Genetic ancestry and population differences in levels of inflammatory cytokines in women

Evolution for the past ~3.8 billion years involves constant (often adverse) environmental signals, being presented as challenges to the cell, to the organism, and the organism’s genome must respond to that challenge in order to survive (i.e., find food, avoid predators, reproduce). Hence, this topic lies within the domain of “gene-environment interactions”. The mammalian immune system provides a primary defense against pathogens external to, as well as within, the body. For the ~300,000 years that modern humans have existed, hominids as they migrated from Africa to the rest of the world encountered vastly different pathogenic environments (e.g. fungus, bacterial, viral), and their survival and reproductive fitness depended on how successful their immune systems fought off infections (before the time of modern medicine).

It has been hypothesized that strong selection pressure due to exposures to life-threatening infectious pathogens endemic to Africa, particularly malaria, shaped a pro-inflammatory immune milieu in populations of African ancestry. This hypothesis is supported by evidence from evolutionary genetic data showing that genomic regions hosting immunity-related genes are under stronger selection pressure than the rest of the human genome. A number of studies have shown that African-ancestry individuals have a higher frequency of DNA variants related to pro-inflammatory cytokines (cell-signalling molecules that help in cell-to-cell communication involving immune responses and stimulate movement of immune cells toward sites of inflammation, infection and trauma), but a lower frequency of variants related to anti-inflammatory cytokines (‘pro-inflammatory’ means to stop infection before it starts; ‘anti-inflammatory’ of course is to fight infection after it has started).

Many variants associated with infectious, autoimmune, and inflammatory diseases discovered from genome-wide association studies (GWAS) display extreme differences in allele frequencies across populations. These ancestral genetic variations –– that were shaped by human evolutionary history –– likely remain influential on the constitutive immune milieu in populations today. The serious smallpox epidemic among Amerindians, following invasion of Europeans into the Americas, represents an extreme example in which the Amerindian genome had never been exposed to smallpox and therefore had virtually no ability to defend against that virus.

In a study integrating genetic, molecular and epidemiologic data, authors [see attached article] compared population differences (between 914 African and 855 European ancestry women), examining plasma levels of 14 cytokines involved in innate (defense against infection that can be activated immediately once a pathogen attacks) and adaptive (acquired immunity, i.e. ‘immunological memory’ is established, after an initial response to a specific pathogen, and leads to an enhanced response to subsequent encounters with that pathogen) immunity. Authors found significant differences in seven cytokines. Levels of two pro-inflammatory chemokines, CCL2 and CCL11, were strongly associated with African ancestry. The signal was pinpointed to the Duffy-null allele of rs2814778. These findings confirm strong ancestral footprints in inflammatory chemokine regulation. The Duffy-null allele may indicate a loss of the buffering function for chemokine levels. These substantial immune differences, by ancestry, may have broad implications to health disparities between African and Eurpean populations.

PLoS Genet June 2o18; 14: e1007368

There are more than 3,500 species of mosquitoes. I doubt that wiping out one of them would create a monster vacuum that would then get filled by something even worse. But, eradication of Anopheles gambiae would save hundreds of thousands of human lives every year.

Be bold. All of those dying, incredibly cute kids would like us to do something. Mosquito nets are not doing the job.

Doing something has unprecedented consequences. We would for the first time use our genetic power to wipe out a species.
Doing nothing has consequences, too. We then choose to let hundreds of thousands die every year

What is your choice? The continued death of about 3 million people per decade, or the death of one species of mosquito? I vote people over mosquito.

Agreed, I had previously commented to Steve that “Nature abhors a vacuum” –– meaning that if a species existing in a particular ecological niche is eliminated, it is virtually 100% certain that some other species will move into that niche. It could be an existing organism closely related to the species eliminated, or (via changes in DNA sequence and/or epigenetic events) a new species might evolve.
Concerning gene drive and eradication of pests, this is a really debatable question, Tony James was on the forefront of this for awhile. Genetically- modified organism (GMO) mosquitoes have been introduced in to Florida previously – so the overall approach has already been field-tested. Key question came from Dr Malcome in Jurrassic Park….”Will Mother Nature find a way?”

As a public health question, there is no doubt it should be tried. The expected ecological impacts will likely be minor, but will it ultimately cause extinction of malaria? In my opinion, this is doubtful, nature will find a way to beat the technology, via selection! But generation of GMO mosquitoes may be the best weapon yet!

FYI, we have colleagues here at NC State that are leading an international effort funded by DOD to develop gene drive approaches to eliminate invasive mice on Australian islands. If you think the mosquito is a controversial target….releasing gene-drive-GMO mammals into the environment – brings new meaning to the word “controversy”..!! (See attached links). These are super-cool ideas, and a lot of effort is being invested in saving many species of sea birds from extinction.

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