The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage.
BACKGROUND
Members of the p47 (immunity-related GTPases (IRG) family) GTPases are essential, interferon-inducible resistance factors in mice that are active against a broad spectrum of important intracellular pathogens. Surprisingly, there are no reports of p47 function in humans.


RESULTS
Here we show that the p47 GTPases are represented by 23 genes in the mouse, whereas humans have only a single full-length p47 GTPase and an expressed, truncated presumed pseudo-gene. The human full-length gene is orthologous to an isolated mouse p47 GTPase that carries no interferon-inducible elements in the promoter of either species and is expressed constitutively in the mature testis of both species. Thus, there is no evidence for a p47 GTPase-based resistance system in humans. Dogs have several interferon-inducible p47s, and so the primate lineage that led to humans appears to have lost an ancient function. Multiple p47 GTPases are also present in the zebrafish, but there is only a tandem p47 gene pair in pufferfish.


CONCLUSIONS
Mice and humans must deploy their immune resources against vacuolar pathogens in radically different ways. This carries significant implications for the use of the mouse as a model of human infectious disease. The absence of the p47 resistance system in humans suggests that possession of this resistance system carries significant costs that, in the primate lineage that led to humans, are not outweighed by the benefits. The origin of the vertebrate p47 system is obscure.
Bekpen
Cemalettin
C
Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany. c.bekpen@uni-koeln.de
Hunn
Julia P
JP
Rohde
Christoph
C
Parvanova
Iana
I
Guethlein
Libby
L
Dunn
Diane M
DM
Glowalla
Eva
E
Leptin
Maria
M
Howard
Jonathan C
JC
D000595:Amino Acid Sequence; D000818:Animals; D004285:Dogs; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D020558:GTP Phosphohydrolases / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology; D007372:Interferons / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000502:physiology; D010802:Phylogeny; D011401:Promoter Regions, Genetic; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D026801:Synteny
D007372:Interferons; D020558:GTP Phosphohydrolases; C491070:Iigp1 protein, mouse