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).
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.
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.
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:
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.
h/t: Matthew Cobb
Sturtevant, A. H. The effects of unequal crossing over at the Bar locus in Drosophila. GENETICS March 1, 1925 10: 117–147