PMC:5985360 / 26457-27849 JSONTXT

{"project":"2_test","denotations":[{"id":"29526279-12364370-2046657","span":{"begin":397,"end":398},"obj":"12364370"},{"id":"29526279-16021928-2046658","span":{"begin":400,"end":402},"obj":"16021928"},{"id":"29526279-12364370-2046659","span":{"begin":668,"end":669},"obj":"12364370"},{"id":"29526279-11148985-2046660","span":{"begin":808,"end":810},"obj":"11148985"},{"id":"29526279-4818434-2046661","span":{"begin":919,"end":921},"obj":"4818434"}],"text":"There are four lines of evidence regarding the age of the sickle mutation: historical data, the simulations of balancing selection, the patriline data, and the analysis of the ancestral recombination graph. Although historical records are sparse, the earliest recorded cases of fevers that could have been caused by malaria were ∼5,000 years ago in China and were possibly due to Plasmodium vivax.2, 43, 44 The earliest recorded case of illness that could have been malaria specifically caused by Plasmodium falciparum could have been ∼4,000 years ago in Egypt and Sumer; however, Plasmodium falciparum could have been present in Africa several thousand years earlier.2 The first recorded cases of sickle cell anemia or, more broadly, sickle cell disease were in Egypt during the predynastic period (∼3200 BC45), in the Persian Gulf during the Hellenistic period (2,130 years before present46), and in Ghana in 1670 AD.47 The existence of the sickle allele in predynastic Egypt constrains the lower bound of the age of the sickle mutation to be 5,200 years. On the basis of these limited data, it is historically plausible that the selective environment preceded the sickle mutation, consistent with our balancing-selection simulations, which showed that the sickle allele would have been lost almost immediately without a heterozygote advantage (under the assumption of recessive lethality)."}