Evolution of the immune system

L.A. Moran lamoran at gpu.utcs.utoronto.ca
Tue Dec 8 12:06:34 EST 1992

In an earlier posting I pointed out that the HSP70 genes which map to the
MHC locus in mammals are the inducible members of the HSP70 family. The
constitutively expressed genes are hsc70 and BiP (among others) and these
are not located anywhere near the histocompatibility locus. It is the
products of the constitutively expressed genes that serve as the major
chaperones within cells - they might play a role in assembly of class I
molecules and peptide binding but that is almost certainly a minor role
for these important and ubiquitous proteins.

Don Forsdyke replied,
     "Genes which have arisen separately, and therefore demonstrate no
      sequence similarities, may become closely linked because they are 
      functionally related. Two genes which map in, or close to, the MHC
      complex are: an HSP70 gene and TCP-1 gene (encoding a chaperonin).
      There is growing evidence that these are involved in immune processes
      (I can get the references for you). Precisely what this role is, is 
      a matter of speculation. A gopher ride to the University of Michigan 
      Biology Archive, and examination of the Bionet. Immunology discussions
      for August 1992, provides a debate on this topic."

There is very little evidence for functional organization of genes that are
not evolutionarily related (in eukaryotes). For example, the genes for
beta-2 microglobulin, t-cell receptors, and class I molecules are on different
chromosomes. There is a chaperone that has been shown to be required for
assembly of class I molecules and beta-2 microglobulin (p88), the gene for 
this protein does not seem to map to the same chromosome as the MHC locus.
Furthermore the genes that encode enzymes of many metabolic pathways are 
unlinked. (Homeotic genes in Drosophila may be one exception that proves 
the rule.)

As I mentioned earlier the hsp70A1 and hsp70A2 genes are found in the class
III region at the MHC loci of several mammals but these genes have no known 
role in immunology and histocompatibility in particular. It doesn't look like
these inducible genes are linked to the MHC locus in chicken and frogs but
we need more data.

The TCP-1 gene (t-complex polypeptide-1) encodes a protein that might function
as a chaperone. It is related to proteins in yeast and archaebacteria and 
forms complexes that are similar to those formed by chaperonins (groEL, 
hsp60). There is very weak similarity between the TCP-1 genes and chaperonins
suggesting that they could be related by evolution. One role of TCP-1 is
thought to be in the assembly of spindle but there are undoubtedly many 
other roles consistant with a chaperone function. There is no evidence that
I am aware of for a role in immunology and even if there were such evidence
it would not be the most important role of this protein (recall that it is
found in yeast and archaebacteria, and also Drosophila).

The mouse TCP-1 gene maps to the t-complex which is located on chromosome
17 - the same chromosome as the MHC (H-2) complex. However, the genes are so
far apart that the linkage is weak. There are several hundred genes in 
between. In humans the TCP-1 gene maps to 6q and the MHC locus is at 6p,
these are pretty far apart.
I realize that immunology is an exiting and important discipline but it is 
wise to remember that organisms do a lot of other interesting and important
things. Certain enzymes and proteins, such as chaperones, play a role in 
production and assembly of immunologically important molecules and they
have attracted the attention of immunologists. However, these same enzymes
and proteins can be found in a wide variety of organisms where they are
essential for functions that have nothing to do with immunology. They have
much  more important things to do. Of the many selective pressures acting on
chaperone genes, those relating to immunology are probably insignificant. 

Laurence A. Moran (Larry)

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