Alfred Sturtevant: a hero of genetics

Alfred Henry Sturtevant (1891-1970), one of the first Drosophila geneticists, is also one of my personal scientific heroes. As an undergraduate at Columbia, and a member of Thomas Hunt Morgan’s famed “fly room”, Sturtevant did a remarkable piece of research, showing that genes on chromosomes are not only arrayed in a linear order, but that, by measuring the amount of recombination (or “crossing over”) between various mutations of those genes (seen by their effect on the fly’s body), we could get an idea not only of the order of the genes, but how far apart they were from each other. The procedure he devised as an undergraduate, and published when he was only 22, is the same procedure we use today to “map” genes.

His achievements were far more than that, however: he did crosses on “repair-able” genetic defects that pioneered biochemical genetics, found evidence for the effect of chromosome rearrangements in inhibiting crossing over, did some of the first work on the genetics of speciation with Drosophila simulans (most of his work had been on that workhorse of genetics, Drosophila melanogaster), and found evidence for “maternal effects”: the fact that the genetic constitution of the mother (in a snail) could influence the trait (coiling direction) shown in its offspring, rather than the genetic constitution of the offspring itself. But he did much more than that; read the link at the beginning of this paragraph. He was ferociously smart, and a polymath. In my view, he should have won the Nobel Prize, but his accomplishments, at least early in his life, were subsumed in the prize given to his mentor Thomas Hunt Morgan.

There’s a new paper in Genetics by Mariana Wolfner and Danny Miller with a cute title (below) that highlights another of Sturtevant’s accomplishments: the finding of unequal crossing over between chromosomes. (Click on the screenshot to go to the article).

screen-shot-2017-01-24-at-8-22-41-am

What is it with Sturtevant walking into a bar? Well, Sturtevant was motivated by the observation of a “bar-eyed” [“Bar’] mutation on the X chromosome of D. melanogaster, which caused small, skinny eyes (see diagram below). Flies with Bar eyes showed extraordinarily high rates of “mutation”: about 1 in 1000 of the offspring of females carrying the gene either reverted to “wild type” (normal eyes) or became “ultra-Bar” (extra skinny eyes; see diagram for both).

This rate was much higher than that of normal gene mutation (around 0.000001), and Sturtevant, based on his previous studies of crossing-over between chromosomes (exchange of genetic material between the pairs of “homologous” chromosomes during gamete formation) hypothesized that Bar “mutations” were really cases not of changes in the gene itself, but changes in the chromosome structure around the gene. By a complicated series of genetic crosses using mutant genes surrounding the Bar region, Sturtevant was able to show that Bar mutants arise from a phenomenon known as “unequal crossing over.”

Normally, during “meiosis,” the genetic process of gamete formation in diploid organisms, “homologous chromosomes” pair (we have two copies of each of our chromosomes, so we have 23 pairs or 46 total; Sturtevant’s flies had 8 total). That pairing is essential to ensure that the homologues separate, because each will go to a different egg or sperm (eggs and sperms have only half the number of chromosomes of a regular cell, and when fertilization ensues the normal number is restored). During that pairing, the homologous chromosomes can exchange genes as the chromosomes break and the bits of different homologues fuse to the other homologue. (For some reason we don’t fully understand, Drosophila females undergo this process but not the males. It was the observation that changes in the Bar eye were seen only from mutant female mothers and not fathers that led Sturtevant to suppose that crossing-over rather than simple mutation was involved.)

Usually this crossing over is exact, with the nucleotides breaking and fusing at the same place, so that if one chromosome has the A allele and the other the A’ allele of a gene, they will swap positions in perfect order. (Of course, the rest of the adjacent genes will be carried along.) Sometimes, though, recombination won’t be perfect, and you can get two copies of a gene on one chromosome and none on the other. For example, ———A——— paired with ———A’——— can give ———AA’——— one on chromosome and —————— on the other. One chromosomes winds up with two copies of the entire gene; the other with none.

By using tricky crosses with mutations flanking the Bar region, Sturtevant showed that this is exactly what was causing the Bar phenomenon. When a normal-eyed fly underwent unequal crossing over, it could produce a fly having two entire copies of the gene region, causing a thin “Bar” eye. Those could also, when paired with a normal fly, produce a fly with three copies of the gene region, producing an even thinner “ultra-Bar” eye. When a Bar eyed fly lost one of its copies by unequal crossing over, it reverted to a normal-eyed fly.

At the time Sturtevant did his experiments in the 1920s, there was no way to confirm his hypothesis by looking directly at the chromosomes. But soon thereafter it was discovered that in the salivary glands of flies, there were “polytene chromosomes” in which the DNA was replicated in tandem hundreds of times, so you could actually look at the physical structure of chromosomes under the microscope. Here, for instance, are the two arms of the second chromosomes, both in photographs and interpretation. The physical markers (“striping”) of the polytene chromosomes are diagnostic: the same for all individuals of a species.

cb2l2r

When the salivary gland chromosomes were examined in regular, Bar, and ultra-Bar flies by Bridges (1936) and Muller et al. (1936) , they confirmed that “Bar” eyes did come from a duplication of the gene region studied by Sturtevant a decade earlier, and that ultra-Bar flies came from a “triplication” of the region, as shown in the diagram below from the Wolfner and Miller paper.

f1-large

Why is this important? Because, in fact, unequal crossing over is one of the main sources for the origin of new genes in evolution.  It leads to a single gene being duplicated precisely on one chromosome, and once that happens, evolution can lead those two copies to diverge, taking on new functions. Further unequal crossing-over can create entire families of genes that have an ancestry from a single copy, but have diverged in function after duplication, triplication, and so on. This is one of the ways that the genome expands, and that we can get new genes with new functions. It is the way, for instance, that the different hemoglobins, α, β, γ and δ, each with a different function, derived from a common ancestor.

Sturtevant’s original research was thus a harbinger of our understanding of how new genetic information arises—all through a mistake in recombination. Similarly, new genetic information can arise via mutations in single genes—also a “mistake” in gene replication. If crossing over and gene replication occurred perfectly, there would be no evolution.

Sturtevant, known to his many friends as “Sturt”, was said to be a terrific guy, free of cant and arrogance, and (like all of Morgan’s offspring—save perhaps H. J. Muller) refreshingly free of a desire to grab credit for his every accomplishment. I’m sad to never have met Sturtevant, but there are some oldsters I’ve known who knew him well, and without exception they’ve all characterized him as a great guy.

Here he is as a stripling:

graphic-1

(From paper) Photo caption: Photo of Alfred Sturtevant, 1922, from History of the Marine Biological Laboratory.  Licensed as Creative Commons Attribution-NonCommercial-Share Alike 3.0

Sturtevant later became a professor of genetics at Cal Tech in Pasadena, where he remained for the rest of his life. And, like a good Drosophilist, he pushed flies with his own hands till the end. Here he is as an older man in his own fly room, doing something now prohibited in all labs: smoking—right next to an “etherizer” that put the flies to sleep using HIGHLY FLAMMABLE ether.

asturtevant-02-news-web-jpg

Alfred H. Sturtevant, the Thomas Hunt Morgan Professor of Biology, Emeritus, in his fly lab at Caltech in 1965. Photo by James McClanahan. Credit: Caltech Archives

h/t: Matthew Cobb

_________

Sturtevant, A. H. The effects of unequal crossing over at the Bar locus in DrosophilaGENETICS March 1, 1925 10: 117–147

44 Comments

  1. Frank
    Posted January 24, 2017 at 12:29 pm | Permalink

    “(eggs and sperms have only half the number of chromosomes of a regular cell, and when fertilization ensues the normal number is restored).”

    Spare me this blatant diploid-ism, with its implication that being haploid is somehow not “normal”! Did Professor CCE ever consider that perhaps those gametes don’t want or need to be “restored”!

    Actually, a very fine column on a very important biologist. I can remember the late Will Provine providing some interesting lecture insights into Sturtevant’s career. Thanks.

    • Posted January 24, 2017 at 2:13 pm | Permalink

      Some simple eukaryots, such as Plasmodium which causes malaria, are haploidists. Only their zygotes are diploid. The disadvantage of haploidism is that if something happens to part of a chromosome, you have no backup copy to look from to repair it. Therefore, highly organized eukaryotes (both animals and plants) are diploidists.

  2. mikeyc
    Posted January 24, 2017 at 12:31 pm | Permalink

    One typo on Dr Hunts name. Last sentence 2nd paragraph.

    • Posted January 24, 2017 at 12:35 pm | Permalink

      will fix, thanks. Oy, that was a bad typo (“Thomas Hung Morgan”).

      • TJR
        Posted January 25, 2017 at 5:48 am | Permalink

        We all assumed it was his p0rn name.

    • jahigginbotham
      Posted January 25, 2017 at 12:58 am | Permalink

      And one in Cal Tech for Caltech.

      I believe there are still some of his irises in a small garden at Caltech.

  3. Mark Reaume
    Posted January 24, 2017 at 12:39 pm | Permalink

    sub

  4. busterggi
    Posted January 24, 2017 at 12:43 pm | Permalink

    Raising fruit flies while studying under Dr. Fu is one of my happier memories of college.

  5. Posted January 24, 2017 at 12:43 pm | Permalink

    In 1965, when I was a graduate student in Chicago, I spent the summer in Jim Crow’s lab at the University of Wisconsin. Alfred Sturtevant was visiting there also while writing a book on the history of genetics. At one lecture by the population geneticist Warren Ewens, Sewall Wright got into a big argument with Ewens, and walked to the board at the front and continued talking without letting Ewens respond. Sturtevant was sitting next to Jim Crow in the audience, and leaned over and whispered “I wonder what it would be like if Wright argued with Wright?”

    Jim also told me that he and his wife Ann took the Wrights and Sturtevant to a local park. Sewall Wright and Sturtevant decided that they would climb a vertical outcrop of rock there. Both were 75 years old at the time. The Crows could only watch with horror, but fortunately disaster was averted.

    • loren russell
      Posted January 24, 2017 at 6:50 pm | Permalink

      Is 75 too old to be rock-climbing? Where I live, we call it “bone-density scans”.

      • loren russell
        Posted January 24, 2017 at 11:39 pm | Permalink

        I could have added: considering that Sewell Wright nearly lived to 100, he likely climbed rocks well past a sprightly 75…

  6. Posted January 24, 2017 at 1:10 pm | Permalink

    Long live Drosophilia melanogaster!

  7. David W.
    Posted January 24, 2017 at 1:19 pm | Permalink

    Thank you for the story!

  8. Posted January 24, 2017 at 1:31 pm | Permalink

    This is why WEIT is among my most frequently visited sites.

    And to think you almost gave up on the science posts!

  9. Posted January 24, 2017 at 1:39 pm | Permalink

    (eggs and sperms have only half the number of chromosomes of a regular cell, and when fertilization ensues the normal number is restored).

    At what point do trisomies arise? During meiosis?

  10. ThyroidPlanet
    Posted January 24, 2017 at 1:51 pm | Permalink

    “It is the way, for instance, that the different hemoglobins, α, β, γ and δ, each with a different function, derived from a common ancestor.”

    … ummm … yes, I knew that. Yes I did.

  11. darrelle
    Posted January 24, 2017 at 2:10 pm | Permalink

    Really enjoyed this article. These science posts about important past science that give insight into the “life and times” of the science and the scientists are my favorite.

    Such articles always make me thing about how badly people who think a new bit of evidence could overthrow the TOE (or any of the well established theories of modern science) misunderstand the process of science and the large mass of mutually supporting data from independent lines of investigation that the process generates.

  12. jeffery
    Posted January 24, 2017 at 2:20 pm | Permalink

    Hmmmm… I dunno….some guy I met told me that it was MUCH easier to just believe that a magical sky man made all these things exactly the way they are: it’s just a “coincidence” that science seems to be uncovering underlying patterns in them 🙂

    • Bent Backenforth
      Posted January 25, 2017 at 5:57 am | Permalink

      I believe the hard-core ID proponientsists would say that the appearance of new traits as the result of gene duplication means that the designer put the information in there at the time of creation. Later duplication just allowed the latent possibilities to become realized.

  13. Garry VanGelderen
    Posted January 24, 2017 at 2:24 pm | Permalink

    Great story, both about the man and the genetics. Learn something new every time you post a science story.

  14. Posted January 24, 2017 at 3:28 pm | Permalink

    Very interesting. Appreciate your effort in explaining it for us.

  15. Scientist
    Posted January 24, 2017 at 3:45 pm | Permalink

    I always mention Sturtevant’s mapping when teaching that subject in my major’s Genetics course. I’ll create a link to this post on BlackBoard and encourage students to check it out. I seem to recall that Sturtevant also wrote a long-used Genetics textbook. As to the pipe, here’s a link to a photo of another pipe smoking geneticist, Tracy Sonneborn of Paramecium fame http://www.bio.indiana.edu/events/lectures/sonneborn.shtml. But, I wonder whether their pipes,like my grandfather’s cigar, were unlit.

  16. rickflick
    Posted January 24, 2017 at 4:16 pm | Permalink

    I’d never heard of the guy. Looks like he should be more widely appreciated.

  17. Posted January 24, 2017 at 5:39 pm | Permalink

    There’s another Sturtevant story that the late Drosophila geneticist, my colleague Larry Sandler told me. In 1932 the Thomas Hunt Morgan lab from Columbia University moved to Caltech. It fell to Sturtevant to drive a truck full of bottles with Drosophila lines across the country. When he came to the California state line there was a shack there with an agricultural inspector who was tasked with checking to make sure “fruit flies” weren’t getting into the state. That was a different genus, Bactrocera but also called fruit flies.

    The inspector came up to the truck window. Sturtevant was worried, and understandably didn’t want to describe his load as “one million fruit flies” so he got very scientifically precise, and the exchange went like this:

    Inspector: Whad’ya got in the back of the truck?

    Sturtevant: Drosophila melanogaster

    Inspector (puzzled): OK, go on through!

    • Posted January 24, 2017 at 6:39 pm | Permalink

      I’ve done the same thing when driving into California with Drosophila, except I call them “vinegar flies”.

      • Posted January 24, 2017 at 7:40 pm | Permalink

        I tried to tell this story to a young inspector at the (large) inspection station on the Oregon border with California. He opened the trunk of my car and found a computer listing entitled “Bibliography of Theoretical Population Genetics” and then asked if I was in that field. He said he had taken a course on that at UC Davis from Professor Ayala.

        I then tried to tell him the Sturtevant story but he cut me off and pointed out that he had to move on quickly to the next car.

        • Posted January 25, 2017 at 1:32 am | Permalink

          The punchline made me laugh, Joe!

      • Posted January 25, 2017 at 1:33 am | Permalink

        There is a big campaign to get ppl to call it a vinegar fly, partly to avoid this kind of thing. It’s also what the French call it – la mouche à vinaigre.

        • Posted January 25, 2017 at 11:24 am | Permalink

          Where does this name come from? I know acetate is made by various processes in organisms, but …

  18. Posted January 24, 2017 at 6:23 pm | Permalink

    What an amazing body of work. It’s incredible the impact some people have had on our entire species’ pool of knowledge.

    • Posted January 25, 2017 at 11:25 am | Permalink

      True, but don’t forget the now hundreds of thousands of minor contributor who provide some stuff too!

  19. Posted January 24, 2017 at 7:27 pm | Permalink

    What sample sizes were regarded as adequate in early studies of Drosophila genetics? With mutation rates in the vicinity of 0.1%, I imagine you’d have to do a lot of “fly pushing” to identify statistically significant effects.

  20. Mark Sturtevant
    Posted January 24, 2017 at 7:33 pm | Permalink

    Sorry to arrive late.
    I wish it be known that I am no relation. But I wish I was.

    • Jonathan Wallace
      Posted January 25, 2017 at 8:56 am | Permalink

      I was wondering!

      I share your pain! I too have a pioneer of evolutionary biology as a namesake but to whom I am not related!

      • Posted January 25, 2017 at 11:27 am | Permalink

        We are *all* related to the two greats mentioned. Some of us a little more than others, I guess, but … 😉

  21. Janet
    Posted January 24, 2017 at 7:54 pm | Permalink

    Bet the pipe is not lit!

  22. Posted January 24, 2017 at 10:15 pm | Permalink

    I always find it amazing that Drosophila, chosen for studies of genetics based on convenient culture, generation time, easily scored phenotypes, etc., turned out to have “giant” chromosomes that facilitated the linkage of abstract genetic maps to the physical reality of chromosomes. What were the odds?

    I also have some Drosophila transport memories: 1) I drove across country (Maryland to Oregon) in a VW camper with a dozen or more stocks. I’m pretty sure we went via California (my home state) without incident. 2) Three years later, we made a similar trek from Oregon to Utah with even more stocks (same camper). 3) After a sabbatical working on Hawaiian Drosophila with Hamp Carson, I was smart enough to ship stocks back to Utah rather than carry them with me.

    And I may have shared this before: famous evolutionary geneticist Theodosius Dobzhansky visited Dave Suzuki’s lab in Vancouver, BC when I was there in 1970. Graduate student, handing him a couple of vials of flies he wanted to take back: “It’s not illegal to take fly cultures to the US, but it might be simpler just to keep them in an inside coat pocket.” Dobzhansky: ” You think maybe I have never smuggled any flies?”

    • Mark Sturtevant
      Posted January 25, 2017 at 6:04 am | Permalink

      I do not know how widely spread is the character of giant chromosomes, but it is my understanding that the character also occurs in a # of other insects.
      Great story about Dobzhansky.

  23. TJR
    Posted January 25, 2017 at 5:55 am | Permalink

    I hadn’t realised how far back Drosophila experimentation goes, but then my knowledge of genetics research (like a lot of people’s, I suspect) pretty much jumps straight from Mendel to Watson/Crick.

    Is it a worry that so much of what we know about genetics comes from this one genus? Or are we highly confident that it all generalises?

    Similarly I always worry that all the things we “know” from twin studies might be specific to twins, who are hardly typical.


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