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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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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