XY and ZW: Is Meiotic Sex Chromosome Inactivation the
Rule in Evolution?
Satoshi H. Namekawa1,2, Jeannie T. Lee1,2*
1Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 2Department of
Genetics, Harvard Medical School, Boston, Massachusetts, United States of America
The sex chromosomes are among the
most rapidly evolving and most diverse
genetic systems in all of biology. Students
of model organisms may, however, have
the false impression that there is only one
chromosomal mechanism of specifying
sex. Among the best-studied metazoans,
the XY system is indeed the rule, with
inheritance of two X’s determining the
female sex (XX), and inheritance of an X
and a Y specifying the male sex (XY) .
In this system, females produce only one
type of oocyte (X), whereas males produce
two types of sperm (X and Y). However,
sex is not always determined this way.
Throughout evolution, the XY system has
co-existed alongside the lesser known ZW
system, a scheme exemplified by members
of the avian clade who diverged from
Mammalia 300 million years ago (Figure 1)
[2,3]. In birds, females are the heteroga-
metic sex, as females have one Z and one
W chromosome (ZW) and can therefore
produce two types of gametes (Z or W
oocytes). By contrast, males are ZZ and
can produce only one type of gamete
(homogametic)—the Z-bearing sperm. In
XY and ZW systems, the homologous sex
chromosomes are genetically unequal due
to suppression of homologous recombina-
tion and accumulation of deleterious
mutations on one chromosome of the
heterogametic sex . In the XY system,
it is the Y that genetically degenerates; in
the ZW system, it is the W. Today, the
mammalian X carries over three times
more genes than the Y does, whereas the
chicken Z carries over ten times more than
There are two intriguing consequences
of having unequal sex chromosomes. The
first relates to dosage imbalance or X- or
Z-borne genes between males and females.
A need to correct for this imbalance has
led to co-evolution of ‘‘dosage compensa-
tion’’ in many organisms that use the XY
system, such as mammals, fruit flies, and
worms [4,5]. In mammals, dosage com-
pensation involves transcriptional inacti-
vation of one X chromosome in the
female. The second consequence of un-
equal sex chromosomes is the absence of a
full pairing partner during meiosis in the
heterogametic sex . During meiosis,
homologous chromosomes pair (align),
synapse (held by the synaptonemal com-
plex), and exchange genetic material via
homologous recombination. But for sex
chromosomes, pairing occurs either par-
tially or not at all. The X and Y of
eutherian mammals pair through their
pseudoautosomal regions, but the X and
Y of marsupial mammals lack significant
homology and come together without
synapsis [7,8]. Lack of pairing triggers
meiotic silencing of unsynapsed chromatin
(or unpaired DNA) (MSUC or MSUD)
[9–11], which is an ancient genome
defense mechanism that silences sequences
without pairing partners . Mammalian
MSUC/MSUD results in meiotic sex
which the X and Y alone become
transcriptionally inactivated during the
first meiotic prophase [6,13–15]. MSCI
is not confined to mammals, as metazoans
as diverse as the fruit fly , grasshopper
, and the nematode worm  also
worm males are XO, with the Y having
How universal are dosage compensation
and MSCI? Analyses in chickens have
reached the consensus that Z genes may
only be partially equalized between ZZ
and ZW individuals, although the mech-
anism of dosage compensation remains
unclear [2,3]. Until now, no evidence of
MSCI had been found in birds [19,20]. In
this issue of PLoS Genetics, Schoenmakers et
al. have re-examined bird oogenesis and
found that MSCI actually occurs in
chickens . This discovery has a
number of implications for the evolution
and developmental behavior of sex chro-
Chicken MSCI is both similar and
different from MSCI in XY animals
. Like mammal and worm MSCI,
chicken MSCI occurs during the first
meiotic prophase (divided into leptotene,
zygotene, pachytene, and diplotene) and is
marked by chromatin changes. Schoen-
makers and colleagues observed hetero-
chromatic marks and exclusion of Pol-II
on both Z and W and verified, by
PCR analysis of a handful of Z and W
genes, that the genes are expressed at
lower levels during pachytene than in
zygotene and diplotene, as is observed
for murine X and Y genes [13,14].
Although how much of Z and W is
silenced remains to be investigated, these
similarities imply a conserved mechanism
based in part on MSUC/MSUD.
There are intriguing differences as well,
one of which is in the timing relative to
chromosome synapsis. In eutherian mam-
mals, MSCI coincides with the failure of
synapsis during pachytene [9,10]. On the
synapsis of Z and W. Thus, chicken MSCI
may be based as much on ‘‘unpairing’’ as
on ‘‘asynapsis.’’ Interestingly, this feature
of ZW MSCI is similar to opossum MSCI,
which occurs in early pachytene before X
and Y colocalization . Therefore, in
chickens and opossum, a homology search
mechanism—rather than asynapsis itself—
might be the trigger for MSCI.
MSCI in birds and mammals also
differs in terms of what chromatin changes
occur. In the mouse and the opossum,
Citation: Namekawa SH, Lee JT (2009) XY and ZW: Is Meiotic Sex Chromosome Inactivation the Rule in
Evolution? PLoS Genet 5(5): e1000493. doi:10.1371/journal.pgen.1000493
Editor: Harmit S. Malik, Fred Hutchinson Cancer Research Center, United States of America
Published May 22, 2009
Copyright: ? 2009 Namekawa, Lee. This is an open-access article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original author and source are credited.
Funding: The authors received no specific funding for this article.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
PLoS Genetics | www.plosgenetics.org1 May 2009 | Volume 5 | Issue 5 | e1000493
chromatin changes and transcriptional
silencing take place concurrently through-
out nonhomologous regions of both sex
chromosomes. Microarray analysis has
shown that very few genes escape MSCI
in mice. Both X and Y exclude Pol-II and
are coated by heterochromatic marks such
as H3-K9me3 and HP1, as well as by
MSUC-associated marks such as cH2AX.
By contrast, chicken W-inactivation slight-
ly precedes Z-inactivation,
Schoenmaker et al. to hypothesize that
MSCI occurs by the spreading of hetero-
chromatin from W to Z . (An
alternative is that W and Z inactivation
occur independently, which cannot be
excluded.) Additionally, cH2AX is absent
on the ZW pair during pachytene and
accumulates only after separation of ZW
during late pachytene—and only on the Z.
Thus, ZW inactivation seems different
from XY inactivation in the eutherian
(mouse), but may partially resemble XY
inactivation in marsupial (opossum), the
mammalian clade that is evolutionarily
closer to birds (Figure 1). These differences
suggest that MSCI in birds and mammals
Figure 1. MSCI in the bird and the mammal. (A) Divergence of birds from mammals approximately 300 million years ago coincides with the split
between XY and ZW sex determination schemes. (B) Schematic representation of MSCI in birds, marsupial mammals, and placental mammals. Unlike
the X and Y, all of the Z and W are co-localized and held together by a proteinaceous bond during mid-pachytene (intertwined), although there is no
homology and no genetic exchange takes place. ZW inactivation is also limited to prophase I, whereas XY inactivation persists into the post-meiotic
PLoS Genetics | www.plosgenetics.org2May 2009 | Volume 5 | Issue 5 | e1000493
both borrowed from MSUD/MSUC, but
independent evolutionary origins led to
unique innovations as well.
A final major difference is found in XY
and ZW transcriptional fates after meiosis.
In mice, the effects of MSCI are felt long
after meiosis is finished—i.e., the X and Y
remain heterochromatic and transcrip-
tionally suppressed during
post-meiotic period [14,22,23]. In two
other XY (or XO) species examined to
date (grasshopper and worm), post-meiotic
silencing is also observed [17,18]. By
contrast, bird MSCI is very transient and
is lost by late diplotene . Thus, post-
meiotic silencing is not an absolute
consequence of MSCI. One school of
thought argues that persistence of silencing
is an active process that evolved for a
specific purpose in mammals [7,14].
Why do the X and Y remain suppressed
after meiosis? And why does MSCI occur
in the first place? Given that early
spermatogenesis genes are enriched on
the mammalian X and that several
spermiogenesis genes can also be found
there , transcriptional suppression is
especially puzzling. One thought suggests
that MSCI was driven by sexual antago-
nism, i.e., a male germline response to a
‘‘feminized’’ X that might adversely affect
spermatogenesis . Another possibility
is that MSCI is merely an evolutionary
relic of MSUD/MSUC; persistence into
the post-meiotic period might occur by
default. The fact that ZW inactivation is
transitory, however, argues against the
latter idea. It is also possible that MSCI
evolved to suppress recombination be-
tween the nonhomologous sex chromo-
somes. Silent post-meiotic sex chromatin
could then have been exploited and
extended to deal with dosage compensa-
tion in the early XX embryo of marsupial
and eutherian mammals, both of which
display imprinted paternal X-chromosome
silencing [7,14,15]. Post-meiotic silencing
is remarkably heritable in the worm, and
possibly also in the grasshopper as well
[17,18]. The inheritance of a pre-inacti-
vated X from the paternal germline would
be an effective way of achieving dosage
balance between XX and XY offspring.
The absence of post-meiotic silencing in
chickens is consistent with this hypothesis,
as dosage compensation is not robust in
avians studied to date [2,3].
Birds are mammals’ closest relatives on
the evolutionary tree (Figure 1). Around
300 million years ago, avian and mam-
malian genetics evolved such that the ZW
system was used in the avian progenitor
and the opposite XY system was used in
the mammalian progenitor. While the XY
system has been intensively investigated,
many questions remain regarding the ZW
system. How is sex determined by the Z
and W, and why did MSCI evolve in birds
if its effects are as ephemeral as they seem?
Does MSCI bear any relationship to
dosage compensation? The cumulative
evidence suggests that MSCI is universal
among organisms bearing heteromorphic
sex chromosomes. Regardless, the ZW
system will be a useful model, because
avian MSCI is so transient, and it should
facilitate teasing out the raison d’etre of
MSCI, separated from post-meiotic silenc-
ing and its after-effects.
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