one show any symptoms until the mid-19th century? The researchers&#8217; next task was to find out when in Iceland’s history people did start showing symptoms of HCCAA. By again using Iceland’s extensive genealogical database, researchers found a significant change in life expectancy for those carrying the mutation, starting in the 19th century. It appears that individuals with the disease who were born after 1825 began to have significantly shorter life spans. By the year 1900, the average life span for HCCAA carriers had dropped to 30 years, where it remains today. But why did life spans not start decreasing until the early to mid-19th century, when records show that this mutation had been present among Icelanders since the 17th century? What changed for the people of Iceland? The answer may lie in their diet. The researchers noticed that, prior to the 19th century, the diet of Icelanders consisted mostly of whey-preserved offal (animal entrails and organs) as well as meat, dried fish, and butter. In other words, a diet low in carbohydrates and salt. However, post-19th century, imports from mainland Europe increased dramatically, and a typical Icelandic diet began incorporating processed carbohydrates and salt (to preserve food). The researchers argue that the movement of imports from Reykjavik to more isolated regions in Iceland throughout the 19th century mirrors the appearance and spread of HCCAA symptoms. As these new kinds of foods spread from the capital to smaller towns and villages, the deadly symptoms of HCCAA did as well. Therefore, it appears that the traditional Icelandic diet ‘masked’ the deadly symptoms of HCCAA, and it wasn’t until they began to eat more processed foods, higher in carbohydrates and salt, that these ‘masking’ effects diminished. The researchers did not speculate on the mechanism by which diet may be triggering the symptoms of HCCAA; but his study is significant for a variety of reasons. First, it is a fascinating example of how environment — in this case, diet — can affect a genetic mutation. In addition, this study is important due to a possible connection between the cystatin C gene and Alzheimer’s disease. Knowing more about the effects of a single mutation in this gene brings us another step toward understanding the complex genetics of Alzheimer’s. The mystery of HCCAA&#8217;s origins was tackled jointly by scientists in Iceland and at Johns Hopkins in the United States. It is reported in June 26 issue of <a href="http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000099" target="_blank" rel="noopener noreferrer">PLOS Genetics</a>

Iceland’s Deadly Disease Mystery

What can we learn from studying how variations of human genes are spread out around the world?
A lot, said population geneticist and Harvard junior fellow Sohini Ramachandran, who spoke at 23andMe this week.
Ramachandran focused on how genes spread from one continent to another, and how they vary within each region as well.
As an example, she referenced some of the research she did as a graduate student at Stanford, tracing how genetic diversity decreases as the populations sampled get geographically farther away from Africa, long considered the cradle of humanity. For the purposes of measuring genetic diversity, distance from Africa is measured along the same paths that people presumably took at they migrated around the world — over land, without crossing major oceans.
<img decoding="async" class="alignright size-full wp-image-283" style="float: right;" title="rsplosg07fig3b" src="https://blog-api.23andme.com/wp-content/uploads/2008/06/rsplosg07fig3b.jpg" alt="" width="401" srcset="https://blogcms.23andme.com/wp-content/uploads/2008/06/rsplosg07fig3b.jpg 866w, https://blogcms.23andme.com/wp-content/uploads/2008/06/rsplosg07fig3b-300x279.jpg 300w, https://blogcms.23andme.com/wp-content/uploads/2008/06/rsplosg07fig3b-768x713.jpg 768w" sizes="(max-width: 866px) 100vw, 866px" />Genetic diversity in the Americas (the darker the color, the more diverse the populations).
<h6>Genetic Diversity</h6>
As people migrated, Ramachandran said, genetic diversity decreased due to what she called “serial bottlenecks.” In these cases, though a fairly large number of people might reach one spot, only part of that group would move farther on. By chance, some of the genes in the population would not make it into the new territory.



For this reason, Ramachandran said, the researchers find more diversity in DNA samples from African populations than they do in samples from American populations.

Because genetic diversity varies based on who got how far, Ramachandran doesn’t just study the genetic variations across continents but between continents as well.
<h6 class="MsoNormal">Guns, Germs Steel</h6>
One of the topics she looks at is how genetics could support the theories outlined by evolutionary biologist Jared Diamond in his 1998 book, <a href="https://www.pbs.org/gunsgermssteel/" target="_blank" rel="noopener noreferrer">Guns, Germs and Steel</a>. One section of the book she focused on — and which she called her favorite part — was Chapter 10, &#8220;Spacious Skies and Tilted Axes.&#8221;

Diamond proposed that continental expansion was partly dependent on how the landmasses are oriented, and that humans brought crops and technology with them as they did so. For example, because Eurasia is on an east-west axis, it was easier for humans to move plants and animals along that axis because the climate was similar. Ramachandran noted that a 2005 study found that humans and domesticated crops for farming spread from east to west about 3,000-5,000 years ago in Europe.


On the other hand, Diamond said, the Americas and Africa are oriented on a north-south axis and as people traveled north and south, they would have found that plants and animals they brought along couldn’t always adapt to the seasonal changes. For example, Diamond noted, the Indians in North and Central America had no pack animals because the llamas and alpacas never moved out of the Andes. And the corn grown in Mexico needed thousands of years to adapt to the changes in growing season and day-length to make its way up north.

<h6 class="MsoNormal">Genetic Differences in the Americas</h6>
If this holds true on a larger scale as Diamond suggested, then there should be population bottlenecks and more distinct genetic differences between populations across the Americas latitudinally (north-south) than there are longitudinally (east-west). Ramachandran also said that the distinct genetic differences between populations across the Americas latitudinally should be greater than the distinct genetic diversity seen longitudinally (east-west) across Eurasia.

Ramachandran and her colleagues <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030185" target="_blank" rel="noopener noreferrer">reported</a> on the genetic diversity of the Americas last year, but she says more data is needed for this region. She also thinks that Diamond’s proposed north-south axis of orientation isn’t quite right, arguing that it should run northwest-southeast. To better study the genetic diversities of the populations across this tilted axis, she and her colleagues change the way they view the map of the world.

If the planet were a ball, the point at which it would be spinning on someone’s finger might be the South Pole. Using points such as the southernmost area of South America, South Korea or Sri Lanka as the axis of rotation on which to turn the map, Ramachandran demonstrated how she and her colleagues can look at the genetic diversities of populations in the Americas and Asia and find patterns in the genetic variations that might not be so easily seen from other perspectives.

Ramachandran said she hopes to publish her research on the populations in the Americas soon. In the meantime, her talk illustrated how studying genetics can support theories raised about human origins in other areas of study such as archeology, anthropology and history.

Image from <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030185">PLoS Genetics: Wang et al, 2007</a>

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