The Interactive Fly
Zygotically transcribed genes
Sex Determination and Dosage Compensation Genes
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The Interactive Fly Sex Determination and Dosage Compensation Genes |
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| A simplified model for sex determination in the somatic gonad and germline |
The variety of primary sex determination cues was appreciated
long before the advent of molecular genetics. The two broadest
categories are genetic sex determination (GSD), in which the sex of
offspring is set by a sex chromosome or an autosomal gene, and
environmental sex determination (ESD), in which sex is determined by
temperature (as with turtles), local sex ratio (as with some tropical
fish), or population density (as with mermithid nematodes). Though
little is known about the molecular mechanisms of ESD, within the GSD
systems many different mechanisms have been uncovered. Dual sex
chromosome systems, in which either the female (ZW/ZZ) or the male
(XX/XY) is heterogametic, are common, as are systems set by the ratio
of the number of X chromosomes to sets of autosomes (X:A). There are
also systems in which heterozygosity at a single locus is required
for female development (known as complementary sex determination), as
well as systems involving sex determination via multiple genes with
additive effects (Haag, 2005; see full
text of article).
Molecular genetic investigations of GSD in model systems such as
Drosophila, Caenorhabditis, and mice have revealed
a clear lack of conservation, underscoring the diversity. For
example, although the primary sex determination signal in both D.
melanogaster and C. elegans is the X:A ratio, the fruit
fly pathway consists of a cell-autonomous cascade of regulated mRNA
splicing, while that of the nematode follows a Hedgehog-like
intercellular signaling pathway. GSD in mammals depends (with some
interesting exceptions upon a Y-specific dominant gene (Sry)
encoding a transcription factor. In the face of such impressive
differences, perhaps the assumption of homology should be questioned:
could it be that sex determination in different taxa has arisen
independently over and over again in evolution? Until 1998, this
seemed like a good bet (Haag, 2005).
The discovery of the homology of the key sex-determining genes
doublesex in Drosophila and mab-3 in
C. elegans provided the first evidence for a common
evolutionary basis of sex determination in animals. Soon, related
doublesex-mab-3 (DM)-family genes with roles in male sexual
development were discovered in vertebrates and even cnidarians. Here
at last was a smoking gun that could link the diverse metazoan sex
determination systems. But as satisfying as the result was, it
immediately gave birth to another mystery: if the enormous diversity
of sex determination systems are all derived from a common ancestor,
how could they possibly have been modified so radically? After all,
sexual differentiation and reproduction are hardly unimportant
developmental processes (Haag, 2005).
To understand how such diversity came to be, differences between
closely related species must be examined. This approach allows the
discovery and interpretation of small-scale sex determination changes
before they are obscured by subsequent changes. The processes
discovered in this way might then be reasonably extrapolated to
explain the seemingly unrelated systems of more deeply diverged taxa.
Work in dipterans has revealed three evolutionary phenomena that
characterize shorter-term sex determination evolution (Haag, 2005).
The first of these is the often astounding rate of molecular
evolution at the level of nucleotide and aminoacid sequences.
Although some sex-determining genes are well conserved, many show
unprecedented substitution rates. An extreme example is the central
integrator of the X:A ratio in Caenorhabditis,
xol-1. The xol-1 orthologues of the closely related
nematodes C. elegans and C. briggsae are a mere
22% identical, even though genes surrounding xol-1 are
much better conserved. Remarkably, the 3′ neighbor of
xol-1, the immunoglobulin dim-1, is only 5 kb away
and is essentially identical between species (Haag, 2005).
A second phenomenon, best exemplified by dipteran insects, is the
modification of genetic control pathways through the gain or loss of
key pathway components. In Drosophila, the first gene to
respond to the X:A ratio is Sxl, whose transcription is
regulated by both autosomal and X-linked factors very early in
development. When X: A = 1 (i.e., in female embryos),
Sxl transcription occurs and produces Sxl protein. Later in
development, transcription from a second promoter occurs in both
sexes, but these transcripts cannot be productively spliced without
the earlier burst of Sxl expression. As a result, only
females sustain Sxl expression, and in turn only females can
productively splice the mRNA of tra, its downstream target.
Productive splicing of tra is required to produce the
female-specific form of dsx, a founding member of the DM
family mentioned above (Haag, 2005).
In a series of groundbreaking papers, Saccone and colleagues
investigated the pathway in the more distantly related heterogametic
Mediterranean fruit fly Ceratitis capitata. The first
surprise was that although a highly conserved Sxl homologue
exists in Ceratitis, it does not undergo sex-specific
regulation similar to that of Drosophila, which suggests
that it does not play a key switch role (Saccone, 1998). Similar
results have also been found for the housefly, Musca
domestica, indicating that the role of Sxl in sex
determination may be restricted to Drosophila and its
closest relatives. In contrast, tra and dsx are key
sex regulators in all dipterans examined thus far (Haag, 2005).
A further surprise came when the Ceratitis tra homologue
was characterized. In the case of this gene, clear evidence for
sex-specific regulation was found, and as with Drosophila,
only females productively splice tra mRNA. However, this
splicing difference can be explained nicely by a positive feedback,
similar to that seen in Drosophila Sxl, in which Tra protein
regulates its own splicing. It has been proposed that the dominant,
male-specifying M factor on the Y chromosome inhibits this
autoregulation. As a result, males cannot make functional Tra
protein, and the male form of Dsx is produced. These experiments show
not only how a pathway can evolve, but also, importantly, how X:A and
heterogametic GSD systems can be interconverted by modifying the cue
that regulates a conserved molecular switch gene (the splicing of
tra mRNA) (Haag, 2005).
Finally, recent studies of Caenorhabditis nematodes have
shed light on the genetic basis of the convergent evolution of sex
determination related to mating system adaptations. An important
factor in this area are new phylogenies of the genus, which
consistently suggest the surprising possibility that the closely
related hermaphroditic species C. elegans and C.
briggsae acquired self-fertilization independently, from
distinct gonochoristic (male/female) ancestors. Although this
scenario is somewhat uncertain purely on parsimony grounds, recent
work on the genetic control of the germline bisexuality that defines
hermaphroditism has tipped the balance toward parallel evolution
(Haag, 2005).
C. elegans fog-2, a gene required for
spermatogenesis in hermaphrodites but not in males, has been cloned.
It became clear that fog-2 is part of a large family of
F-box genes and was produced by several recent rounds of gene
duplication. The C. briggsae genome sequence suggested that
while C. briggsae possesses a similarly large family of
F-box proteins, the duplication event giving rise to fog-2
was specific to the C. elegans lineage. This work has been
extended by the rigorous demonstration that fog-2 is indeed
absent in C. briggsae. A short, C-terminal domain has been
identified that makes FOG-2 uniquely able to perform its germline
sex-determining function. This domain is probably derived from a
frame-shifting mutation in an ancestral gene. Working with C.
briggsae, evidence has been found of important species-specific
regulation of germline sex determination. RNA interference and gene
knockout approaches have shown that while C. elegans
requires the male-promoting genes fem-2 and fem-3
to produce sperm in hermaphrodites, C. briggsae requires
neither. Given that both genes have conserved roles in male somatic
sex determination, this suggests that C. briggsae evolved
hermaphroditism in a way that bypasses these genes (Haag, 2005).
The long-standing mystery of sex determination and its diversity
began by comparisons between distantly related species. Recent work
on closer relatives has uncovered processes that through a reasonable
extrapolation enable the connection of these disparate dots into a
fascinating picture of developmental evolution. Though the divergence
is extreme, it is likely that a better understanding of the evolution
of sex determination genes and pathways holds lessons about the
evolution of development in general. The next major challenge will be
to integrate the comparative developmental data with the ecological
and population processes that are driving the evolution of sex
determination. Only then will it be possible to say that the picture
is complete (Haag, 2005).
Haag, E. S. and Doty, A. V. (2005). Sex determination across
evolution: connecting the dots. PLoS Biol. 3(1): e21. 15660158
Saccone, G., Peluso, I., Artiaco, D., Giordano, E., Bopp, D., et
al. (1998). The Ceratitis capitata homologue of the Drosophila
sex-determining gene sex-lethal is structurally conserved, but not
sex-specifically regulated. Development 125: 1495-1500. Medline abstract: 9502730
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