On 12/03/96, Chris wrote:
>Why do these women (especially in the case of 4 X,s) suffer from
>physical and mental defects?
>>Are the inactive X,s truelly inactive?
>Is it the fact that each cell of the body will express 1 of 3 or more
>X phenotypes instead of 1 of 2 (as it is random which X stays active
>and which X's are domant).
On 12/03/96, Diane Lavett wrote:
>Chris: Not all of the X chromosome is inactivated. Those
>genes be the cause of abnormalities due to their unbalancing
Hi Chris and all,
There are indeed genes that have been shown to "escape" X inactivation in
normal females. Soon after Mary Lyon proposed the single-active X
hypothesis in 1961 some (Ferguson-Smith, 1965) predicted that there
must be genes on the human X that escape inactivation. The double dose
of at least some genes is necessary for normal female development
since 45,X individuals have Turner syndrome - short stature, premature
ovarian failure, webbed neck, lymphodema, etc. For clinical
description of Turner syndrome see:
It had also been predicted that the situation is different in mice since
XO (39,X) female mice are essentially normal. My quick guess of the
current count is that there are about 10 genes that escape in human
and only two in mouse. We now know that the genes on the human X that
escape inactivation are interspersed among genes that are subject to
inactivation. A good review of this data and mouse/human comparisons
Disteche, C.M., Escape from X inactivation in human and mouse.
Trends in Genetics 1995 Jan. 11(1). P 17-22.
In all situations only a single active X remains active in a cell - so for
the case of (47,XXX) X-triploidy two X's are inactivated - and in
general the choice of which X remains active is random. The abnormal
phenotype of XXX or XXXX or XXXY, individuals is likely the result of
the extra dosage of at least some of the genes that escape
inactivation - genes that are subject to inactivation will be of
normal dosage in such individuals. Another developmental complication
is that prior to X-inactivation (occurs around day 3-5 after
fertilization) the double dose of expression from both X chromosomes
may be important for normal early development of female embryos.
Genes that escape X inactivation will in fact have an unusual sex-linked
inheritance pattern. This will depend on the particular gene - some
human X-linked genes have functionally equivalent copies on the Y
chromosome - ZFX and ZFY are examples, and this will also may alter
the inheritance. It is the genes that are subject to X inactivation
that will show the expected, typical sex-linked inheritance - such as
Duchenne muscular dystrophy or hemophilia.
[BTW: Since the retinal receptor genes on the X chromosome *are*
subject to inactivation color-blindness act as typical sex-linked
genes: males are more commonly effected and heterozygous females are
uneffected or minimally effected carriers. Unexpected frequencies of
color-blindness alleles in the population likely has nothing to do
with the phenomenom of escape from X-chromosome inactivation.]
Hope this useful and understandable,
David A. Adler, Ph.D.
Scientist, Zymogenetics Inc.
Pathology, University of Washington
"Science is nothing but trained and organized common sense"