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EVIDENCE FOR EVOLUTION FROM IMMUNE MECHANISMS

HOMOLOGIES ARE PREDICTED BY THE EVOLUTIONARY MODEL

       When comparing cell adhesion proteins within one organism or between organisms, there is no pattern of similarities which would be expected if evolution had not occurred. 

 

1) HOMOLOGIES IN GENE FAMILIES

 

     If organisms owe their origin to the sudden appearance of a small group of ancestors which were completely unrelated to each other, each gene could have its own unique structure.  The proteins involved in cell adhesion would not have to share structural motifs with other proteins, nor would they necessarily have to form gene families.  One of the most significant conclusions which has resulted from modern genome analysis is that large sets of genes in the genomes of complex organisms originated from modified duplications of ancestral genes. 

     Many of the proteins which are most important in determining the vertebrate immune response belong to one of the largest gene families known, the immunoglobulin/fibronectin gene superfamily.  The immunoglobulin domain has been incorporated into a wide diversity of molecules.   Some members are the gene family are classified as fibronectins.  White blood cells rely on fibronectins in migrating to a wound site and neural crest cells (cells around the neural tube in vertebrate embryos which will produce many of the characteristic structures of the vertebrate head) rely on fibronectins in their migrations during embryonic development.  Many immunoglobulin-domain containing proteins are not part of the immune response.     For example, there are about a dozen genes arranged in tandem which form a family of pregnancy specific glycoproteins in a stretch of about 1.1 megabases.  They are made in the placenta and low levels of these proteins are correlated with problems in pregnancy.  Inside the family of PSGs, there is a family of CEACAM pseudogenes.  Ephrin Receptors and Ephrin-related receptors are the largest subfamily of receptor protein tyrosine kinases.  They are important in development, especially in the nervous system.  Neural Cell Adhesion Molecules (N-CAM) molecules possess 5 Ig-like domains and 2 fibronectin domains.  All 5 Ig-like domains are required for N-CAM molecules to bind other N-CAM molecules in cell adhesion (Ranheim, 1996).

     There are also other gene families which function in intercellular interactions, such as cadherins.  The cadherin superfamily can be divided into at least 6 subfamilies: the classical cadherins, the nonclassical cadherins, desmocollins, desmogelins, protocadherins, and Flamingo cadherins.  In addition to these subfamilies, there are other isolated genes which include most of the cadherins known in invertebrates (Nollet, 2000).  The integrin gene family in animals functions in cell adhesion, cell signaling, and (in vertebrates) specialized functions in embryonic development, platelet plug formation, and leukocyte migration.  Most are receptors for proteins of the matrix surrounding cells but some interact with other cell membrane proteins. 

 

2) HOMOLOGIES IN DISTANTLY RELATED ORGANISMS

 

   There is no expectation that homologs of human genes would exist in other organisms if they were not evolutionarily related.  There are arguably many molecular structures which would allow cells to interact with the cells around them and with the extrecellular matrix.  Non-human organisms would not be expected to possess similar cell-surface molecules if they were completely unrelated to humans.   This is especially true of the immunoglobulins which determine the adaptive immune response in higher vertebrates.

     One of the main arguments in “Intelligent Design” is that of “irreducible complexity.”  Advocates of Intelligent Design have argued that molecular systems such as the adaptive immunity of jawed vertebrates must be designed since they involve multiple interacting genes and that such complex pathways could not have evolved gradually.  A cursory examination of immune responses might suggest such a conclusion.  After all, antibodies and T cell receptors are highly specialized molecules which can recognize the microbial pathogens which threaten the body.

ANTIBODY
TCR
Antibody genes are complex with multiple regions which can be randomly assorted to create the ability to recognize millions of specific antigens.
CHAIN

When antibodies bind an antigen, they activate a cascade of complement proteins which generate holes in microbial membranes.

 

COMPLEMENT
The cells which express antibody and T cell receptors (such as the T cells in the image of the thymus below) interact with other body cells in extremely complex ways.
THYMUS
T cells often interact with antigen presenting cells which have ingested microbes and have bound parts of the microbe to special cell surface proteins called MHC proteins.
MACROPHAGE

    Although a cursory examination of immune responses might suggest a complex network which could not have evolved from simpler mechanisms because “nothing works unless everything works”, analysis of the distribution of immune responses and immunoglobulins strongly refutes the evolutionary model rather than “Intelligent Design”.  The complex immune systems found in humans are not irreducibly complex in that, while their multiple interacting parts may be required for human life, no such system is a requirement for life in general.   Ancestral organisms evolved new immune proteins and new molecular systems through the duplication and modification of existing genes, the shuffling of protein domains, mutation, etc.  At first these novelties would not have been essential for life, but rather supplementary systems which gave their bearers an advantage over other organisms.  The descendants of these organisms evolved in ways so that these molecular mechanisms were required to support greater molecular complexity.

     It was once thought that adaptive immunity were completely unrelated to innate responses.  It is now known that adaptive and innate immune systems are actually integrated and should not be treated separately (Dixon, 2001). The adaptive immune system was superimposed upon the innate system which had already existed in ancestral invertebrates.  The complement system and the Toll-like cascade were primitively part of innate responses but which became required for adaptive responses (Du Pasquier, 2004).  MHC and natural killer cells are parts of the innate responses which interact with mechanisms of adaptive immunity (Dixon, 2001).  In both mice and humans, it seems that NK cells of innate defenses and T cells of acquired defenses develop from a common precursor cell type.   NK cells can lyse tumor cells and cells infected with certain viruses, such as herpes viruses and adenoviruses.  They can also respond to antigens which have bound IgG.  The cytokines and interferon which they produce mediate the responses of leukocytes and the development of inflammation (Moretta, 2002).

      Antigen-Presenting cells (APCs) are cells of innate responses which can recognize microbial carbohydrates, proteins, lipids, or nucleic acids even without the immunoglobulins of the adaptive immune system.  APCs utilize innate receptors such as lectins and Toll-like receptors to recognize these microbial molecules (Lu, 2002).

     Jawless fish have no organized lymphatic tissue and lack both a spleen and thymus.  Lampreys and hagfish seem to lack antibodies, T Cell receptors, MHC proteins, and RAG. (Zarkadis, 2001).

They do, however, possess serum heterodimeric proteins which resemble both antibodies and T cell receptors (Varner, 1991). 

     Lamprey blood contains cells which are morphologically indistinguishable from mammalian lymphocytes although no MHC, T cell receptor, or antibodies are known from lampreys.  These cells express genes associated with mammalian lymphocytes and occur in tissues (such as the intestines) where lymphocytes are common in higher vertebrates (Mayer, 2002).  Lymphocyte-like cells in lampreys are small with little cytoplasm and produce lymphocyte transcription factors (Spi and Ikaros), CD45, BCAP, and CAST (which in mammals are primarily expressed in lymphocytes), CD98 and CD9 (which mammals use in lymphocyte proliferation and migration), proteasome subunits (PSMB4, PSMB7, 26S subunit pUb-R3, PSMA2, PSMA6, and PSMF1), and ABC9 (similar to the ABC proteins which mammals use to transport peptides to the MHC)., the complement protein C1q, and a number of other genes expressed in mammalian lymphocytes (hepsin, sygin 2, RAMP4, and talin) (Mayer, 2002).

Lampreys lack antibodies, but they possess C1q, serine proteases of the C1s/C1r/MASP family, and C3.  It seems that C1q originally functioned as a lectin before it was modified to bind antibodies.  (In mammals, C1q can bind to substances other than antibodies to initiate the complement cascade (Matsushita, 2004). 

     The genes of MHC I and II are immunoglobulins which are most similar to antibodies and T cell receptors (TCR).  The ancestral MHC is likely to have been duplicated to produce MHC class I and class II regions; MHC I and II are almost identical in their tertiary structures.  Additional duplications and modifications have occurred since this original duplication to produce the different MHC I and II genes (Gaudieri, 1999; Ohta, 2000).   Cartilaginous fish have 3 types of MHC molecule (MHCIa, MHCIIa, and MHCIIb) despite the fact that they do not have T cells.   (Berstein, 1996; Kasahara, 1992). 

    While most T cells function through complex interactions with other cells, they are also capable of independent function.  The receptors of γδ T cells bind to antigens in a manner similar to the antibody receptors on B cells and do not require the processing of antigens by antigen presenting cells as do the αβ T cells (Richards, 2000).  

 

 

COMPLEMENT

     All gnathostomes possess adaptive immunity while jawless fish lack it.  Although the complement system is an important component of adaptive immunity, it also functions in innate immunity.  Jawless fish possess complement proteins which function in the lectin pathway.  Cartilaginous fish were the first vertebrates to develop a classical pathway of complement proteins and this pathway had developed components similar to the mammalian pathway by the evolution of bony fish.

     The complement system is thought to have evolved from a simple mechanism similar to that found in lectin and alternative pathways. 

COMPLEMENT

Three proteins might have functioned in this system: a C3-like protein (magenta, in the above drawing), a serine protease similar to factor B (green), and a complement receptor on immune cells (red).  Complement proteins (factor B and C3) are known in echinoderms and complement-like proteins are known in more primitive invertebrates.  The complement system seems to have evolved from a simple pathway involved in opsonization (Zarkadis, 2001).  C3 is the main component in all 3 complement pathways.  In all three pathways, it is cleaved (by C3bBb in the alternative pathway and C4bC2a in the classical and lectin pathways) into two fragments, and exposes its thioester region which binds the target molecule (Nakao, 2003).   The thioester bond of C3 can bind to microbes serving in opsonization and as the site for the late complement proteins (C5 through C9 to generate a membrane pore) (Fujita, 2004). 

     From this simple opsonization pathway, three additional pathways developed which involve additional complement proteins which form a permanent membrane hole on the microbe, causing its lysis.  The most complex and most well-known of the three is the Classical Pathway, a part of the adaptive immune response which involves antibodies.  However, most of the same components in the complement cascade of adaptive immunity are also functional in the Lectin and Alternate Pathways, which function in innate immunity.  The classical pathway originated in cartilaginous fish and the lectin pathway in urochordates (Matsushita, 2004)

    Although primitive invertebrates possess the domains used by the complement system, a complement system did not evolve until the deuterostomes.  Primitive deuterostomes evolved the components of the complement cascade and the genome duplications early in the history of the vertebrates allowed the integration of several related pathways (Fujita, 2004).

PATHWAY
PATHWYA

 

     Parts of the complement pathway known in jawed vertebrates evolved long before jawed vertebrates.  Sponge molecules possess the SCR/CCP domains which are found in complement proteins (Zarkadis, 2001).  Elements of the lectin pathway, MBL and MASP, are known since protochordates.  Elements of the alternative pathway, C3 and factor B, are known in echinoderms and factor D in bony fish. (Zarkadis, 2001; Lundqvist, 1999;Pearce, 2001). The sea urchin protein SpBf is a complement protein which possesses SCR domains, a von Willebrand factor domain, and a serine protease domain.  Sea urchins possess complement C3 proteins which seem to function in opsonization and whose levels increase in response to infection.  Sea urchin proteins possess a thioester region, which in vertebrate complement proteins C3, C4, and C5, is the region which are exposed and bind target molecules in complement activation.  Some insect proteins have molecules similar to complements with thioester regions (Smith, 2002). 

     Urochordates possess proteins in both the alternative pathway (C3, Bf) and lectin pathway (MBL, MASP).  Although tunicates lack acquired immunity, they do possess complement genes, lectins, and 2 interleukin receptor genes which probably function in innate immunity (Dehal, 2002).  Tunicates seem to have homologs of complement receptors and complement proteins are known to mediate phagocytosis in bony fish (Zarkadis, 2001).

 

      Not only have complex immune response evolved from simpler systems, different organisms have utilized different molecules for equivalent purposes in their immune systems.  For example, rodents seem to lack KIR genes, but they possess a variety of Ly49 genes which perform the same function.  Humans possess a Ly49 pseudogene on chromosome 12 (Wilson, 2000a).

 

THE GENE CLADOGRAM

Many of the genes which humans require to be human evolved long before humans.  The distribution of these genes among modern organisms supports that modern groups of organisms can be organized into clades which share a common ancestry.  The same clades of organisms which are supported through the analysis of signaling molecules are supported by the analysis of other genes, anatomical features, embryological development, and the fossil record.  The organization of modern organism into a nested hierarchy of clades is predicted by the evolutionary model but not alternative models.

 

EUKARYOTES

--It appears that some of the proteins that animals use for cell adhesion existed prior to the evolution of multicellular animals.  Choanoflagellates are unicellular protists which possess both cadherin and lectin domains.  Yeasts possess a molecule similar to α integrin and cellular slime molds possess Ig-like homologs of CAM molecules.  Unicellar choanoflagellates possess cadherin domains in their genome (Hartwood, 2004). 

--Both a and b integrin subunits are known throughout the animal kingdom, including in sponges and there evidence that integrin-like molecules exist in plants and fungi (Brower, 1997).  

--Galectins are known in sponges, nematodes, and fungi but not in protozoa or plants (Muller, 2001; Vasta, 1999). 

 

ANIMALS

--Sponges possess fibronectin, originated in animals (there is one case in bacteria, probably horizontal transfer (Muller, 2001; Muller, 2001b). 

--Phagocytic cells are known in the most primitive animal groups, such as sponges and starfish, and are present in invertebrates which lack a true circulatory system (Hoar, 1983). 

--A cytokine-like molecule known in sponges which is similar to an enzyme functional in inflammation in mammals (Muller, 2001).  

Two cytokines are known in sponges (Muller, 2001).

--Lectins are known from sponges (Schacke, 1994a). 

--Variable immunoglobulin domains are known in cell surface molecules of plants and fungi in addition to a diversity of animals, including the most primitive animals, the sponges (Muller, 2001; Muller, 2001a). 

--Sponge molecules possess the SCR/CCP domains which are found in complement proteins (Zarkadis, 2001). 

--A number of domains evolved before the separation of sponges which allow interaction with the surrounding matrix and neighboring cells: fibronectin, scavenger receptor cysteine-rich domains (SRCR), and short consensus repeats (SCR) (Muller, 2001). Both a and b subunits are known throughout the animal kingdom, including in sponges and there evidence that integrin-like molecules exist in plants and fungi (Brower, 1997).  

--Sponges possess integrins, an extracellular matrix, and transcription factors of the ets, paired-box, and homeobox (several including an NK class gene and one Hox-like gene) classes (Peterson, 2002; Muller, 2001). 

--Variable immunoglobulin domains are known in cell surface molecules of plants and fungi in addition to a diversity of animals, including the most primitive animals, the sponges (Muller, 2001; Muller, 2001a). 

 

METAZOANS

--There are a number of features which unite the metazoans such as collagen, ACh and AchE systems, ets gene family, ras-related gene family, histone gene clusters, receptor tyrosine kinases, Immunoglobulin superfamily, S-type lectins, extracellular matrices, antistatin, integrins, Hox genes, the internal location of reproductive cells. (p. 1-2), multicellularity with cell differentiation, oogenesis with polar bodies, omnipotent cells, integrin receptors, (Morris, S. Conway, from Muller, 1998., p. 72)

 

BILATERANS

---Drosophila uses Toll-like receptors which, after binding microbes, induces the expression of antimicrobial peptides.  C. elegans possesses one Toll-like receptor which seems to affect its reaction to microbes (Nicholas, 2004).  C. elegans possesses 135 proteins with the C lectin domain compared to the 35 known in Drosophila (Nicholas, 2004).

--Titin, twitchin, and projectin form a family of large kinases which possess a series of immunoglobulin and fibronectin domains.  The immunoglobulin domains are intermediate between constant and variable Ig domains.  Titin isoforms may possess 165 immunoglobulin and 132 fibronectin domains.  Twitchin is known in C. elegans (Kenny, 1999).

--FAT-like cadherins exist in vertebrates, nematodes, and flies (Hill, 2001).  Seven-helix transmembrane cadherins (which include the secretin GPCRs) are known in vertebrates, nematodes, and flies (Hill, 2001).

--MIF is similar to a number of other enzymes such as D-dopachrome tautomerase (DDT), -carboxymethyl-2-hydroxymuconate isomerase, 4-oxalocrotonate tautomerase, chorismate mutase, and glutathione S-transferase (GST) of the mu-class.  DDT and GST are linked to the human MIF gene and related enzymes are known in nematodes (Sato, 2003a).

 

COELOMATES

--Insects and Aplysia possess immunoglobulin molecules homologous to NCAM (Ranheim, 1996).

--Lectins are the primary opsonins in tunicates.  Lectins also perform opsonization in mollusks and arthropods (Pearce, 2001). 

--Titin in muscle (Champagne, 2000). 

--TNFα is known in bony fish and there are some reports of its presence in protostomes and primitive deuterostomes (Magor, 2001).

--Protocadherin homologs are known in Drosophila and the existence of 3 clusters of protcadherin genes on human chromosome 5q31 suggests that gene duplication has produced some of the diversity of the gene subfamily (Wu, 2000).

--MAGE proteins are known in flies and thus predate the evolution of adaptive immunity (Pold, 2000). 

--Mollusks and arthropods possess a number of lectins which can bind to human blood groups (Kilpatrick, 2002). 

--J chain is expressed in a number of protostome invertebrates as well as in diverse groups of vertebrates.  In invertebrates, it is expressed on macrophage-like blood cells and epithelial surfaces.  Since these animals lack antibodies, it appears that the J chain functions in other capacities as well (Takahashi, 1996). 

-- Drosophila possesses a protein with V and C chains showing homology to nectin (Du Pasquier, 2004).

--Peroxidase can bind integrin in an immune respose which seems conserved in coelomates (Johansson, 1999).

--Flamingo cadherins are known in vertebrates and flies (Nollet, 2000).

--Tight junctions are a chordate feature, although they have also been found in blood-brain and blood-testis barriers in arthropods. 

--Mammals possess about 20 claudin genes which maintain junctions such as the tight junctions of the blood-brain and blood-testis barriers.  Many of these genes (and even their intron position) predate the split of bony fish and tetrapods (Kollmar, 2001).

 

DEUTEROSTOMES

--Insects and Aplysia possess immunoglobulin molecules homologous to NCAM (Ranheim, 1996).

--Elements of the lectin pathway, MBL and MASP, are known since protochordates.  Elements of the alternative pathway, C3 and factor B, are known in echinoderms and factor D in bony fish. (Zarkadis, 2001; Lundqvist, 1999;Pearce, 2001).

 

CHORDATES

--Ascidian blood (such as that in the tunicate larva pictured below) includes macrophages, different kinds of granular amoebocytes with odd-shaped nuclei which perform phagocytosis, cytotoxic cells, and a number of other cell types (Parrinello, 1996;Burighel, from Harrison, 1997, p. 269). 

--Although they lack MHC genes, urochordates possess a region which seems to be ancestral to the multiple MHC regions which resulted from the genome duplications in early vertebrates (Kasahara, 2004). 

--Tunicates, among the most primitive chordates, possess JAM, CTX and PVR genes which possess both a V and a C domain (Du Pasquier, 2004).

--Urochordates possess proteins in both the alternative pathway (C3, Bf) and lectin pathway (MBL, MASP).  Although tunicates lack acquired immunity, they do possess complement genes, lectins, and 2 interleukin receptor genes which probably function in innate immunity (Dehal, 2002).  Tunicates seem to have homologs of complement receptors and complement proteins are known to mediate phagocytosis in bony fish (Zarkadis, 2001).

--The lectin-based opsonization pathway seems to be the original pathway.  Tunicates seem to have a minimal complement system involving a lectin which binds to serine proteases (forming GBL-MASP complex), C3, and a C3 receptor on blood cells (Fujita, 2004).

α2M/C3/C4/C5 form a gene family.  Tunicates have 2 molecules similar to α2M and two which are similar to C3.  They also possess 3 linked Bf genes, nine ficolin-like molecules, and 2 C1q like molecules (Fujita, 2004).

--Tunicates, among the most primitive chordates, possess JAM, CTX and PVR genes which possess both a V and a C domain (Du Pasquier, 2004).

 

CRANIATES

--The enzyme alkaline phosphatase found in neutrophils is known from jawless fish and all higher groups (Hine, 1990).

--Hagfish possess a protein CLP (complement-like protein) which functions in immune defenses is structurally similar to a mammalian complement protein (Hanley, 1992).  Although the complement system is an important component of adaptive immunity, it also functions in innate immunity.  Jawless fish possess complement proteins which function in the lectin pathway

--Lampreys and hagfish seem to lack antibodies, T Cell receptors, MHC proteins, and RAG. They do, however, possess serum heterodimeric proteins which resemble both antibodies and T cell receptors (Varner, 1991). 

--Hagfish, lampreys and jawed fish possess homologs of the macrophage migration inhibitory factor (MIF).  MIF is similar to a number of other enzymes such as D-dopachrome tautomerase (DDT), -carboxymethyl-2-hydroxymuconate isomerase, 4-oxalocrotonate tautomerase, chorismate mutase, and glutathione S-transferase (GST) of the mu-class.  DDT and GST are linked to the human MIF gene and related enzymes are known in nematodes (Sato, 2003a).

 

VERTEBRATES

--Lymphocyte-like cells in lampreys are small with little cytoplasm and produce lymphocyte transcription factors (Spi and Ikaros), CD45, BCAP, and CAST (which in mammals are primarily expressed in lymphocytes), CD98 and CD9 (which mammals use in lymphocyte proliferation and migration), proteasome subunits (PSMB4, PSMB7, 26S subunit pUb-R3, PSMA2, PSMA6, and PSMF1), and ABC9 (similar to the ABC proteins which mammals use to transport peptides to the MHC)., the complement protein C1q, and a number of other genes expressed in mammalian lymphocytes (hepsin, sygin 2, RAMP4, and talin) (Mayer, 2002).

--It seems that the clusters of protocadherins are unique to vertebrates (Frank, 2002).

 

GNATHOSTOMES

--Of the terminal lytic proteins C5-C9, C5 and C8 are known in sharks (Zarkadis, 2001).

--MHC genes themselves seem to have arisen with the in the evolution of the gnathostomes, coinciding with the proposed rounds of genome duplication which seem to have occurred at the base of this group (Ohta, 2000; Bartyl, 1994). 

--antibodies (Roux, 1998). 

--IgM antibody  (Wilson, 1997)

 --All gnathostomes possess adaptive immunity while jawless fish lack it.  Cartilaginous fish were the first vertebrates to develop a classical pathway of complement proteins and this pathway had developed components similar to the mammalian pathway by the evolution of bony fish.

--The adaptive immunity of higher vertebrates depends on the ability of recombination activating genes (RAG) to randomly join segments of antibody genes to create an enormous variety of antibodies and T cell receptors.  The RAG proteins in vertebrate genomes seem to have resulted from the insertion of a bacterial transposon of the Hin recombinase family and the RAG sequence functions in a way similar to transposons.  When the RAG transposon was inserted into the ancestral immunoglobulin gene, it seems to have separated V and J segments which were once part of the same exon (Kasahara, 2004).

RAG-1 regulates the recombination of B cell receptor regions κ, λ, and μ and the α, β,δ, and γ regions of T cell receptors (Schatz, 1989).

The RAG rearrangements only affect one type of leukocyte—it did not interrupt the preexisting innate responses (Du Pasquier, 2004).  All gnathostomes can rearrange antibody and T-cell receptor segments using RAG genes.  RAG I is homologous to integrase and RAG II is homologous to integration host factor; these two genes cause site specific recombination in bacteria (Bernstein, 1996).

 

BONY

--The Ia set of MHC genes are known as classical loci and are the major determinants of antigen presentation.  Classical MHC proteins are present in bony fish and are expressed on similar cell types as those in higher vertebrates (Dijkstra, 2003). 

--CC cytokines, CC receptors, and CXC receptors are known in bony fish (Magor, 2001).

--The enzyme eosinophil peroxidase is not known in jawless fish, its activity is weak or absent in cartilaginous fish, and is present in at least some of the members of all higher groups.  The enzyme alkaline phosphatase found in neutrophils is known from jawless fish and all higher groups (Hine, 1990).

--The response of the cells of the bowfin aorta to bradykinin is comparable to those of mammals.  There is only one amino acid difference between the forms of bradykinin in humans and bowfins (Conlon, 1995).

--Interferons are definitely known from amniotes and possible homologs have also been identified in fish (Magor, 2001). 

--Tight junctions are a chordate feature, although they have also been found in blood-brain and blood-testis barriers in arthropods.  --Mammals possess about 20 claudin genes which maintain junctions such as the tight junctions of the blood-brain and blood-testis barriers.  Many of these genes (and even their intron position) predate the split of bony fish and tetrapods (Kollmar, 2001).

 

SARCOPTERYGIAN

--The MHC molecules in coleocanths possess a similar intron-exon organization compared to those in mammals and are very similar to those of amphibians (Betz, 1994).  

 

AMNIOTES

--IL2 was formerly called T cell growth factor.  IL2 and 15 use the same β and γ chains but differ in their α chains.  They are only known in amniotes.  IL2 stimulates T cell production (Kaiser, 2004).

IL18 stimulates natural killer cells.  It is involved in inflammatory skin reactions and graft vs. host disease.  IL18 is only known in amniotes (Kaiser, 2004).

--Interferons are definitely known from amniotes and possible homologs have also been identified in fish (Magor, 2001). 

 

MAMMALS

--Interleukin-6 is only known from mammals (Magor, 2001). 

--It seems that there was a duplication of the IgY gene in the ancestors of mammals and the two forms were modified to form IgG and IgY (Vernersson, 2004). 

--All mammals use IgM, IgG, IgA, and IgE and lack the IgY used in reptiles (Belov, 2003).  IgD is known in rodents, primates, artiodactyls and teleosts (Belov, 2003).

--IgE only exists in mammals but present in all 3 groups groups of mammals (Vernersson, 2004).

--Much of the expansion of the expansion of the interleukin family has occurred recently in separate events in early vertebrates and mammals (Huising, 2004).

--It seems that there was a duplication of the IgY gene in the ancestors of mammals (prior to monotremes) and the two forms were modified to form IgG and IgE (Vernersson, 2004). 

 

THERIANS

--Sequence comparisons indicate that Class Ic genes diverged before the separation of therian mammals (Hughes, 1999).  

--The class II gene families are only known in therian mammals.  The majority of the genes in the class II families are of recent origin, being shared by Old World monkeys and apes but not by New World monkeys.  There may be ancient genes which predate the split of anthropoid primate lineages, such as DQB, but this gene seems to be nonfunctional (Kreiner, 2001).

 

PRIMATES

--The IFNα family seems to have arisen from after the primate lineage arose (Gillespie, 1983).

--CEACAM family of genes is expressed in epithelial and myeloid cells.  Loss of their expression often leads to colorectal cancer.  There are 8 genes in tandem near the family of pregancy derived glycoproteins, to which they are related (Carl, 2001).  There are 29 members (genes and pseudogenes) of the carcinogenoembryonic (CEA) gene family in humans in a 1.5 Mb section of chromosome 19..  Much of this expansion has occurred in primates after separation from other placental orders (Zhou, 2001).

 

ANTHROPOID PRIMATES

--The polymorphism of this locus predates the split of human and chimp ancestors and gives evidence for multiregional evolution of human evolution.  About 135 alleles are known (of which over 90% evolved after the split between human and chimp ancestors); some alleles offer resistance to malaria (OMIM). Although the DR region of the MHC complex was established before the split with NW monkeys, many of the DRB genes have arisen since then (Satta, 1996).

 

CATARRHINE PRIMATES

--The majority of the genes in the class II families are of recent origin, being shared by Old World monkeys and apes but not by New World monkeys.  There may be ancient genes which predate the split of anthropoid primate lineages, such as DQB, but this gene seems to be nonfunctional (Kreiner, 2001).

--Although the DR region of the MHC complex was established before the split with NW monkeys, many of the DRB genes have arisen since then (Satta, 1996).

--The number of functional alleles of the MHC-G varies in different primate groups: there are the highest number of alleles in New World monkeys, less in Old World monkeys, and the greatest invariance in apes, especially humans.  The selection for this invariance may be related to the increased length of pregnancy in apes and humans (Arnaiz-Villena, 1999). 

 

APES

--There is a 51 base pair deletion in exon 8 of the MHC-G gene which is shared by apes but not OW monkeys (Castro, 2000).

 

AFRICAN APES

--Some alleles of the HLA-A and HLA-B genes are shared between humans and chimps and thus arose before the split between their lineages. The HLA-Cw*0702 seems to have arisen before the separation of the higher ape lineages, producing alleles in humans, chimps, and gorillas (Matsui, 1999).

--Human and chimp recognition systems are clearly similar in that NK receptors of one species can recognize the MHC proteins of the other (Khakoo, 2000).

-- HLA-DRB polymorphism of this locus predates the split of human and chimp ancestors and gives evidence for multiregional evolution of human evolution.  About 135 alleles are known (of which over 90% evolved after the split between human and chimp ancestors); some alleles offer resistance to malaria (OMIM). Although the DR region of the MHC complex was established before the split with NW monkeys, many of the DRB genes have arisen since then (Satta, 1996).

 

HUMAN

The HLA-H pseudogene is homologous to a functional gene in gorillas.  Human pseudogenes HLAS-COQ and HLA-DEL also are homologous to functional genes in gorillas (Golos, 2003)..