Abstract
Lactoferrin is a multifunctional mammalian immunity protein that limits microbial growth through sequestration of nutrient iron. Additionally, lactoferrin possesses cationic protein domains that directly bind and inhibit diverse microbes. The implications for these dual functions on lactoferrin evolution and genetic conflicts with microbes remain unclear. Here we show that lactoferrin has been subject to recurrent episodes of positive selection during primate divergence predominately at antimicrobial peptide surfaces consistent with long-term antagonism by bacteria. An abundant lactoferrin polymorphism in human populations and Neanderthals also exhibits signatures of positive selection across primates, linking ancient host-microbe conflicts to modern human genetic variation. Rapidly evolving sites in lactoferrin further correspond to molecular interfaces with opportunistic bacterial pathogens causing meningitis, pneumonia, and sepsis. Because microbes actively target lactoferrin to acquire iron, we propose that the emergence of antimicrobial activity provided a pivotal mechanism of adaptation sparking evolutionary conflicts via acquisition of new protein functions.
Highlights
Genetic conflicts between microbes and their hosts are an important source of evolutionary innovation [1]
We have traced the evolutionary history of the lactoferrin gene in primates, which in addition to an ancient iron-binding function, acquired antimicrobial peptide activity in mammals
In contrast to the related gene transferrin, lactoferrin has rapidly evolved at protein domains that mediate iron-independent antimicrobial functions
Summary
Genetic conflicts between microbes and their hosts are an important source of evolutionary innovation [1]. J.B.S. Haldane originally speculated on the importance of infectious disease as an “evolutionary agent” over 60 years ago [2], and the Red Queen hypothesis later posited that predators and their prey (or pathogens and their hosts) must constantly adapt in order to sustain comparative fitness [3,4]. More recent studies have demonstrated how evolutionary conflicts progress at the single gene or even single nucleotide level, as molecular interfaces between host and microbial proteins can strongly impact virulence and immunity [5,6,7]. Host-pathogen interactions provide fertile ground for studying rapid gene evolution and acquisition of novel molecular traits [8]
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