Pharyngula

Evolution of the mammalian vagina

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Q: What unique organ is found only in mammals, but not in fish, amphibians, reptiles, or birds?

The title and that little picture to the left ought to be hint enough, but if not, read on.

A: The vagina. Aren’t we lucky?

There’s an old joke going around about poor design: what kind of designer would route the sewer pipes right through the center of the entertainment center? It’s a good point. It doesn’t make sense from a design standpoint to have our reproductive and excretory systems so intimately intermingled, but it does make a heck of a lot of sense from a purely historical point of view. In a sense, reproduction is an excretory function—we are shedding gametes produced internally, and we already have a perfectly good set of pipes running from our insides to the outside, so why not use them? It’s just that in our lineage, which has specialized in giving great care to our gametes and zygotes, that plumbing has become increasingly elaborate, and that part of the system that was once just a convenient throughway has become a destination and a long-term residence in its own right.

Development tells us part of the story. The reproductive and urinary tracts are all tangled together in early development, arising together from two pairs of ducts, the Müllerian and Wolffian ducts, which are modified in complex ways to form a series of kidneys (we keep only the last one, the metanephros), one set of pathways for the male testes, and yet another set for the female ovaries.

In non-therian mammals, all of these complicated pipes have one common destination, a single outlet to the external world: the cloaca. “Cloaca” is Latin for sewer, and it is appropriately named. The terminus of the large intestine is here, as well as the ends of the ureters from the kidneys and the ducts from the ovaries or testes. Everything gets dumped in to the cavity of the cloaca, making a nice stew of feces, urine, and sperm or eggs. Mmm-mmm. The cloaca is the grey cylinder at the bottom of figure A, below, in the first three organisms, amphibians, birds/reptiles, and monotremes (my apologies for the murkiness of the image; it’s the best copy I have).

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(Click for larger image)

Evolution of the tetrapod reproductive system. (A) Female urogenital system from major tetrapod lineages. Inf,
infundibulum; Ov, ovary; Ovd, oviduct; Ut, uterus (or shell-producing region in non-therian animals); Vg, vagina; Kd, kidney;
Ud, urinary duct; Rc, rectum; Ub, urinary bladder; Cl, cloaca. (B) Tetrapod egg. *, the shell coat of birds and some reptiles
is highly calcified. MPS, marsupial-specific mucopolysaccharide layer. (C) Tetrapod phylogeny showing major transitions
in mammalian reproduction. Divergence of amphibians and amniotes (A). Divergence of birds/reptiles and mammals
(B). Divergence of monotremes and therians (C). Divergence of marsupials and placentals (D).

The fundamental organization of the reproductive part of the vertebrate urogenital tract is straightforward: it’s a tube with a funnel at one end that captures eggs released by the ovary, and conducts them to an external orifice. Along the way, cells lining the tube secrete useful products like albumin and yolk, and deposit a shell, and may act to temporarily store the egg before its final release.

Marsupial and placental mammals have dispensed with most of those functions, and expanded on others. One part of the oviduct has acquired a richly vascularized epithelium and specializations for investing and nurturing a resident embryo, becoming a uterus. That’s an amazing and innovative function in itself, but in addition, it has formed a new, separate channel, the vagina. The vagina is an entirely new structure, which has no homolog in amphibians or reptiles.

That is an interesting observation. It’s a wholly original structure that arose sometime after the monotreme-marsupial split, an evolutionary novelty. How did that happen? How can we study a unique event that occurred over 150 million years ago?

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(click for larger image)

Evolutionary tree showing placement of
the three groups of living mammals (colored boxes and icons at top) with respect to selected Mesozoic taxa. Branching times for the black tree are based on the earliest known fossil occurrences of taxa (black dots).The red tree is based on molecular divergence times for monotremes-therians and eutherians-
metatherians.

Wagner and Lynch have a proposal to answer both questions. The general mechanism for generating novel structures is evo-devo orthodoxy:

  1. An epigenetic side effect of other evolutionary changes in the body leading to a novel physical structure in the organisms.
  2. The genetic consolidation and individuation of the novel structure.

(Note that this proposes phenotype before genotype, which is somewhat heretical for neodarwinism. It shouldn’t trouble the evo-devo gang in the slightest, of course.)

How to study such a process from the past?

The basic assumption of a molecular evolutionary approach to the study of evolutionary novelties
is that changes in developmental regulation have
left traces in the molecular structure of the
genome and a comparative study of genomic
structures should be able to identify genetic
changes coincidental with a phenotypic novelty. (emphasis mine)

That process of consolidation and individuation would have left detectable scars in the genome—the genes involved would have acquired changes necessary to fix the phenotype in the population. Again, as we’d expect from the evo-devo perspective, those changes would have been made to the regulatory genes that control tissue-specific gene expression. What genes should we examine? Let’s look at the therian organs of interest, and here are some likely candidates: the HoxA genes that have region-specific domains in the female reproductive tract.

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Hox gene expression pattern and the evolution of
the female reproductive tract. (a) HoxA-13 to HoxA-9 are
located at the 5′ end of the HoxA cluster and are expressed in
the same regions in the adult as in the embryo: HoxA-13
(green), HoxA-11 (yellow), HoxA-10 (orange) and HoxA-9
(blue). (b) Tetrapod phylogeny showing representative female
reproductive systems from each group (amphibian ovaries
shown only on the left).
i-8c9f651b86bd0715979cc2c24dae419c-hoxa11_phylo.gif
Phylogenetic relationships among a small set of
vertebrate species including representatives of the major
mammalian clades: monotremes (platypus), marsupials (opposum) and placentals (Hyrax and human). Above some
branches the estimated number of non-synonymous and
synonymous substitutions of HoxA-11. The estimates are
obtained from a maximum likelihood codon model as
implemented in PAML. Note that in the stem lineages of
therians (i.e., the lineage leading to the most recent common
ancestor of opossum and the placentals), there are five to
six non-synonymous substitutions but no synonymous
substitution. This indicates a very strong selection coincidental with the evolution of the internal developmental mode
of mammals.

The HoxA-9 through HoxA-13 genes are expressed in order along the length of the embryonic Müllerian duct, and also continue to be expressed in adulthood; so the cells of the vagina are all expressing HoxA-13, while the cells of the cervix all have HoxA-11 turned on (for some reason, I find that to be a wonderful piece of knowledge, and I just have to say…Hooray for HoxA-13! It has just become my favorite Hox gene.)

So the question is whether there is any evidence that these particular Hox genes have signs of any set of changes that are associated with particular transitions in vertebrate evolution—in particular, are there differences that can be traced to the transition between monotremes and the theria, and between the placentals and marsupials. The answer seems to be yes: the diagram to the right is a measure of the number of synonymous to nonsynonymous changes in HoxA-11, which is an indicator of the selective pressures that have shaped the gene.

Furthermore, they’ve identified where these changes have occurred, and they are not in the homeodomain (the part of the protein that binds to specific sequences in the DNA, but in the amino terminal end.

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Approximate positions of the amino acids positions of HoxA-11 which are under directional selection between the
most recent common ancestor of all extant mammals and the most recent common ancestor of placentals. Note that all of these
substitutions are N-terminal of the homeodomain and affect small clusters of amino acids.

The 3-D models below show where the relevant amino acids (in yellow) end up in the folded protein. The interesting thing here is that regulatory proteins don’t just interact with each other, but also with other regulatory proteins that are simultaneously binding. It’s a whole chain of interactions—regulatory proteins binding to the DNA, and also binding between each other in a complex called the enhancersome—that determines the level of expression of a particular gene.

i-0a9f4c1c1247c46d7fb7a65032f4f5ca-hoxa11_struc.jpg
HoxA-11 protein structure. This three-dimensional protein model was calculated by comparative modeling as part of
the MODBASE project. (A) Model shown as ribbons. (B) Model rendered with a molecular surface. The DNA-binding
homeodomain is shown in red. The carboxy-terminal region of exon 2 is shown in blue. Residues identified as being under
directional (positive) selection in the stem lineage of eutherians are shown in yellow. Residues replaced in the stem lineage of
therians but not identified under selection are shown in green. Note that all of these amino acid sites affect amino acids that are
predicted to be placed on the surface of the molecule as expected if selection is driven by novel protein-protein interactions.

There is a great deal left to be done. Hox genes are rather high up the chain of regulatory genes, so there are many more genes downstream that have to be puzzled out. We also are a long ways from figuring out how these patterns of gene expression define the morphogenetic processes that create this lovely novel structure, the vagina. The important thing, though, is that there are these questions waiting to be answered—the investigators have a research program.

We propose that a research program to explain
evolutionary novelties has to focus on the question
of whether novel characters arise through the
evolution of novel regulatory links among developmental genes. We further propose that a
detailed analysis of the evolution of developmental
genes involved in the development of a derived,
novel character can reveal molecular changes that
could be causally involved in the origin of evolutionary novelties. The case study presented here
suggests that the statistical methods of molecular
evolution are strong enough to provide specific
hypothesis for experimental test. The success of
this research program will depend on the ability to connect the patterns of molecular evolution with
the functional role of these molecular changes.

That’s the cool thing about evolutionary biology: exciting questions, titillating ancestors, and the promise of tools to answer more.


Lynch VJ, Roth JJ, Takahashi K, Dunn CW, Nonaka DF, Stopper GF, Wagner GP (2004) Adaptive evolution of HoxA-11 and HoxA-13 at the origin of the uterus in mammals. Proc Biol Sci. 271(1554):2201-7.

Wagner GP, Lynch VJ (2005) Molecular evolution of evolutionary novelties: the vagina and uterus of therian mammals. J Exp Zoolog B Mol Dev Evol. [Epub ahead of print]

Cifelli RL, Davis BM (2003) Marsupial Origins. Science 302:1899-1900.

Comments

  1. #1 David Marjanovi?
    January 15, 2007

    Does this mean that hair/fur and mammary glands developed at the same time in the same lineage, or was there a hairy, non-mammalian (or mammalian, non-hairy) lineage that died out? It just seems odd that there are two diagnostic features that match up so accurately.

    Extinction can make anything match up accurately. Soft tissue doesn’t preserve well… both hair and lactation evolved somewhere between here and two pages later.

    Similarly, nobody seems to have an idea when exactly the vagina or for that matter live birth evolved. There are lots and lots and lots of extinct mammal clades that are more closely related to Theria than to Monotremata.

    The extended version of the joke is priceless!!!

  2. #2 David Marjanovi?
    January 15, 2007

    Does this mean that hair/fur and mammary glands developed at the same time in the same lineage, or was there a hairy, non-mammalian (or mammalian, non-hairy) lineage that died out? It just seems odd that there are two diagnostic features that match up so accurately.

    Extinction can make anything match up accurately. Soft tissue doesn’t preserve well… both hair and lactation evolved somewhere between here and two pages later.

    Similarly, nobody seems to have an idea when exactly the vagina or for that matter live birth evolved. There are lots and lots and lots of extinct mammal clades that are more closely related to Theria than to Monotremata.

    The extended version of the joke is priceless!!!

  3. #3 Ichthyic
    January 16, 2007

    the Argentine Lake Duck, for example, has a penis over 40 centimetres long – ridiculously long, in fact, unless it’s using it as pogo-stick.

    shhh! You better not let the penis enlargment crowd hear about that, it’ll mean the endangered species list for that species of duck for sure; and yet more emails about the wonders of “argentine duck penis” appearing in my inbox.

  4. #4 Ichthyic
    January 16, 2007

    Similarly, nobody seems to have an idea when exactly the vagina or for that matter live birth evolved.

    huh?

    did you mean in mammals or in animals in general?

    fish were giving live birth long before there were mammals.

    earlier in the thread, sharks were mentioned.

    within the elasmobranchii, just about every gradation between viviparity and oviparity can be seen, still extant, no less, and there haven’t been many changes in the last 50 million years or so. In fact, you can go back about 140 my before you start seeing significant changes, although I can’t recall off the top of my head at the moment what the current thinking is to when the earliest viviparous sharks started appearing. Most extant groups of sharks had appeared before about 100mya, so I can reasonably assume viviparity in sharks is at least that old.

  5. #5 MSavell
    February 6, 2010

    Rebeca,
    It would be my guess that male mammals have their gonads visible on the outside due to temperature sensitive tissues. Internal body temperature is too high for the production of sperm.

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