An Interview with Manuel F. Varela and Ann F. Varela; Alfred H. Sturtevant and the First Gene Map of the Fruit Fly

Dec 21, 2020 by

Alfred Henry Sturtevant

Alfred Henry Sturtevant.” Embryo Project Encyclopedia (1922). ISSN: 1940-5030 with permission.

He truly liked to work with Drosophila, with which he was extraordinarily adept. He was the only Drosophila worker I have known who transferred flies from one bottle to another without banging. For him, it was sufficient to hold two bottles mouth-to-mouth, with the receiving bottle directed towards the window and upwards at a forty-five-degree angle, and the flies would begin a mass migration into the new bottle. I wonder how many others have tried as often as I to induce the same phenomenon. I have found it difficult not to believe that the flies liked Sturt and wished to please him.”

—Sterling Emerson

Michael Shaughnessy

1) Alfred H. Sturtevant was born before the turn of the century. Where exactly was he born, and where did he go to elementary school?

Alfred Henry Sturtevant’s most noteworthy discoveries consist of genetic mapping, the first reparable gene defect, the principle underlying fate mapping, the phenomena of unequal crossing-over, and position effect. His significant contributions to science include his analysis of genetic “linkage groups,” which became a classical chromosome mapping method that we still use today.

Sturtevant was born on November 21, 1891, in Jacksonville, Illinois. His parents, Alfred Henry Sturtevant and Harriet Evelyn Morse had six children, of which Alfred was the youngest. Sturtevant’s father was a mathematics faculty at Illinois College. His siblings included Edgar Howard, Hellen Morse, Charles Alfred, Julian Monson, and Bradford Sturtevant. When Alfred Henry was seven, Sturtevant’s family moved to southern Alabama to take up farming. Before entering a public high school in Mobile, he attended a one-room schoolhouse. While growing up on the farm, Sturtevant had created pedigrees of his father’s horses.

Sturtevant was fascinated with taxonomy as well as genetics. He loved deciphering all kinds of puzzles and saw genetics as a puzzle for him to decode. Sturtevant was highly intellectual. He had an extraordinary memory and composed and edited papers in his head before writing them down from memory.

2) In 1908, he traveled to Columbia University and received his Ph.D. What were his initial forays into research?

Sturtevant was admitted to Columbia University in 1908 and was fortunate enough to reside with his older brother Edgar. Edgar was employed as a linguist at Barnard College in Columbia and taught Sturtevant about scholarly activities and how to conduct research.

Little did Sturtevant know that he would read about Mendelism in college, which would explain the traits expressed, such as coat color, in the horse pedigrees. In 1910, Sturtevant published an article about how horses inherit their coat colors. This article caught the attention of Thomas Hunt Morgan. He offered Sturtevant a position in his research lab at Columbia University. Sturtevant started as a laboratory bottle washer and somehow became skilled at fly genetics research despite his color-blindness. It is reported that he could distinguish eye colors between mutants with red versus white eyes and other phenotypic characteristics. See Figure 86.

File:Biology Illustration Animals Insects Drosophila melanogaster.svg

Figure 86. Drosophila melanogaster.

As an undergraduate in 1913, Sturtevant produced a technique to show a fruit fly chromosome’s genetic mapping. He was a member of Thomas Hunt Morgan’s research laboratory in New York City, known affectionately as the “Fly Room,” where the study of genetics was advancing rapidly by studying the fruit fly Drosophila. Sturtevant, Morgan, and other investigators determined that chromosomes play a role in the inheritance of traits. These maps displayed the relative positions of genes all along the chromosome. Sturtevant completed his doctoral degree in 1914, with Morgan as his advisor.

After he completed his Ph.D., Sturtevant was a research investigator for the Carnegie Institution of Washington at Columbia in 1915.

3) Drosophila—why study the fruit fly, and what can we generalize about it?

The fruit fly, known scientifically by its species name Drosophila melanogaster, was paramount in the origins of molecular biology. Also called the vinegar fly, its scientific genus name, Drosophila, is derived from Greek Drosos, meaning dew, and Philia, meaning love. Thus, Drosophila is Greek for dew-loving, a behavior that sort of explains their affinity for eating fruits. The specific epithet name, melanogaster, describes their blackened gut phenotypes. The term is derived from Ancient Greek, Melas, meaning dark or pigmented, and Gaster, meaning belly or gut. As part of their morphological development, the fruit flies were observed to form bellies with their visible gut contents.

The fruit flies made desirable subjects for studies for several fundamental reasons. First, the insects were easily culturable. It seemed that only rudimentary laboratory facilities were required to grow these laboratory organisms. A simple room of small size, with one or two tables, shelves, windows, glassware-washing capabilities, and microscopes could fit the bill for these early studies of genetics. The investigators could supply readily available nutrients that were simple in composition to small glass vessels. The fruit flies would do the rest.

The fruit flies were easily countable, and discrete data could be collected. These numerical data could be evaluated scientifically, and astute investigators could glean genetic information from the data. Early morphological studies were possible because of its readily observable characteristics, which led early geneticists to study its genomic contents. Again, these fruit fly phenotypes could be evaluated systemically in mathematical terms.

The fruit fly chromosome numbers were few. The four fruit fly chromosomes could be seen with a simple light microscope. See Figure 87. Investigators could distinguish between each of the four chromosomes. Furthermore, the male and female chromosomes could be discerned. These sorts of genetic and reproductive features could be exploited to permit mating studies. The various types and numbers of the resulting offspring in new generations could be examined.

File:Drosophila metaphase chromosomes.jpg

Figure 87. Giemsa-stained Drosophila melanogaster chromosomes in metaphase of mitosis as viewed using a standard light microscope. The male genomic content is shown in panel (a), with the male chromosome marked as Y. In panel (b), the female chromosomal complement is depicted.

Another significant reason that the fruit flies made good test subjects for genetic studies was their ability to produce mutants. Many of these mutants were visibly different from their parental counterparts. The mutants would be mated with parental backgrounds. The offspring could be counted. Their chromosomes would be isolated and evaluated. The mutant phenotypes could be traced. The genetic data would be mathematically associated with offspring phenotypic properties. Soon these pioneering fruit fly geneticists assigned particular chromosomes as being responsible for conferring specific fly characteristics. With time, these geneticists could map the locations of particular phenotype-conferring “units,” now called genes, down the lengths of the fruit fly chromosomes. See Figure 88.


Figure 88. The chromosomesof the Drosophila melanogaster fruit fly. The Mbp term refers to mega-base pairs of DNA. Centimorgan (cM) distances were assigned according to NCBI and Carvalo (2002), in Curr. Op. Genet. & Devel. 12:664-668.

A startling discovery was the fact that these fruit fly genes could switch their chromosomal locations. The phenomenon was called genetic crossing over. These crossing over events could be mapped between areas within a given chromosome and, shockingly, between chromosomes! Genes were moving from one chromosome to another!

These discoveries, and others, paved the way for bacteriologists and virologists to study genetics. Studies of bacteria and bacteriophage viruses that infected them suffered from their lack of easily observable characteristics under the microscope. The fruit flies had the distinct advantage of having many traits to observe. Together, genetic studies of fruit flies, supported by corresponding investigations of phage infection in bacteria, led to new molecular biological studies of higher organisms, such as fungi, plants, and eventually humans.

4) World War I and the Great Depression—how did these events impact the work of this illustrious group?

In 1913, Sturtevant determined that genes were linearly arranged on chromosomes, resembling beads on a necklace. Also, he showed that the gene for any specific trait was in a fixed location, called the locus. He took his Ph.D. in 1914 under Thomas Hunt Morgan from Columbia University, where the famous “Fly Room” was housed.

In 1915, Sturtevant was promoted to an associate investigator. Between 1915 and 1928, Sturtevant studied heredity in fruit flies and determined that Drosophila genes are arranged linearly. Before starting the Great War, also known now as World War I, Sturtevant became an associate at the Carnegie Institution of Washington. It provided the funding necessary for his study of fruit fly genetics at Morgan’s Fly Room at Columbia. From 1917 to 1919, Sturtevant was drafted into the U.S. Army and served as a military soldier. One source described his Army nickname as “Hot Dog.” Although the details are not entirely clear, we surmise that World War I interrupted Sturtevant’s research program.

Sturtevant took a year of leave in 1932 to teach in England and Germany as a visiting professor sponsored by the Carnegie Endowment for International Peace. Before World War II, funding for scientific research in the U.S. was provided by private donations. After the Second World War, however, the primary source of research funding was the U.S. federal government. Interestingly, we found that Sturtevant was funded by the same organization, the Carnegie Institution of Washington, during the Great Depression. During the 1930s, Sturtevant made significant contributions to genetics due to his collaborations with George Beadle.

5) Gregor Mendel is a name universally known to geneticists—but how did Sturtevant build on his work?

Sturtevant’s Ph.D. work at Columbia in Thomas Hunt Morgan’s Fly Room supported the Mendelian theory of genetics. Gregor Mendel’s life and scientific work are highlighted in chapter seven of our 2018 book titled “The Inventions and Discoveries of the World’s Most Famous Scientists.” Using a variety of pea plant generations in the 1860s, Mendel formulated his principles of heredity. He had proposed the concepts of gene dominance and recessive natures. Mendel had propagated his notions of allelic segregation called independent assortment that occurred during gametogenesis. It can be said that Mendel’s works, which Sturtevant had read about while in college, deeply inspired him. Strikingly, Sturtevant would provide a wealth of data supporting the Mendelian theory of heredity.

Sturtevant’s entry into the studies of fruit fly genetics occurred when Mendel’s largely forgotten work had experienced a reawakening. Sturtevant’s fruit fly data all pointed to Mendel’s version of the gene. The Fly Room workers’ studies supported Mendel’s concept of the “discrete unit,” a principle we now know as the gene. Sturtevant would go through his mathematical analysis of mutant phenotypes and the results of fruit fly mating with their progeny phenotypes. The phenotypic ratios supported Mendel’s views of allelic dominance and recessiveness.

Building on Mendel’s fundamental genetic inheritance principles, Sturtevant and Morgan would then show that individual genes conferred specific fruit fly traits. Sturtevant had been a convert from the beginning of his mating studies. Still, it is said that Morgan went down grudgingly and would slowly accept Mendel’s view of genetic heritability when Sturtevant’s data pointed to movable genes within and between fruit fly chromosomes, a process known as crossing over. It built directly upon Mendel’s law of independent assortment.

Sturtevant would show that various genes for specific traits fell into a linearity type of relationship along the fruit fly chromosome’s span. He indicated that the genes occupied physical locations within chromosomes. Importantly, Sturtevant had demonstrated that specific traits, such as sex determination, etc., were linked to genes for unrelated characteristics. These gene linkage analyses showed their utility as potential markers for gene mapping along the chromosomes. Sturtevant would be one of the first investigators in the world to construct a genome map of the fruit fly. Each of these scientific contributions to genetics by Sturtevant has its origins in Mendel’s pea plant studies.

6) George W. Beadle—another name—what was his involvement with Sturtevant?

Later, he taught an undergraduate course in genetics at Caltech and collaborated with George Beadle to write a textbook called “An Introduction to Genetics.”Sturtevant led a new genetics research group at Caltech, whose participants included George Beadle (see Chapter 2), Theodosius Dobzhansky, Sterling Emerson, and Jack Schultz.

In 1936, Beadle and Sturtevant published an influential paper dealing with the results of gene inversions within the chromosomes of the fruit fly. Beadle and Sturtevant had encountered two conflicting sets of paradoxes. The first paradox held that female fruit flies whose chromosome inversions failed to keep the centromere did not produce progeny with just one cross over event inside the inverted region. Nevertheless, this progeny underwent two cross overs within the inversion. The second paradox involved the same fruit flies. The females also produced progeny with no maternally derived X chromosomes.

Sturtevant and Beadle discovered that the single cross over event in the inverted chromosomes was deleted during meiosis. Further, they proposed that the mechanism for this selective elimination of the first paradox was tied to the lack of material X chromosome inheritance paradox. During meiosis, they suggested that within the sex cells, only division of the nucleus occurs, but cellular division. With multiple nuclei present within the cell, only the nucleus located in the innermost arrangement along the egg cortex undergoes fertilization. The remaining outermost nuclei were eliminated. When the work was published, it became a classic paper in the field of genetics.

Beadle and Sturtevant also examined the phenomena of allelic segregation, chromosome disjunction, and gene cross-over. Concerning segregation and disjunction, Beadle and Sturtevant shed light on the processes. According to the process, chromosomes exhibited a sort of tendency to form pairs during mitosis and separate during meiosis. During these associations and disassociations, gene cross over was known to occur in which genetic elements exchanged locations. However, occasionally, specific mutations would occur in which progeny had an abnormal chromosomal composition, pointing to a nondisjunction process. The chromosomes were thought to have undergone a failure to separate, leading to extra copies of chromosomes in mutant individuals. Beadle and Sturtevant studied the physical mechanics of these nondisjunction events. They also examined the crossing over mechanics. These works shed new insights into the evolutionary consequences of inversions during cross overs, helping to explain the fates of chromosomes that suffered from nondisjunction.

George W. Beadle would garner a Nobel Prize for his work with Edward Tatum (Chapter 23) and their notion of the gene conferring a protein’s production as its gene product.

7) Apparently, Sturtevant’s work on the “fruit fly” facilitated the geneticists’ ability to map chromosomes of higher organisms and, of course—human beings.

In later years, Sturtevant would write about his experiences in Morgan’s Fly Room at Columbia. In late 1911, he was Morgan’s undergraduate student. Sturtevant reminisced that he had suddenly realized that differences in the degrees of gene linkages could be exploited to determine a linear sequence of genes along the length of the chromosome. He had reasoned that crossing over events would be less frequent between genes that were close in proximity. Similarly, genes that were more distantly located from each other would experience more frequent cross overs.

Sturtevant said he went home that night unable to sleep, knowing the magnitude of the insight and its ramifications. He neglected his undergraduate study assignments and instead worked all night to produce a chromosome’s gene map. It was the first time in genetic history that such a gene map had been constructed for the fruit fly!

In his mind, Sturtevant envisaged that the genes for the body color, eye color, wing structure, wing size, and sex determination were linked in a gene sequence along the chromosome. He based the gene map on the cross over frequencies. Conducting the necessary fly mating and counting the cross over frequencies, Sturtevant collected the resulting data. He analyzed the frequencies in the number of crossing over events between the sex-linked gene, called y, the genes for body and eye colors, and the genes for distinct wing structures. Interestingly, Sturtevant’s unit of measure (Sturt) to denote genetic distance is now, ironically, called the centimorgan.

Based on the observed crossing over frequencies, Sturtevant discovered that the gene for yellow body color was 1.5 centimorgans (cM), physically near the gene for white eyes in the fruit fly chromosome. Likewise, Sturtevant discovered that the gene for white eyes was 5.4 cM in physical distance from the gene, called bifid, for the cleft wing structure, on the chromosome. Sturtevant further demonstrated that the bifid gene was 6.9 cM from the gene for yellow body color.

This new gene mapping work was first published in 1911 in the journal Science with T.H. Morgan as the sole author. In 1915, Sturtevant would be included by Morgan as a co-author of an influential book called “The Mechanism of Mendelian Heredity.” Additional authors included other members of Morgan’s famous Fly Room at Columbia, Hermann J. Muller, and Calvin B. Bridges.

In addition to gene mapping, Sturtevant made other significant contributions while in Morgan’s laboratory. For example, Sturtevant had been the first to speculate on the phenomenon of multiple alleles. The idea was that for a gene, more than two alleles were possible. Indeed, multiples alleles can occur from a mutation in the same gene.

In the 1920s, Sturtevant and Morgan studied a mutant fly with abnormally small eyes. The mutated element is called Ultra-bar. Together, they reasoned that the nature of the mutation involved so-called unequal crossing-over events. In this process, the eye’s normal gene, called Bar, was lost during the cross over. The result was a tandem duplication of Bar, creating Ultra-bar and small eyes in the fruit fly.

Another chief scientific contribution by Sturtevant was his notion of the inversion process. Here, Sturtevant predicted that a small region of the chromosome would break off its place, turn itself upside down, and insert itself back into the chromosome but set itself upside down! It would be another 15 before the supporting evidence for inversions would be published. Sturtevant was ahead of his time among the world’s leading geneticists of the day.

8) How did Sturtevant spend the vast majority of his later years?

In 1928, Sturtevant relocated to Pasadena to work at the California Institute of Technology. Sometime after the retirement of Morgan from Caltech, Sturtevant took charge of the biology division. He was also the so-called biological council chair starting in 1942, a post he held for four years. From 1947 to 1962, Sturtevant accepted the Thomas Hunt Morgan Professor of Biology position at Caltech. He became a Professor of Genetics and stayed for the remainder of his career.

In 1965, Sturtevant published a book of his own titled “A History of Genetics.” It has been reported that he spent a lot of his later years reading and solving puzzles. He wrote articles from memory that he had composed in his head beforehand. During the same year, he penned a candid autobiography of his early years, entitled, “The ‘Fly Room,’” published in American Scientist, a magazine sponsored by Sigma Xi: The Scientific Research Honor Society. Many of Sturtevant’s writings consisted of topics geared towards radiation’s effects on humans, human genetic’s social ramifications, and molecular and cellular models for genetic recombination.

9) What were some of his awards? I know he never received the Nobel Prize.

In 1949, Sturtevant was elected a Fellow of the American Academy of Arts and Sciences. The National Academy of Sciences awarded him the John J. Carty Award in 1965. In 1967, he accepted the National Medal of Science for his longtime research on Drosophila and other organisms’ genetics. He had become a world authority on the genetics of Diptera taxonomy, especially of the Drosophila genus and horses, birds, mice, ants, and plants.

10) What have I neglected to ask?

Sturtevant married Phoebe Curtis Reed in 1922, and the couple later had three children; William C. Sturtevant was the first-born.

Sturtevant was a candid adversary of eugenics and was interested in the effects of the atomic bomb on human populations due to his former research on lethal genes. Sturtevant had been vocal in his opposition of eugenics research of any sort. He also held an interest in the long-lasting effects of radiation on humans, such as those of individuals who were exposed to high doses of radioactive fallout in human populations living near atomic bomb blasts. In the 1960s, he had warned of the potential dangers to human health and well-being from exposure to nuclear fallout, especially in those who lived around atomic bomb testing sites in the U.S.

Sturtevant died in Pasadena, California, on April 5, 1970, at the age of 78.

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