Specific inactivation of two immunomodulatory SIGLEC genes during human evolution.
Sialic acid-recognizing Ig-like lectins (Siglecs) are signaling receptors that modulate immune responses, and are targeted for interactions by certain pathogens. We describe two primate Siglecs that were rendered nonfunctional by single genetic events during hominin evolution after our common ancestor with the chimpanzee. SIGLEC13 was deleted by an Alu-mediated recombination event, and a single base pair deletion disrupted the ORF of SIGLEC17. Siglec-13 is expressed on chimpanzee monocytes, innate immune cells that react to bacteria. The human SIGLEC17P pseudogene mRNA is still expressed at high levels in human natural killer cells, which bridge innate and adaptive immune responses. As both resulting pseudogenes are homozygous in all human populations, we resurrected the originally encoded proteins and examined their functions. Chimpanzee Siglec-13 and the resurrected human Siglec-17 recruit a signaling adapter and bind sialic acids. Expression of either Siglec in innate immune cells alters inflammatory cytokine secretion in response to Toll-like receptor-4 stimulation. Both Siglecs can also be engaged by two potentially lethal sialylated bacterial pathogens of newborns and infants, agents with a potential impact on reproductive fitness. Neanderthal and Denisovan genomes show human-like sequences at both loci, corroborating estimates that the initial pseudogenization events occurred in the common ancestral population of these hominins. Both loci also show limited polymorphic diversity, suggesting selection forces predating the origin of modern humans. Taken together, these data suggest that genetic elimination of Siglec-13 and/or Siglec-17 represents signatures of infectious and/or other inflammatory selective processes contributing to population restrictions during hominin origins.
Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Xiaoxia
X
Wang
Nivedita
N
Mitra
Ismael
I
Secundino
Kalyan
K
Banda
Pedro
P
Cruz
Vered
V
Padler-Karavani
Andrea
A
Verhagen
Chris
C
Reid
Martina
M
Lari
Ermanno
E
Rizzi
Carlotta
C
Balsamo
Giorgio
G
Corti
Gianluca
G
De Bellis
Laura
L
Longo
William
W
Beggs
David
D
Caramelli
Sarah A
SA
Tishkoff
Toshiyuki
T
Hayakawa
Eric D
ED
Green
James C
JC
Mullikin
Victor
V
Nizet
Jack
J
Bui
Ajit
A
Varki
D000818:Animals; D019143:Evolution, Molecular; D017353:Gene Deletion; D020868:Gene Silencing; D006801:Humans; D007107:Immune System; D037102:Lectins / Q000235:genetics*; D011323:Primates; D063265:Sialic Acid Binding Immunoglobulin-like Lectins
D037102:Lectins; D063265:Sialic Acid Binding Immunoglobulin-like Lectins