PT  - JOURNAL ARTICLE
AU  - Matthew F. Barber
AU  - Zev Kronenberg
AU  - Mark Yandell
AU  - Nels C. Elde
TI  - Antimicrobial functions of lactoferrin promote genetic conflicts in ancient primates and modern humans
AID  - 10.1101/043091
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 043091
4099  - http://biorxiv.org/content/early/2016/03/10/043091.short
4100  - http://biorxiv.org/content/early/2016/03/10/043091.full
AB  - 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 pathogens 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 pathogens. 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 pathogenic bacteria 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.AUTHOR SUMMARY Immunity genes can evolve rapidly in response to antagonism by microbial pathogens, but how the emergence of new protein functions impacts such evolutionary conflicts remains unclear. Here 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. We show that, in contrast to the related gene transferrin, lactoferrin has rapidly evolved at protein domains that mediate iron-independent antimicrobial functions. We also find evidence of natural selection acting on lactoferrin in human populations, suggesting that lactoferrin genetic diversity has impacted the evolutionary success of both ancient primates and humans. Our work demonstrates how the emergence of new host immune protein functions can drastically alter evolutionary conflicts with microbes.