Mosquitos – fine-tuned by evolution to preferentially feed on humans

Would you look at that! The story of mosquitos, cheese and body odour has taken another leap into scientific respectability with a paper being published in the pinnacle of journals, Nature. “Evolution of mosquito preference for humans linked to an odorant receptor” by McBride and colleagues was published towards the end of last year and looks at how the domestic form of the mosquito Aedes aegypti has evolved striking evolutionary adaptations that help it to find, bite, and spread disease to humans.

Aedes aegypti during a human blood meal.
By James Gathany [Public domain], via Wikimedia Commons

I picked up some of this story in my Science Museum Lates talk, Science’s Silliest Stories. The story began in 1996 with a study looking at how mosquitos are attracted to Limburger cheese – a rather silly study that got itself an IgNobel prize in 2006. But the moral of this story, and my talk in general, was that science and scientists often need to be silly to be great. Andre Geim and his voyage from IgNobel to Nobel is my favourite example so far, but I think these studies on mosquitos’ sense of smell may be the next silly-to-great science story.

In late 2013 researchers established that mosquitos infected with malaria have an enhanced attraction to humans and their smell. Malaria-infected Anopheles gambiae mosquitos bite humans more than non-infected mosquitos! A pretty terrifying result if you live in a malaria endemic region. In this latest study, McBride and colleagues study a different species of mosquito, Aedes aegypti, the main worldwide vector of yellow and dengue fevers.

Two forms, or subspecies, of Ae. aegypti exist side-by-side in yellow fever endemic countries like Kenya. The forest form lives and breeds in forests and bites non-human animals whereas the domestic form, like the malaria mosquito, An. gambiae, preferentially bites humans.

(a) A bite preference test - it's man vs guinea pig in there. (b) The domestic form (gold dots) prefers humans over guinea pigs and bites a lot more than the forest form (black dots). From figure 2: Evolution of mosquito preference for humans linked to an odorant receptor. McBride et al (2014).
(a) A bite preference test – it’s man vs guinea pig in there. (b) The domestic form (gold dots) prefers humans (hand) vs guinea pigs (guinea pig) and bites a lot more than the forest form (black dots).
From figure 2: McBride et al., 2014, Evolution of mosquito preference for humans linked to an odorant receptor, Nature.

The two forms are closely related enough that they can interbreed, just like the cavefish I study, allowing McBride’s team to find specific genes that are more highly expressed in the domestic form – candidate genes for preference for human meals. They choose to focus on genes expressed in the antennae of the mosquitos as these form part of the animals ‘smell’ system and could be linked to food preference.

Taking a rather brute force, but now common, approach, they sequenced RNA from every expressed gene (a technique called RNA-seq) to find which genes were genetically associated with host preference. 14 genes popped out of the analysis, two of which were odourant receptors. One gene, Or4, was very highly expressed in the antenna of domestic mosquitos. It’s a gene that codes for an olfactory receptor, and it therefore became prime candidate for the domestic form’s love of human hosts.

The next experiment used a common technique of expressing the gene of interest in a more commonly used scientific animal – in this case they used Drosophila, a fruit fly. When they put the Or4 gene in a neuron of Drosophila, it showed a very high activity when wafted with human odour. Narrowing down the multi-faceted fragrance of humans, they found one compound that strongly triggered the neuron – sulcatone, an odourant given off by the skin of a number of animals and plants, but given off in uniquely high levels in humans. These are the two key results – a gene, Or4, expressed very highly in the human-biting mosquito, is very sensitive to a compound, sulcatone, that humans emit in copious amounts.

The researchers expressed the Or4 gene in Drosophila neurons - they respond when exposed to human odour and sulcatone. Figure 4: Evolution of mosquito preference for humans linked to an odorant receptor. McBride et al (2014).
(a) The researchers expressed the Or4 gene in Drosophila neurons – (b) they respond strongly when exposed to human odour and sulcatone.
From figure 4: McBride et al., 2014, Evolution of mosquito preference for humans linked to an odorant receptor, Nature.

That’s not the end of the story. They also found that the Or4 gene has many small variations, called alleles. These different alleles also affect host preference – some alleles are more sensitive to sulcatone than others, simply due to a few different amino acids in the protein – this is the amazing fine tuning of a protein, the base stuff of evolution. In a final experiment they reanalysed their RNA-seq data in light of this information. They confirmed that mosquitos with a strong human preference more frequently possess alleles with both high sensitivity and expression – causing the domestic form of the mosquito to be ruthlessly efficient in seeking human meals.

Thus evolution has created a persistent annoyance and danger in tropical climates. The authors acknowledge that Or4 isn’t the whole story, but as examples of specific genes associated with specific behavioural changes are extremely rare, this study is vitally important. The work unravels how a single gene can result in host preference shifts, not only impacting the efficiency of mosquitoes as vectors of infectious disease but also playing a key role in the formation of new species. From smelling cheese to specific gene evolution – that’s quite an advert for curiosity driven science.

Featured research: 

McBride et al., 2014, Evolution of mosquito preference for humans linked to an odorant receptor, Nature


 

Update

A free mini review on genes and odours underlying mosquito preference was published in Current Biology in Jan 2016. The study in this blog focused on Aedes mosquitos but this mini review presents research that shows human preference has evolved in parallel in Anopheles mosquitos. It also reviews the data on how odourant blends are important in determining preference and how odourant compounds can have quite different effects on mosquitos when they are presented together with different compounds. Finally, though genes like Or4 are important in human preference, a likely important but little researched aspect is the amount olfactory neurons respond when receiving specific odour signals. This neuronal processing is a further layer of complexity on this fascinating story of evolution and tropical health.

McBride, 2016, Genes and Odors Underlying the Recent Evolution of Mosquito Preference for Humans, Current Biology

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