Retrotransposon sequences control sex determination in mice

A new paper in Science generated a lot of buzz and has an interesting combination of nifty molecular genetics and evolution.

Sex determination is wildly variable in evolution, and that is worthy of its own theme/thread here at PS for people interested in evolution. The new work looked hard at the gene (called Sry) that is most influential in this process, in mice. (Those last two words are more important than usual.) They found a previously unknown exon, that when spliced into the final transcript generates a different version of the protein. This version of the protein is required for sex determination; the other version, which has always been thought to be the only version, contains a degradation signal and is unstable.

But there’s more. Most (70%) of the new exon is a retrotransposon sequence, specifically a LINE element called L3. In fact, all of the coding sequence in the exon is from the L3 element, and the poly-A sequences (this is @Art territory) come from the LTRs of the L3 element. The mostly jargon-free version of that: this newly discovered piece of this interesting and important gene comes completely from a retrovirus-like piece of DNA.

The history of this setup is not emphasized in the paper but their data show that the mechanism (turning the LINE element into a part of the protein) is specific to mice and not even to other rodents, even though all of the rodents have the LINE element. Most (maybe all?) other rodents avoid degradation of the Sry protein by avoiding the degradation signal that is present in the gene. (The other rodent lineages have a stop codon before the degradation sequence, so that sequence is not included in the protein. Without this, there would be no males, admittedly a tempting outcome in 2020.) Mice, instead, use this other version of the protein to overcome the fact that the “main version” is in fact quickly degraded and therefore worthless. This is shown in Figure S9 in the supplement, and they provide this summary diagram of their proposed evolutionary trajectory in Figure S10:

Here is the journal’s summary of the paper. Link to the full paper is below. PDF cheerfully sent on request.

Two rather than one

For several decades, it has been believed that the mammalian sex-determining gene Sry contains a single exon. Miyawaki et al. have now identified a cryptic second exon of mouse Sry . Loss- and gain-of-function analyses revealed that the two-exon SRY (SRY-T), not the canonical single exon–encoded SRY (SRY-S), is the bona fide testis-determining factor. Sry exon2 is composed of retrotransposon-derived sequences. The SRY-S carboxyl terminus contains a degradation sequence (degron), whereas the SRY-T carboxyl terminus encoded in the Sry exon2 is degron free, thereby conferring protein stability on SRY-T.

2 Likes

That’s really interesting. The fact that variant is idiosyncratic to mice, and the function of the SRY is essentially the same, may have implications about the difficulty of evolving new functions…

With each passing week, I become more convinced that most of biology is just transposons doing their thing. The rest of us are just along for the ride.

3 Likes

When they say “mice”, I presume Mus musculus. When they say “other rodents”, which rodents are we talking about? I presume, again, that Rattus norvegicus is one of them, but what of other sigmodontines?

Here’s Figure S9

Sry paper Fig S9.pdf (575.6 KB)

1 Like

All of the listed animals are in Murinae. I don’t know why the authors referred to ‘rodents’ when examining only one subfamily.

I don’t think they intended to claim that they surveyed rodents more broadly. IMO, their more focused snapshot is already very interesting in that it suggests the M. musculus solution is very recent. Plus, and this might be more important, they were more interested in the specific differences with regard to the degron. FWIW here’s what they wrote:

We found that DNA sequences similar to the mouse Sry-S degron are conserved in Sry from other rodents (fig. S9A), but SRY was not destabilized in those species (fig. S9B) because the degron was blocked from translation due to preceding stop codons (fig. S9, A to D). In mice, a different mechanism has evolved to avoid degron translation through exonization of distal retrotransposon-derived sequences (Fig. 1C and fig. S3) and splicing to excise the degron (fig. S10). The apparent replacement of SRY-S by SRY-T to overcome degron activity provides an example of Y-chromosomal gene evolution by gain of function.

And only four species in the subfamily, at that.

Not sure I follow your reasoning, but this story seems to be about a kludgy, clunky way to solve the problem of a degron in an important protein. The “function” of the added amino acids (from the LINE element) isn’t known (the authors note this in their final paragraph) but it seems a strong possibility that there is no “function” and that the advantage of the new isoform is simply the absence of the degron by virtue of the splicing away of that sequence. It would be very interesting if the extra amino acids bring something new to the picture. My money is against that, and instead I’m really curious about the history of the degron and whether the various “solutions” among the close relatives of M. musculus are convergent. I haven’t checked.