Scientists have unraveled the sequence of one of the most importantfamilies of genes in the human immune system, the beta T-cellreceptor locus, which marshals the body's defenses against bacteria,viruses and cancer.
This analysis _ of the longest continuous segment of human DNAever sequenced _ is expected to yield provocative insights into howthe body wards off disease and why the immune system sometimesgoes awry, causing such debilitating ailments as arthritis and multiplesclerosis.
Moreover, it signals that the goal of sequencing the complete humangenome may be within reach.
"It suggests we will be able to complete the analysis of the entirehuman genome in a reasonable time span," said Leroy Hood, amember of the sequencing team and chairman of molecularbiotechnology at the University of Washington, in Seattle. In 1986,Hood helped devise a prototype of the automated sequencingequipment that made possible the Human Genome Project, currentlyscheduled for completion in seven to nine years.
The T-cell receptor is located on chromosome seven. It contains684,973 bases, organized into 46 functional genes, 19 pseudogenesand 22 relics, according to a report in the June 21, 1996, Science.The functional genes make it possible for T cells to recognizevirtually any foreign molecule and produce a vast array of receptorscapable of intercepting these interlopers.
"The sum total of receptors that can be generated from this genefamily probably numbers in the millions," Hood said.
All told, the body can make a million million antibody-encodingimmune recognition cells, and the beta T-cell receptors generate halfof them. Another immune-system workhorse, the B cell, produces therest.
One secret of the T cell's success is the mechanism that enables it torecognize invading organisms and develop an infinite number ofunique versions of itself, each designed to fight a specific germ ortype of cancer cell.
"The genes that do the recognition work kind of like a slot machine,"Hood said. "The recognition parts of the gene are divided into threetypes of elements, and they contain many copies of those threeelements. There are 10 copies of the first type, 10 of the second typeand 10 of the third."
Each time a T cell recognizes a foreign protein lodged in thehistocompatibility locus antigen of a macrophage, it begins to createnew T cells, combining those elements in a configuration that isuniquely suited to seek out the protein. "It gives you the ability torecognize thousands of combinations and create an enormousrepertoire of T cells," Hood said.
The researchers were surprised to find that the gene families alsocontained eight genes that encode trypsinogen, an enzyme that breaksdown proteins in the digestive tract.
Lee Rowen, another member of the University of Washingtonresearch team, said the "relationship between these genes iscompletely unexpected."
The trypsinogen genes also are found in the Beta locus of the mouseand the chicken, which diverged from humans 65 million and 350million years ago, respectively. The presence of these genes in the T-cell family suggests that they have a regulatory role, or perhaps someother function that has not yet been described, according to theScience report.
"Genes that live together work together," Hood said.
The researchers were surprised to find that a portion of the genefamily was duplicated and translocated from chromosome seven tochromosome nine.
A preliminary reading of the sequence suggests that one of the T-cellgenes encodes the third trypsinogen mRNA found in the pancreas.Although the researchers have not yet determined how thistranslocated segment functions, they believe it may help to explainhow multigene families originate.
It suggests, Rowen said, that the Beta T cell is a dynamic locus that"continues to be the subject of a fair amount of evolutionary change."
In addition, the team found that the functional T-cell genes expresslarge quantities of RNA that can be detected in complimentary DNA.This RNA is literally "junk" that the body degrades and disposes of.
This means, Hood said, "that the body has an efficient mechanism fordegrading junk. How it works we don't know. It's a fascinatingquestion. Something complicated, strange and new is going on hereand we don't understand it."
Ultimately, he said, "understanding this entire family will let us thinkabout ways to manipulate T cells themselves _ so that we can eithermultiply good ones, to use as vaccinations against tumors orinfectious agents, or eliminate bad T cells, such as the ones that causeautoimmune disease."
Martha Krebs, director of research for the U.S. Department ofEnergy, which sponsored the research along with the NationalInstitutes of Health, said in a statement that the researchers' efforts"have created new and powerful tools that can pave the way for anew era of preventive medicine."
A Canadian scientist, Ben Koop, of the Center for EnvironmentalHealth at the University of Victoria, B.C., was the third member ofthe research team. n
-- Steve Sternberg Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.