August 20, 1998
Ancient "Jumping DNA" May Have Evolved into Key Component of Human Immune System
The human immune system, an elegant and intricate biological defense
system unmatched in most life forms, may have evolved from a mobile
piece of DNA that inserted itself into the mammalian genome more than
450 million years ago.
A team of researchers led by David G. Schatz at the
Howard Hughes Medical Institute at Yale University has found evidence
that tiny gene particles vital to the task of producing millions of
different kinds of antibodies act like a gene segment that can "jump"
into foreign DNA. Although there are many examples of such genes in
lower organisms, it is the first cut-and-paste "transposase" ever found
in humans.
“This helps explain why the jawed vertebrates are the only species that have a second, adaptive immune system, in addition to the innate immune system that all other species have.”
David G. Schatz
"This helps explain why the jawed vertebrates are the only species
that have a second, adaptive immune system, in addition to the innate
immune system that all other species have," says Schatz, an
immunologist. His study, conducted with Yale researchers Alka Agrawal
and Quinn M. Eastman, is published in the August 20, 1998, issue of the
journal Nature.
An adaptive immune system relies on two lines of defense to detect
and destroy invaders. Both parts of the immune system belong to a class
of white blood cells called lymphocytes, found in the blood and
lymphoid organs. B lymphocytes produce antibodies that bind tightly to
a foreign molecule, inactivating it or marking it for destruction by
other cells in the immune system. T lymphocytes detect the presence of
foreign molecules inside special "processing" cells once those cells
have displayed a fragment of the foreign molecule-those pieces are
called antigens-on the processing cell's surface. So-called T-cell
receptors on the surface of the T lymphocyte bind strongly to the
antigen.
Although they perform different functions, both B and T lymphocytes
use the same unique genetic mechanism to economically generate an
almost unlimited number of antibodies and T-cell receptors. Indeed, the
human immune system is capable of producing a larger number of
different antibodies and receptors than there are numbers of genes in
the entire human genome. To accomplish this feat, the immune system
uses a smaller number of gene segments that can be shuffled and joined
to one another to produce many distinct combinations. Each
recombination essentially produces a new gene, and provides an almost
infinite database of genetic information from which to generate
antibodies and T-cell receptors.
This system of genetic recombination is at the heart of Schatz's
study. Two closely linked genes, RAG1 and RAG2 (for
recombination-activating genes 1 and 2), code for proteins that promote
this genetic recombination. The Schatz team has found that RAG1 and
RAG2 work together as a transposase, an enzyme that snips pieces of DNA
out of one location in a chromosome and transposes these pieces
elsewhere. This ability to slice and recombine genes accounts for the
"split nature" of antibody and T-cell receptor gene DNA, allowing
vertebrates to create millions of different antibodies and T-cell
receptors from a limited number of genes, Schatz believes.
Schatz's team and other research groups have explored the genomes of
a variety of vertebrates for the presence of RAG1 and RAG2 and have
found these two genes in all jawed vertebrates examined thus far. All
of these species possess immune systems that use genetic recombination.
However, jawless hagfish and lamprey, which lie just below the jawed
vertebrates on the evolutionary tree and do not possess the system of B
and T lymphocytes, lack RAG1 and RAG2 or any close relatives of these
genes. Based on these findings, Schatz and his colleagues suggest that
the RAG transposase must have acted something like a virus, inserting
itself into the genome of jawed vertebrates after that lineage split
from its jawless relatives approximately 450 million years ago.
"No other genes in mammals are split up like this and then
recombined at the DNA level," Schatz says. He cautions, however, that
although the researchers have shown transpositional activity in
vitro, they have not proven it works that way in the human body.
The RAG genes now may just work to slice and connect pieces of genes
without inserting the excised piece of DNA in a different location.
"One question we are interested in now is to understand why RAG1 and
RAG2 may have once functioned as a [more general] transposase, but
don't now. What has changed?" Schatz says. "Has the body found a way of
suppressing their ability to insert genes elsewhere in the genome? That
would make sense, because moving your DNA around that way randomly
could kill you."
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