Directional asymmetry: how does it develop and how did it evolve? Part 2. Mechanisms for generating handedness

I was going to make this discussion a two-part post, but after writing a bit of this post, I think I’ll divide it into three, as it would be too long. The last bit, on artificial selection for directional asymmetry, will be tomorrow.

In my first post on this issue yesterday, I discussed the problem of evolved directional asymmetry (a trait is always different on the right than on the left, and in the same direction) as opposed to antisymmetry, in which the trait varies between the right and left sides among individuals, but randomly. An example of directional asymmetry is the male narwhal’s tusk, which is an enlarged left canine tooth, so the “tusk” (the enlarged tooth) is always on the left side of the midline. An example of antisymmetry is the large claws of male fiddler crabs, which are random with respect to body size: half of male crabs have big right claws, and the other half big left claws.

Here’s one example of directional asymmetry in a species, the twospot flounder, which always develops to flatten on its right side (flounders begin developing vertically, like normal fish, but then flatten out, with the eyes migrating over the top of the head so both are on one side). Other species of flounders lie on their left sides, and some lie randomly on either side (anti-symmetry). Crossing experiments between species suggest that the directional asymmetry has some genetic basis.

bothus_robinsi

SEFSC Pascagoula Laboratory; Collection of Brandi Noble, NOAA/NMFS/SEFSC. The twospot flounder lies on the seafloor on its right side, with both eyes on its left side. (From Quanta Magazine article)

My question yesterday was this: to get directional asymmetry, there must be a genetic program that recognizes right versus left so that a trait’s formation can be genetically activated on only one side of the body. But that presupposes some cue, perhaps a molecule in the internal environment, that can activate and/or repress genes on one side only.  Such cues seem unlikely in a bilaterally symmetrical organism, for the chemical “gradients” from the midline to the right or left margins should be the same for equivalent points (as opposed to the top/bottom or front/back gradient). So how, in an ancestor that is perfectly symmetrical bilaterally, can a directional asymmetry evolve? What cues could those genes use to know where they are?

Now of course once a single directional asymmetry has evolved, then there’s already a left-right difference, and further directional asymmetries can evolve cueing off of that first one. And that could, in turn, produce any number of directional asymmetries. But the question remains: how does the first directional left-right asymmetry evolve in a bilaterally symmetrical organism?

In the past eight years, scientists have been coming up with answers, and the issue is discussed in a nice piece at Quanta magazine by Tim Vernimmen.  There are two possibilities.

  • In 2009, Nobutaka Hirokawa et al. reported that the “node” in vertebrate embryos—a pit in the bottom midline of the early embryo—is surrounded by cilia that beat in a rotational motion in one direction only, causing a flow of embryonic fluid toward the left. As the authors say:

Through studies of the flow of materials within cells, we serendipitously found that nodal cilia are actually motile and vigorously rotating. This rotation generates the leftward flow of extraembryonic fluid in the nodal pit. The directionality of this flow, termed nodal flow, determines laterality. Thus, quite unexpectedly, a physical process, fluid flow, was identified as the initial L/R symmetry-breaking event. In this review, we first summarize the discovery of nodal flow and then discuss how this leftward linear flow is generated in a fluid dynamic manner by the rotational movement of cilia.

You can see the directional beating of the cilia and the leftward flow of fluid in the movies embedded in Hiokawa et al.’s paper—particularly movies 3 and 4. Have a look!

What the authors found, then, was that a directional motion of the cilia produced directional asymmetries in the embryo, so that the flow itself can differentially activate genes on the right versus left sides. But why do the cilia beat in only one direction? Well, if they all beat in different directions, there would be no fluid movement, and which direction they all “decided” to beat initially in may have been a random result of an ancestral gene. But once that’s determined, then it sets up a consistent left-right asymmetry. This may be the cue for directional asymmetry in many vertebrates. Support for this comes from the observation that mutations that damage cilia or their movement in vertebrates species cause screw-ups in the antisymmetry.

  • Some organisms, though, don’t have these nodes with cilia. The Quanta article implicates another instigator of handedness in such species: the presence of the protein myosin (a “motor protein”) that appears to act asymmetrically in organisms like fruit flies and worms, making cell division asymmetrical and producing  handedness. How this happens isn’t specified in the original paper nor in the Quanta article, but we know that screwing with myosin through mutations screws up handedness. Perhaps something about the asymmetry of the molecule itself induces a directionality in its action.

The figure below shows directional asymmetry in two organisms lacking ciliated nodes, the fruit fly Drosophila and the worm Caenorhabditis, as well as an organism with nodes—H. sapiens. The figure is taken from a 2011 paper by Christian Pohl:

screen-shot-2017-02-08-at-9-03-42-am

(From paper) L-R Asymmetry of internal organs in Caenorhabditis elegans, Drosophila melanogaster and Homo sapiens. Selected organs are shown for each organism, endodermal/intestinal organs are shown in red. Lower right of each part: Schematized topology of selected asymmetries for each organism. Arrows indicate tissue movements that lead to coiling of the respective tissue.

Now there are other possible mechanisms for generating handedness as well, and I suspect that the two listed above don’t exhaust all the possibilities.  Amino acids themselves have handedness, as all organisms use the L- configuration rather than the mirror image R- configuration.  The figure below shows the mirror-image symmetry of a single amino acid, with has two “enantiomers”, left and right. All organisms use only the L-isomer, and the adoption of that versus R- forms may have just been an initial accident, like the directional beating of the cilia. There’s no reason why we couldn’t have proteins composed of only R- amino acids, but we couldn’t have them with both L and R forms, as proteins couldn’t form properly if they used both types—just like you couldn’t have a group of cilia beating in all different directions. 

slide_4

This gives an inherent asymmetry to amino acids, and thus to the proteins they form. And proteins themselves, once synthesized, may also fold up asymmetrically, giving another way for a bilaterally symmetric organism to have a cue for handedness.

Still, to a large extent the evolutionary and developmental basis of directional asymmetry remains mysterious, largely because the molecular underpinnings of development are mysterious and hard to study.

One question that occupied me when I was younger was this: if you take an organism that is, by and large, bilaterally symmetrical, like Drosophila (though there is a bit of handedness in a couple of its traits), could you impose artificial selection on it to produce handedness? That is, could you select for a line of flies whose right eyes were bigger than their left, or who had more bristles on their left side than on their right (and vice versa in both cases)? How hard would that be? Given the absence of marked bilateral asymmetries in species like Drosophila that could act as developmental cues for the successful selection of directional asymmetry, you might think it would be hard—even though virtually every other trait in Drosophila can be successfully changed by artificial selection. Tomorrow we’ll learn the answer to my question.

42 Comments

  1. eric
    Posted February 8, 2017 at 10:33 am | Permalink

    Very cool. I would never have expected it to be liquid flow, though like many things, in hindsight its obvious that a consistently CW or CCW motion could be a basis of asymmetry just as well (or better!) than a static chiral structure.

    This also brings up the possibility that the coriolis effect (in liquids) could be something organisms in a local area use to build asymmetric bodies. I’m more blue-skyying here than proposing anything serious because the effect in microscopic amounts of liquid would be practically infinitesimal. But it’s possible at least in theory. And using the Earth’s coriolis effect has the elegant advantage of not requiring the organism to pre-produce any chiral structures or organs to begin with.

    • Posted February 8, 2017 at 11:00 am | Permalink

      The Coriolis effect is negligible, perhaps even unmeasureable, at cellular scales. It’s already at the limits of measurement for amateurs at human scales and totally irrelevant for things like toilet flushes and dust devils. You need to get up to the scale of hurricanes for it to be significant, though it’s of course relevant for precision artillery…if those two words have any meaning when used in conjunction….

      Cheers,

      b&

    • darrelle
      Posted February 8, 2017 at 2:02 pm | Permalink

      Interestingly, the direction of rotation of the cilia is determined by their chiral structure.

      • Mark R.
        Posted February 8, 2017 at 8:47 pm | Permalink

        Yes, and what is below the chiral structure…all the way down to molecules. If only Feynman were still around. Not a biologist, him, but he was good at figuring out molecular puzzles.

        • Mark R.
          Posted February 8, 2017 at 8:48 pm | Permalink

          he…not him. I should have capitalized it. He!

  2. Somite
    Posted February 8, 2017 at 10:35 am | Permalink

    This is great. Keep the science posts coming!

    • Steve Pollard
      Posted February 8, 2017 at 3:53 pm | Permalink

      Hear hear!

  3. Mark Reaume
    Posted February 8, 2017 at 10:37 am | Permalink

    sub

  4. W.Benson
    Posted February 8, 2017 at 11:03 am | Permalink

    Given that asymmetry can be coded by genetics, what was the selective force behind flatfish evolution?

    • eric
      Posted February 8, 2017 at 11:12 am | Permalink

      My guess: being able to see better while you lie flat in the sand provides an advantage. So the progenitor would likely have been a flounder-like fish that lay flat in the sand but didn’t have an eye that migrated that far, and the progenitor of that would have been flounder-like fish that lay flat in the sand but whose eye migrated even less, and so on.

      • Darren Garrison
        Posted February 8, 2017 at 11:54 am | Permalink

        Not to mention an eye lying against the sediment would have the possibility of getting infected, weakening or killing the fish and selecting against it.

      • Posted February 8, 2017 at 12:01 pm | Permalink

        Plus – the flatfish I’ve seen at aquariums often squirm down into the sand until the body is almost entirely invisible; you can hardly see them, except for the eyes.

  5. ThyroidPlanet
    Posted February 8, 2017 at 11:14 am | Permalink

    Sub

  6. Diana MacPherson
    Posted February 8, 2017 at 11:50 am | Permalink

    When I saw the hands and “chirai” I thought it was obvious because it was basically using Ancient Greek to label “hands”. 🙂

    • Posted February 8, 2017 at 11:53 am | Permalink

      I remember seeing at the UBC library a reference work called something like _Greek and Latin for Science and Medicine_. Might be interesting …

  7. Posted February 8, 2017 at 11:52 am | Permalink

    Fascinating. I look forward to the exciting conclusion! (As the saying goes.)

  8. mikeyc
    Posted February 8, 2017 at 12:17 pm | Permalink

    That is so kewl. The motion of cilia. I would never have thought it.

    When I was a deeply confused undergraduate trying to decide what to major in, a professor who befriended me gave me a copy of Lewis Thomas’s “Medusa and the Snail”. That book put me on the road I am now on – doing biological research. It was amazing biology, beautifully written, that helped me decide. It’s exactly this kind of natural story that draws me to biological science.

    Thanks, Dr CC.

  9. Posted February 8, 2017 at 12:55 pm | Permalink

    The predominance of right-handedness in human populations is puzzling. Many people attribute it to handedness in our brains, but that just changes the location of the puzzle. My pet theory is that it is the result of our hearts being on the left side. A mother prefers to hold an infant in her left arm so it can hear her heart beating, which keeps the baby calmer. Thus being more proficient with the free right hand got favorable selection. The theory leaves some questions. First, why did the heart end up on the left side in the first place? I think that is accidental. Why do we not see right-handed predominance in Chimp populations? Don’t know. Perhaps because infant chimps can grip mom’s body hair?

    • Mark R.
      Posted February 8, 2017 at 1:52 pm | Permalink

      That’s an interesting and imaginative theory.

      Though I believe there are differences in left/right handed people. There are interesting tests you can take. I’m left handed and I always “test” left handed. Some of the testing is looking at mirror images of faces and asking which looks happy, which sad. Also, which side of a theater do you prefer. I don’t know if eye dominance could affect the tests.

      • Posted February 8, 2017 at 2:56 pm | Permalink

        Yes there are definitely differences in brain lateralization between left- and right-handers. I doubt we know which causes which.

        I am right-handed and right-eyed and I invariably sit on the right side in a concert, unless there is a pianist of course. Probably just habit but I feel distinctly less comfortable sitting on the left side.

        • Mark R.
          Posted February 8, 2017 at 9:03 pm | Permalink

          I am left-handed and right-eyed, and I always answer re. the theater question: I like to sit in the middle. Supposedly that’s the ambidextrous pick. I don’t know. What I do right-handed (fishing, brushing my teeth, shooting) were all actions taught to me by my right-handed dad and mom. I’ve always wondered if my parents’ right-handedness infringed upon my (obviously superior LOL!) left-handedness.

    • Michael Scullin
      Posted February 8, 2017 at 7:06 pm | Permalink

      A mother holds a baby in her left arm because most mothers (by far) are right handed and need that hand to get anything done. This leads to the development of all manner of clever holding devices so that both arms can be used and the baby can nurse on demand (and demand they do). !Kung mothers carry their somewhat older children on their left hips so they can gather fruits and other edibles. As long as they are nursing they are also less apt to get pregnant again. Thus the really excellent anthropologist Richard Lee summed it up as the !Kung (Formerly and disparagingly known as “Bushmen”) women carried their birth control on their left hips. Expediency and not chirality or heartbeat.

      • Posted February 8, 2017 at 7:39 pm | Permalink

        I was speculating about how right-handedness might have been selected and hence evolved in ancestral humans. Once right-handedness evolved it is surely expedient to hold the baby in the left arm.

  10. Posted February 8, 2017 at 12:55 pm | Permalink

    Very interesting. Looking forward to part III.

  11. Mark R.
    Posted February 8, 2017 at 1:56 pm | Permalink

    …we serendipitously found…

    The best type of discovery!

  12. darrelle
    Posted February 8, 2017 at 1:59 pm | Permalink

    Fascinating.

  13. Vaal
    Posted February 8, 2017 at 2:15 pm | Permalink

    Loved this post, thanks.

  14. Mark Sturtevant
    Posted February 8, 2017 at 3:05 pm | Permalink

    Yahoo! You brought up the handedness of cilia in the amniote vertebrate ‘primitive pit’, aka Hensen’s node. This is suspected to –> early left/right asymmetry in amniotes during development. I was hoping you would bring this up.
    Looking forward to part III.

  15. Posted February 8, 2017 at 3:47 pm | Permalink

    Prof. Coyne, myosin is first mentioned in the post as “mysosin”. I even thought at first that this is another, less popular protein.

  16. Neil Taylor
    Posted February 8, 2017 at 4:47 pm | Permalink

    Fantastic science post. Thanks.

    Are Narwhales like people and occasionally have righties seen as sinisterly different from the dominant lefties?

    • Posted February 9, 2017 at 11:36 am | Permalink

      I couldn’t help but wonder what happens in narwhals with situs inversus. 😉

  17. Posted February 8, 2017 at 7:36 pm | Permalink

    Great post! I’m looking forward for part 3. I think the experiment you described (selecting for a right trait) has been done in zebrafish asymmetric neurons which is not 100% fixed trait. I think what happened was that after a couple generations the selected trait reverted to the original handeness. I’ll find the paper and post it.

  18. Posted February 9, 2017 at 2:25 am | Permalink

    Fantastic stuff. I’m learning a lot from these posts.

  19. HaggisForBrains
    Posted February 9, 2017 at 4:47 am | Permalink

    Yes, fascinating.

  20. Andrew West
    Posted February 9, 2017 at 7:20 am | Permalink

    How about gravity? I assume the effects are very small at that scale, but they should still exist.

    If you orient so that front/back experiences the same gravitational push, left/right can be differentiated by that becoming top/down along the gravitational gradient.

    • darrelle
      Posted February 9, 2017 at 8:57 am | Permalink

      At the scale that obtains, and that this is all taking place in a fluid environment, gravity isn’t likely to be strong enough to have an affect and based on experimental data so far doesn’t seem to play a role.

      In this case, the underlying source of handedness in vertebrates (specifically fish, mice & rabbits), it appears to be all about fluid dynamics in a central cavity (node). Cilia in cells lining the cavity create a steady flow pattern in which at the lower layer of the cavity there is a steady leftward flow. At the top layers there is a less steady return flow (towards the right).

      Cells lining the bottom of the node also produce and release tiny sacks that contain signaling molecules. These are moved by the steady leftward flow to the left side of the cavity where they go *splat* and release their contents and thereby are not distributed to other areas of the node by the return flow. So far they are not sure how the sacks of signaling molecules are opened when they hit the left side of the cavity.

  21. Posted February 9, 2017 at 10:16 am | Permalink

    Thank you Professor Coyne, for pushing me to understand some of this interesting matter of left- and righthandedness! Articles like this one remind me of our textbook during my last year at high school. Although many things will keep changing,I conserve it. Re-reading now on page 113:

    “A mixture of sugar with diluted sulphuric acid contains saccharose (right-R), glucose (right-R) and fructose (left-R), turns out to be left-rotating because the gyration of fructose is the strongest of the three forces”,

    brings back my fascination by those left- and right-rotating molecules being introduced to me in 1949.
    .-

  22. Catherine
    Posted February 9, 2017 at 1:06 pm | Permalink

    Professor Coyne–just so you know–I am LOVING the science postings. This topic particularly thought-provoking (side benefit– makes me forget about political reality for a while). Incredible cilia videos. BRAVO.

  23. Catherine
    Posted February 9, 2017 at 1:22 pm | Permalink

    I’m a neonatologist and abnormalities in the development of “sided-ness” manifest in newborns in heterotaxy syndromes. Too much right-handedness-typically with serious heart disease and no spleen with liver across the midline. Sick babies–sometimes lethal. To much left handedness-polysplenia, also heart disease but typically less severe.Intestines can also rotate incorrectly putting babies at risk for obstruction. Sometimes there is situs ambiguus” where sided-ness can not be determined. >20 genes have been identified to be abnormal in these people, and as stated, some involve ciliary abnormalities. So this is a great learning experience/update for me. Looking for part 3.

  24. Posted February 10, 2017 at 9:08 am | Permalink

    Interesting. (Just letting you know I’ve read this science post.)


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