Biology Reference
In-Depth Information
between a disease gene and a genetic marker, then it is likely that the chro-
mosomal location of the disease gene is very close to that of the genetic
marker.
3.1 Localizing and Identifying Genes
One goal of genetic research is to localize, identify, and establish the base
sequence of all genes. Genetic linkage analyses of families in which some
members have an inherited disorder provide the chromosomal location
of the deleterious gene. A linkage study may require typing hundreds
of genetic markers before the disease gene is localized, but once this step
is accomplished, research to identify candidate genes in the region begins.
For recessive hearing impairment, affected individuals whose parents are
related are likely to have the same homozygous genotype. Thus, the search
for the location of the gene may be accelerated by screening pooled DNA
samples from these individuals and selecting markers for which they are
all homozygous for the same allele (Sheffield et al. 1994). If pooling is fea-
sible, the number of samples that need to be typed can be reduced dra-
matically. For example, Scott et al. (1995) used this approach in their study
of
DFNB1
Bedouin families (Mueller, Van Camp, and Lench, Chapter 4;
Griffith and Friedman, Chapter 6). When the gene is identified and muta-
tions are detected, diagnostic tests that examine the DNA within the gene
itself are applicable to all individuals. Mueller, Van Camp, and Lench
describe the methodology used to identify genes and detect mutations in
Chapter 4.
As well as providing the approximate location of a disease gene, linkage
analysis permits more precise genetic counseling (Arnos and Oerlich,
Chapter 9). For example, by examining the transmission in a family of
a closely linked genetic marker, relatives of individuals affected with a
recessive disorder can be informed as to whether they are likely to be
carriers.
The development of high-resolution genetic and physical maps, together
with the construction of genomic and cDNA libraries, and the availabil-
ity of sequence databases for many species, provide the tools for finding
genes once they have been localized by linkage analysis. Giersch and
Morton (Chapter 3) describe some of these tools. Detecting a mutation
in a candidate gene in affected individuals may mean that the search for
the gene responsible for the hearing impairment is over, particularly if
that mutation is not found in a sample of unaffected individuals. However,
DNA sequence varies from one individual to another, so a sequence
difference may not necessarily make the gene deleterious; it may simply
reflect normal variation. Some mutations, though, such as a deletion
or insertion of several bases, or a point mutation (single base change)
