Research carried out by Francis Crick Institute scientists
provides new insights into sex chromosome disorders which typically
cause infertility, such as Turner syndrome and Klinefelter
syndrome. Through their research, the scientists have discovered an
exception to a 'rule' or 'principle' of chromosome biology first
hypothesised in 1967.
Our sex - male or female - is determined by the pair of sex
chromosomes we have in our cells. Females have two copies of the
gene-rich X chromosome but males have only one X chromosome, plus a
much smaller sex-determining Y chromosome.
This difference creates a biological problem, as females have
double the dose of the genes on the X chromosome. To account for
this there is a process of 'dosage compensation' which balances the
dosage, so that females have the same dosage from the X chromosome
as males, not double.
The hypothesis of 'dosage compensation' was proposed by Susumu
Ohno in 1967 and experiments have confirmed that this process does
indeed take place within cells, by mechanisms which vary from
organism to organism. His hypothesis took on the status of a rule;
it was assumed that dosage compensation would be found within all
cells.
Using RNA sequencing, James Turner's group discovered that mouse
and human germ cells, which develop into gametes, i.e. sperm and
eggs, do not conform to Ohno's 'rule' of dosage compensation.
Germ cells are special because they have to be able to give rise
to the creation of a brand-new organism, with all its different
types of tissue and organs and structural complexity. In order to
be able to do this germ cells undergo a process of genome-wide
'reprogramming', in which information from the previous generation
is erased.
The scientists suspected that this 'reprogramming' could disrupt
dosage compensation within those germ cells. Their experiments
demonstrated that their hypothesis was correct: in male germ cells
expression from the X chromosome was very low, while in female germ
cells it was very high.
The discovery of this exception to Ohno's rule of dosage
compensation provides new insights into a key topic of
developmental biology, namely the development of an organism's
sex.
James Turner said: "The discovery challenges the idea that germ
cells are initially 'sex neutral' before the Y chromosome 'kicks
in' and instructs the gonad to develop into either a testis or an
ovary. Our research demonstrates that prior to any overt 'fork' in
development the germ cells are already sex-differentiated; they
have different and imbalanced X chromosome dosages."
The research is clinically significant because it provides a
better understanding of the biology underlying sex chromosome
disorders, such as Turner syndrome, which affects about 1 in every
2,000 females and Klinefelter syndrome, which affects around 1 in
every 660 males. Both of these syndromes typically cause
infertility.
The Crick scientists looked at germ cells within Turner and
Klinefelter syndrome mice. To their surprise, they discovered that
germ cells in female Turner syndrome mice display the dosage found
in normal male germ cells. They also discovered that germ cells in
male Klinefelter syndrome mice display the dosage found in normal
female germ cells. Their hypothesis is that the cause of
infertility is this confusion, or conflict, between the sex of the
organism, in terms of the presence or absence of the Y chromosome,
and the sex identity of the germ cell, in terms of its X chromosome
dosage.
The paper, Non-canonical and sexually dimorphic X dosage
compensation states in the mouse and human germ line, is
published in Developmental Cell.