Biology Reference
In-Depth Information
in a number of individuals with Alport syndrome (Tryggvason et al. 1993).
Perhaps not surprisingly, mutations have also been detected in the
COL4A3
and
COL4A4
genes on chromosome 2 in persons with the autosomal-
recessive forms of Alport syndrome (Boye et al. 1998).
Because of the limited knowledge of the detailed structure and function
of the inner ear, the candidate gene approach has found limited use in the
identification of genes responsible for inherited hearing impairment, espe-
cially in the case of genes for nonsyndromic inherited hearing impairment.
As in most other areas of inherited human diseases, the positional candi-
date approach has found widespread use in the identification of genes for
inherited hearing impairment.
2. Positional Cloning
Positional cloning involves identifying transcripts in the interval of the
region of the chromosome to which a gene has been mapped and screen-
ing those transcripts for mutations. Therefore, the first step in positional
cloning is the mapping of the gene responsible through linkage analysis in
family studies.
2.1 Linkage and Linkage Analysis
Mendel's third law, the principle of independent assortment, states that
members of different gene pairs assort to gametes independently of one
another. While this is true of genes on different chromosomes, it will not
always be true for genes that are on the same chromosome. An exchange
of genetic material, or what is known as crossing-over or recombination,
occurs on average two to three times in each meiosis between homolo-
gous chromosomes. However, if two loci are positioned sufficiently close
together on the same chromosome, recombination between them will be a
rare event (Fig. 3.1). If the alleles at two loci are inherited together more
often than would occur by chance, then they are said to be linked. Link-
age analysis involves studying the pattern of segregation of polymorphic
DNA markers located throughout the chromosomes in families in which a
disorder is segregating.
2.2 Polymorphic DNA Markers
Variation in the nucleotide sequence, or what are called DNA sequence
variants, of the human genome is common. This variation is inherited in a
Mendelian codominant manner and usually occurs in intergenic noncoding
DNA, and therefore has no phenotypic consequences. There are different
