Biology Reference
In-Depth Information
Deaf mouse mutants are therefore very helpful in studying genetic deaf-
ness, but are they good models for human hereditary deafness? The answer
is, with very few exceptions, yes. The cochlea of the mouse has a virtually
identical organization to that of humans, with differences, such as differ-
ences in size, being trivial. Also, the cochleas of deaf mouse mutants and
profoundly hearing impaired humans show very similar types of pathology
(as far as can be determined, given the limitations in studying humans). Syn-
dromic deafness occurs in both species, and the range of associated defects
in the two species is very similar, suggesting that the biological mechanisms
underlying the disease are the same. A number of mouse mutants with
mutations in orthologous (equivalent) genes to those known to be involved
in deafness in humans have been studied, and there is generally a good
correlation between the phenotypes in the two species.
There are a few exceptions to the general rule that the mouse models
accurately reflect the pathology seen in humans with mutations in ortholo-
gous genes. In some cases, it is likely that genetic background differences
between mice and humans can account for the differences. For example,
mice with a single
Pax3
mutation are not deaf, while humans with a muta-
tion in the same gene have Waardenburg syndrome, which includes occa-
sional deafness (Steel and Smith 1992; Tassabehji et al. 1992). However, at
least part of the phenotype of Waardenburg syndrome, the widely spaced
eyes, can be seen in mice with a
Pax3
mutation on a different genetic back-
ground (Asher et al. 1996).
The mouse and human genomes show many similarities. Large stretches
of chromosomes are conserved between mouse and human, with ortholo-
gous genes arranged in the same order, a phenomenon known as conserved
synteny. It appears that an ancestral mammalian genome has been cut up
and rearranged during the course of evolutionary divergence of the two
species, with only a few tens or hundreds of cuts required to explain the
present-day organization of genes. This is an extremely useful feature for
the molecular geneticist. It means that genes within regions of conserved
synteny can be studied in one species and the information used to predict
the genes and their order in the other species. Thus, if a deafness mutation
is located between two known genes in the mouse, a human deafness gene
can be predicted to occur between the two human versions of the known
genes. This lining up of the two genomes has been invaluable for suggest-
ing candidate deaf mouse mutants as models for particular forms of human
deafness. An example was the proposal that the shaker1 mutation on mouse
chromosome 7 might involve the same gene as in Usher syndrome type 1B
on human chromosome 11q because both were linked to another gene,
Omp
(Evans et al. 1993). Positional cloning of the
Myo7a
gene involved in
deafness in shaker1 mutants led rapidly to the finding of mutations in the
human version of the gene,
MYO7A
, in humans with Usher syndrome,
emphasizing the value of identifying deafness genes in the mouse (Gibson
et al. 1995; Weil et al. 1995). Such comparative analyses of mouse and
