Not long after Karl Landsteiner first described the different ABO blood types, scientists started looking for associations between blood type and other human traits.  Some of their theories were truly weird (more on these tomorrow!), but some have held up to scientific scrutiny.

Venous Thromboembolism (VTE)
People with non-type O blood (A, B and AB) have been shown to be at increased risk for VTE.  The reason is thought to be that these people have higher levels of the clot-inducing proteins factor VIII and von Willebrand factor in their blood.  Having non-type O blood further raises the already increased risk for VTE in people who carry the Factor V Leiden and prothrombin G20210A mutations.

Cancer
Since the 1950s, scientists have found that people with type O blood have decreased risk for stomach cancer compared to people with type A.  Other cancers (pancreatic, breast, ovarian, cervical) also occur at lower rates in people with type O blood.  No one is quite sure why this is.  It could be that the sugars found on type A blood cells, which are also expressed by other cells in the body, might somehow help cancers grow more aggressively.  Alternatively, some research has shown that regardless of person’s own blood type, tumors express the type A sugars. In people with type A blood, these sugars go unnoticed by the immune system because they are considered normal.  But in people with type O blood, these new sugars are recognized as foreign, spurring the immune system to destroy the tumors.

Stomach Ulcers
Although stomach cancer is less prevalent in people with type O blood, stomach ulcers are more common in people with this blood type.  The sugars that define the different blood types are also found on cells in the gastrointestinal tract.  Research has shown that these sugars influence the ability of H. pylori, a type of bacteria responsible for a large number of stomach ulcers, to attach to the lining of the stomach.  People with type A or B blood (and hence A or B sugars on their stomach cells) have fewer H. pylori receptors than people with type O.

Severe Malaria
In people infected with malaria, more severe disease is seen in those whose red blood cells are induced to form rosettes, large aggregates that block small blood vessels.  Studies have shown that people with type O blood form fewer, smaller and more easily broken up rosettes than people with type A, B or AB blood.  This is probably because the sugars found on the non-O blood cells end up helping to create larger clumps of cells.

Infectious Disease
Some studies have shown that certain bacterial and viral infections are more or less likely in certain blood types.  For example, type A blood has been linked to a predisposition to “glue ear,” which is caused by infection with Pseudomonas aeruginosa. And some studies suggest that people with type O or B blood are less susceptible to smallpox. The research supporting these and other claims of an impact of blood type on infectious diseases are not as strong as the other associations listed above, however.

(23andMe customers can get a prediction of their ABO blood type based on their DNA data through the new ABO Lab feature.)

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Malaria, a strong evolutionary pressure in humans, has also shaped the baboon genome, new research says.

Each year at least 350 million people around the world are infected by malaria parasites.  More than one million people, mainly young children, succumb to the disease.  But these numbers would be even higher if it weren’t for genetic adaptations that have evolved in populations living in areas where malaria is a common threat.

Populations in Africa, Papua New Guinea and Brazil, for example, carry variations in the DARC gene that protect them from infection by the P.vivax malaria parasite.  DARC encodes the Duffy antigen, a protein exploited by P.vivax to enter red blood cells. The protective variations prevent expression of the Duffy antigen by the DARC gene, leaving the parasite without a mode of entry to establish an infection.

Wild baboons are not usually infected by P.vivax or other malarial parasites that affect humans, but they are vulnerable to several closely related species.  In a new report, Duke University researchers show that, like some humans, groups of yellow baboons from Kenya’s Amboseli National Park carry variants affecting DARC gene expression that provide protection against malaria. These findings, published this week in the journal Nature, mark the first time that a genetic variation has been linked to complex trait in a wild non-human primate population.

While the genetic variations that produce P. vivax malaria resistance in humans turn the DARC gene off, the variations that protect baboons from malaria actually increase the amount of protein made from the gene.  This suggests the mechanisms of resistance to malaria infection are different between the two species.  Researchers, however, are still impressed with the parallel nature of these evolutionary adaptations.

“It’s a nice example of how – in the vastness of the genome – the same gene was modified in the same way in two different species to produce the same kind of resistance,” Greg Wray, senior author of the report, said in a statement.  “That’s a pretty remarkable thing when you think of all the different ways malaria resistance might have evolved.”

Gathering the data for this study was no easy feat.  Graduate student Jenny Tung, lead author of the report, spent three summers in the East African savanna collecting DNA-laden baboon feces and darting animals in order to take blood samples.  Wray says that the success of her work shows the power of combining fieldwork and genomic analysis.  According to him, the next challenge will be to understand how genetic variation contributes to complex behavioral traits like social status and aggression in wild primates.

(23andMe customers can see what their data says about variations associated with malaria resistance in the following Health and Traits articles: Malaria Resistance (Duffy Antigen), Sickle Cell Anemia & Malaria Resistance and G6PD Deficiency.)

Photo: Paul Mannix/flikr

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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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Last week in the Spittoon we reported on a new study that identified an interesting genetic trade-off — a genetic variant known that has one effect on a person’s vulnerability to malaria, and the opposite on susceptibility to HIV infection. The “Duffy negative” 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.  Here are some of the most interesting:

1.    Sickle Cell Anemia vs. Malaria

Sickle cell anemia is caused by a genetic mutation that alters the shape of an individual’s red blood cells.  This mutation, called Hb^s, 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 Hb^s 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 Hb^s 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 Hb^s.  Occasionally, a pair of malaria-resistant parents will both pass Hb^s — 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 Hb^s mutation continues to exist in in spite of the disease burden it causes.

2.    Hereditary Hemochromatosis vs. Iron Deficiency

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.

3.    The Paleolithic Diet vs. Obesity

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.

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Art Nouveau architecture at the Codorníu winery outside of Barcelona.

So much new research was discussed in Barcelona it’s hard to decide which were the most notable presentations. But here are a few of the ones I found most interesting:
Were humans shaped more by history or local environment?
A major debate in the human evolutionary genetics talks and posters considered the origin of the genetic differences seen in humanity today: Were they shaped more by populations splitting apart and coming together, or evolutionary adaptation to local environments? Interestingly, people from the lab of our SAB member Jonathan Pritchard presented arguments on both sides. Both talks presented strong evidence using similar data sets. Perhaps one phenomenon has more impact locally and the other more regionally. Certainly the debate continues.

James Cai and coauthors from Stanford (including our very own R&D scientist Mike Macpherson) and The Hebrew University of Jerusalem showed that the history of the human genome cannot be explained simply by neutral variants – variants that do not cause a functional change. All across the genome there is evidence of “selective sweeps” where an advantageous version of a gene quickly increased in frequency in a population or species. For example, the gene FOXP2 has undergone a selective sweep in all humans within the past several hundred thousand years and may have contributed to our ability to use advanced language. More recent selective sweeps in the Duffy and Lactase genes (both have variants that 23andMe customers or demo account holders can read more about in My Gene Journal (now called Health and Traits)) happened after human populations diverged and thus didn’t sweep across the entire globe but are confined to specific regions: primarily western Africa for the Duffy-0 variant and Europe, the Near East, eastern Africa, and southern Asia for Lactose Tolerance.

Selective sweeps tend leave evidence in the form of nearby DNA that gets dragged along with the variant as it sweeps across a population. Similarly, new variants that are disadvantageous (or become disadvantageous when, say, moving into a new environment) can leave these similar signals as they are dragged out of the population. However, it is often difficult to separate out effects of population history from these selective forces. By using a novel statistic that controls for population history, Cai and colleagues show that many locations on the human genome have been affected by these selective sweeps. While previous scans for positive selection required these selective sweeps to be incomplete (see here and here, for example), the authors use a metric which can go back even further to look at the timing and strength of selective sweeps which have affected the entire human population, even going back as far as one million years. This work is an extension of previous research on Drosophila.

Interestingly, one of the data sets used for this work was the complete genome of Jim Watson, who co-discovered the structure of DNA.

Population Structure, History, and Migrations
Sarah Tishkoff of U. Penn gave a talk on her incredible data set of sub-Saharan African populations. So much of the world’s genetic diversity is located in this region, yet its inhabitants have been relatively under-sampled so far. Tishkoff’s data, in the context of global variation, makes it apparent just how important it is to understand the history of sub-Saharan populations in order to understand the history of our species. In one example, Tishkoff used a technique known as Principal Components Analysis (PCA) to collapse all their genetic data into three dimensions. Individuals near each other in PCA are more similar. In her plot, a hunter-gatherer population from Tanzania known as the Hadza can be found in their own dimension on the plot, which suggests that the Hadza, while having a small population size, have been isolated for a long, long time and are quite divergent from other populations, even including the 52 in the CEPH-HGDP data.
Tishkoff also showed how difficult it is to extrapolate from one African population to the next, even if they neighbor each other. One example of this is in parts of western Africa where the Fulani have increased malaria resistance compared to other groups such as the Mossi and Rimaibe – even within the same town.
Several talks and posters looked at the new lactase persistence variants discovered last year in sub-Saharan Africa and the Near East. These variants are functionally the same as their much more common counterparts, which allows Europeans and South Asians to drink milk into adulthood without experiencing lactose intolerance (23andMe customers can look up their genotype for this variant in My Gene Journal (now called Health and Traits)). But because they differ genetically, these newly discovered variants illustrate the importance of milk digestion for populations that relied on herding in their past. Multiple research groups showed that the eastern African persistence variants made their way down to the San Bushmen and neighboring populations of southern Africa.
When normal inheritance breaks down

Genomic imprinting in action. Here, the color of the offspring comes from the father, regardless of which genotype he has.

Andrew Clark of Cornell has been looking at versions of genes in mice that change the traits of offspring depending on whether they are inherited from the mother or father. This phenomenon, called Genomic Imprinting, has been detected in many mammals before, including humans, although interestingly it isn’t found in marsupials or the egg-laying monotremes like the Platypus. However, the traits affected by genomic imprinting have not been surveyed using a genome-wide approach.
Clark and colleagues used the Solexa sequencing platform to look for differences in the mouse brain between mice crossed from two different strains. By switching the strains of the mother and father researchers can detect traits that derive exclusively, or “imprint on”, one parent.
It turns out a good number of genes exhibit genomic imprinting Genes imprinted on the father tend to show only the trait of the father. Genes imprinted on the mother tend to let some of the father’s trait come through, albeit at much lower numbers. In addition, the researchers found differences in the organs affected by imprinting: genes imprinted on the mother were more likely to be expressed in the reproductive organs and those imprinted on the father were found more in the brain.
It appears that imprinting has no immediate benefit for offspring and may have originated in mammals completely by accident, a quirk of our histories. But learning about how imprinting evolved will help us understand how they came to be.

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