Sunday, March 26, 2017

There Was Intense Selection For Vivax Malaria Protective Genes In Africa 40kya

The Secret History Of Mankind's Struggle With Malaria In Africa

Now, vivax malaria is the second most common variety of malaria discussed in the article below (and is the most common type outside of Africa). According to Wikipedia first discussing malaria generally and then the two most common types of it:
The disease is widespread in the tropical and subtropical regions that exist in a broad band around the equator. This includes much of Sub-Saharan Africa, Asia, and Latin America. In 2015, there were 214 million cases of malaria worldwide resulting in an estimated 438,000 deaths, 90% of which occurred in Africa. . . .  
Although P. falciparum traditionally accounts for the majority of deaths, recent evidence suggests that P. vivax malaria is associated with potentially life-threatening conditions about as often as with a diagnosis of P. falciparum infection.
But, ca. 40,000 years ago in parts of Africa (not those less tropical areas where the Khoi-san bushmen lived), a genetic mutation protective against vivax malaria "conferred a selective advantage of about 4.3%, leading to effective fixation in about 8,000 years." 

A parallel story mostly involving P. falciparum is told in the genetics of similarly intense selective pressure on genes including sickle cell trait, thalassaemia traits, and glucose-6-phosphate dehydrogenase deficiency. The combined lethality of all kinds of malaria was thus almost certainly considerably greater than indicated by the selective advantage against one kind of malaria conferred by this gene (which related to what are called "Duffy antigens") alone.

Duffy antigen genes also have multiple applications in population genetics.

A Hint About Intra-African Human History?

Anatomically modern humans have been present in African from ca. 150,000 to 250,000 years ago and archaic hominins have been present in Africa for millions of years. Moreover, it is unlikely that malaria vivax was limited to modern humans. Many forms of malaria can also affect other great apes beside humans, and archaic hominins would have been very similar to modern humans in terms of traits that would have made them vulnerable to, or resistant to, modern humans.

So, the most notable aspect of the protective Duffy antigen genes in humans is not that they are present, but that they arose so recently and only after the founding population of non-Africans left the continent.

In particular, the TMRCA date for the Duffy antigen gene that has reached fixation in tropical Africans isn't that far from the 60,000 years before present TMRCA date for African Pygmies, an African population with one of the most basal divisions from other modern humans in Africa (together with the Khoisan people who are somewhat more basal) that lives mostly in the rainforests of the vast Congo River basin jungle of tropical Africa.

So, while it could be that modest population sizes meant that it simply took a long time for a protective Duffy antigen mutation to occur, it is also quite plausible that the timing is an indication that modern humans in Africa did not live in tropical areas heavily afflicted with malaria mosquitos until ca. 40,000 years ago (plus however long it took for a mutation to emerge once they started live there).

This, combined with knowledge about which parts of Africa were historically deserts or rain forests could shed a lot of light in the question of the historical range of modern humans and their archaic hominin ancestors in the time frame from their earliest evolution to ca. 40,000 years ago, ruling out much of West Africa and Central Africa from that range.

The Article

As explained by a new article revealing this fact:
The human DARC (Duffy antigen receptor for chemokines) gene encodes a membrane-bound chemokine receptor crucial for the infection of red blood cells by Plasmodium vivax, a major causative agent of malaria. Of the three major allelic classes segregating in human populations, the FY*O allele has been shown to protect against P. vivax infection and is at near fixation in sub-Saharan Africa, while FY*B and FY*A are common in Europe and Asia, respectively. Due to the combination of strong geographic differentiation and association with malaria resistance, DARC is considered a canonical example of positive selection in humans. 
Despite this, details of the timing and mode of selection at DARC remain poorly understood. Here, we use sequencing data from over 1,000 individuals in twenty-one human populations, as well as ancient human genomes, to perform a fine-scale investigation of the evolutionary history of DARC. 
We estimate the time to most recent common ancestor (TMRCA) of the most common FY*O haplotype to be 42 kya (95% CI: 34–49 kya). We infer the FY*O null mutation swept to fixation in Africa from standing variation with very low initial frequency (0.1%) and a selection coefficient of 0.043 (95% CI:0.011–0.18), which is among the strongest estimated in the human genome. We estimate the TMRCA of the FY*A mutation in non-Africans to be 57 kya (95% CI: 48–65 kya) and infer that, prior to the sweep of FY*O, all three alleles were segregating in Africa, as highly diverged populations from Asia and ≠Khomani San hunter-gatherers share the same FY*A haplotypes. We test multiple models of admixture that may account for this observation and reject recent Asian or European admixture as the cause. 
Infectious diseases have undoubtedly played an important role in ancient and modern human history. Yet, there are relatively few regions of the genome involved in resistance to pathogens that show a strong selection signal in current genome-wide searches for this kind of signal. We revisit the evolutionary history of a gene associated with resistance to the most common malaria-causing parasite, Plasmodium vivax, and show that it is one of regions of the human genome that has been under strongest selective pressure in our evolutionary history (selection coefficient: 4.3%). Our results are consistent with a complex evolutionary history of the locus involving selection on a mutation that was at a very low frequency in the ancestral African population (standing variation) and subsequent differentiation between European, Asian and African populations.
Kimberly F. McManus, et al., "Population genetic analysis of the DARC locus (Duffy) reveals adaptation from standing variation associated with malaria resistance in humans" PLOS Genetics (March 10, 2017).


This suggests that vivax malaria was very lethal (or at least reproduction preventing) in tropical Africa at the time, killing 4.3% of the entire unprotected population each generation (and a higher percentage of unprotected people who were infected, as not every single person in each generation would have been infected).

About 6% of the population in malaria vulnerable areas of the world are infected with malaria each year also it is predominantly lethal in children aged five and younger who account for 70% of deaths from malaria. Infection rates are much higher in tropical Africa where about 90% of malaria deaths occur.

Infection rates were much higher, about 15%-30% each year as recently as the early 20th century in Africa and sometimes more; there was a dramatic drop in malaria from 11.4% to 0.4% from 1940 to 1942. It is this pervasive infection rate that makes it particularly deadly. "A 2002 report stated that malaria kills 2.7 million people each year, more than 75 percent of them African children under the age of five. "

Thus, vivax malaria would have been more lethal than

* the Spanish flu of 1918
* untreated whooping cough
* measles in modern developing countries 
* lassa fever
* mumps
* treated Dengue fever
* treated tularemia
* diphtheria
* botulism
* perhaps even untreated typhoid fever or SARS (if the infection rate wasn't that high).

Of course, this lethality estimate assumes that the mutation is 100% protective, which it probably isn't. So, due to its probable less than 100% infection rate and its probable less than 100% protectiveness, the actual lethality of vivax malaria in this time period was probably significantly greater than 4.3% per generation of unprotected people.

Modern malaria (all kinds) kills only about 1 in 300 of people infected with it - this ancient strain that lasted 8,000 years would have been more than 14 times more lethal than malaria is today.

It is also possible that the selective advantage may have had a significant fertility component as opposed to purely a lethality effect since in modern populations: "Malaria in pregnant women is an important cause of stillbirths, infant mortality, abortion [i.e. miscarriage] and low birth weight, particularly in P. falciparum infection, but also with P. vivax." If malaria infection rates were very high (as seems likely), these fertility effects could have given rise to a large share of the selective fitness benefit even if the lethality of an infection was only modest.

New World History - Disease As A Factor In The Slave Trade

This evolutionary history shaped the early days of the Americas by contributing to the history of slavery in the Americas. As a result of genetic adaptations to tropical diseases including vivax malaria, the mortality of African working on plantations in the American South, the Caribbean, and South America was lower than that of Europeans.

This lower mortality rate, in turn, is one of the factors that caused these parts of the America to develop an agricultural economy based upon African slave labor rather than European colonists as the Northern United States and Canada and some other parts of South America did.

Basque Genetics

Duffy antigen genes are one area among many in which Basque population genetics are distinctive (although some assumptions of this 2005 article are now outdated).
The Basques live at the western end of the Pyrenees along the Atlantic Ocean and are thought to represent the descendants of a pre-Neolithic people. They demonstrate marked specificities regarding language and genetics among the European populations. We review the published data on the population genetics and Mendelian disorders of the Basques. 
An atypical distribution in some blood group polymorphisms (ABO, Rhesus, and Duffy) was first found in this population. Subsequently, additional characteristics have been described with regard to proteins (enzymes and immunoglobulins) and the HLA system. The advent of molecular biology methods in the 1990s allowed further insights into Basque population genetics based mainly on Y-chromosome and mitochondrial DNA. In addition, the Basques demonstrate peculiarities regarding the distribution of various inherited diseases (i.e., unusual frequencies or founding effects). Taken together, these data support the idea of an ancient and still relatively unmixed population subjected to genetic drift.
Frederic Bauduer, J. Feingold, and Didier Lacombe, "The Basques: Review of Population Genetics and Mendelian Disorders" 77(5) Human Biology 619-637 (October 2005) (closed access).

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