Page 160 - Genetics_From_Genes_to_Genomes_6th_FULL_Part1

152 Chapter 5 Linkage, Recombination, and the Mapping of Genes on Chromosomes

FAST FORWARD

GENE MAPPING MAY LEAD TO A CURE FOR CYSTIC FIBROSIS
For 40 years after the symptoms of cystic fibrosis were first de- Figure A How molecular markers helped locate the
scribed in 1938, no molecular clue—no visible chromosomal gene for cystic fibrosis (CF).
abnormality transmitted with the disease, no identifiable protein
defect carried by affected individuals—suggested the genetic 1 cM 1 cM
cause of the disorder. As a result, no effective treatment existed
for the 1 in 2000 Caucasian Americans born with the disease, 5 cM 10 cM 18 cM
most of whom died before they were 30. In the 1980s, however,
geneticists were able to combine recently invented techniques Chromosome 7
for looking directly at DNA with maps constructed by linkage
analysis to pinpoint a precise chromosomal position, or locus, D7S15 PON met CF J3.11 TR
for the cystic fibrosis gene.
The mappers of the cystic fibrosis gene faced an over-
whelming task. They were searching for a gene that encoded
an unknown protein, a gene that had not yet even been as-
signed to a chromosome. It could lie anywhere among the 23
pairs of chromosomes in a human cell. Band 7q31
• A review of many family pedigrees confirmed that cystic
fibrosis is most likely determined by a single gene (CF).
Investigators collected white blood cells from 47 families marker to CF was 15 cM; from the DNA marker to PON,
with two or more affected children, obtaining genetic 5 cM; and from PON to CF, 10 cM. They concluded that
data from 106 patients, 94 parents, and 44 unaffected the order of the three loci was D7S15-PON-CF (Fig. A).
siblings. Because CF could lie 15 cM in either of two directions
• The researchers next tried to discover if any other trait is from the DNA marker, the area under investigation was
reliably transmitted with cystic fibrosis. Analyses of the approximately 30 cM. And because the human genome
easily obtainable serum enzyme paroxonase showed that consists of roughly 3000 cM, this step of linkage analysis
its gene (PON) is indeed linked to CF. At first, this knowl- narrowed the search to 1% of the human genome, in a
edge was not that helpful, because PON had not yet been small region of chromosome 7.
assigned to a chromosome. • Finally, investigators discovered linkage with several other
• Then, in the early 1980s, geneticists developed a large markers on the long arm of chromosome 7, called J3.11,
series of DNA markers, based on new techniques that βTR, and met. Two of the markers turned out to be sepa-
enabled them to recognize variations in the genetic ma- rated from CF by a distance of only 1 cM. It now became
terial. A DNA marker is a segment of DNA representing possible to place CF in band 31 of chromosome 7’s long
a specific locus that comes in identifiable variations. arm (band 7q31, Fig. A). By 1989, researchers had used
These allelic variations segregate according to Mendel’s this mapping information to identify and clone the CF
laws, which means it is possible to follow their transmis- gene on the basis of its location.
sion as you would any gene’s. Chapter 11 explains the • In 1992, investigators showed that the CF gene specifies
discovery and use of DNA markers in greater detail; for a cell membrane protein that regulates the flow of chlo-
now, it is only important to know that they exist and can ride ions into and out of cells (review Fig. 2.25). This
be identified. knowledge has become the basis of new drug therapies
• By 1986, linkage analyses of hundreds of DNA markers to open up ion flow, as well as gene therapies to intro-
had shown that one marker called D7S15, and known to duce normal copies of the CF gene into the cells of CF
reside on the long arm of chromosome 7, is linked with patients. Although only in the early stages of develop-
both PON and CF. Researchers computed recombination ment, such gene therapy holds out hope of an eventual
frequencies and found that the distance from the DNA cure for cystic fibrosis.

located at the two ends will not produce more than 50% Gene Mapping May Lead to a Cure for Cystic Fibrosis
recombinant progeny. describes how researchers used linkage information to
Linkage mapping has practical applications of locate the gene for this important human hereditary
great importance. For example, the Fast Forward Box disease.