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Thomas Hunt Morgan, Genetic Recombination, and Gene Mapping

By: Ingrid Lobo, Ph.D. (Write Science Right) & Kenna Shaw, Ph.D. (Executive Editor, Nature Education) © 2008 Nature Education 
Citation: Lobo, I. & Shaw, K. (2008) Thomas Hunt Morgan, genetic recombination, and gene mapping. Nature Education 1(1):205
How would you feel if you had to be the one to challenge Gregor Mendel's paradigm-shifting laws of inheritance? Yet Thomas Hunt Morgan did exactly this and in the process made gene mapping possible.
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In 1911, while studying the chromosome theory of heredity, biologist Thomas Hunt Morgan had a major breakthrough. Morgan occasionally noticed that "linked" traits would separate. Meanwhile, other traits on the same chromosome showed little detectable linkage. Morgan considered the evidence and proposed that a process of crossing over, or recombination, might explain his results. Specifically, he proposed that the two paired chromosomes could "cross over" to exchange information. Today, we know that recombination does indeed occur during prophase of meiosis (Figure 1), and it creates different combinations of alleles in the gametes that result (i.e., the F1 generation; Figure 2).

A two-part schematic shows allele combinations on chromosomes following meiosis two. Crossing over does not occur between the chromosomes shown on the left side of the diagram. Crossing over does occur between the chromosomes shown on the right side of the diagram. In both scenarios, two sets of homologous chromosomes are shown: the first set is orange, and the second set is green. The chromosomes are shown before and after meiosis two has occurred, illustrating how each is affected by the presence or absence of a cross-over event.
Figure 1: Recombination and gamete production.
A comparison of nonrecombination (left) with recombination (right), shows how recombination affects the way chromosomes are passed into gametes in Meiosis II. On the right, a single crossover event produces half nonrecombinant gametes and half recombinant gametes.
© 2014 Nature Education Adapted from Pierce, Benjamin. Genetics: A Conceptual Approach, 2nd ed. All rights reserved. View Terms of Use

When proposing the idea of crossing over, Morgan also hypothesized that the frequency of recombination was related to the distance between the genes on a chromosome, and that the interchange of genetic information broke the linkage between genes. Morgan imagined that genes on chromosomes were similar to pearls on a string (Weiner, 1999); in other words, they were physical objects. The closer two genes were to one another on a chromosome, the greater their chance of being inherited together. In contrast, genes located farther away from one another on the same chromosome were more likely to be separated during recombination. Therefore, Morgan correctly proposed that the strength of linkage between two genes depends upon the distance between the genes on the chromosome. This proposition became the basis for construction of the earliest maps of the human genome.

A diagram outlines a genetic cross between two organisms, beginning with the formation of gametes in each, a fertilization event, and ending with the formation of gametes in the resulting F1 generation. The genotypes for the two parent organisms, the unfertilized gametes, the resulting F1 generation, and the F1 gametes are shown using uppercase and lowercase letters A and B. Recombinant and nonrecombinant gametes occur in the F1 generation and exhibit different combinations of alleles.
Figure 2: Allele recombination.
Recombination is the sorting of alleles into new combinations. Following the formation of gametes over two generations shows how recombination can produce new allelic combinations (lower right) or stay the same (lower left).
© 2014 Nature Education Adapted from Pierce, Benjamin. Genetics: A Conceptual Approach, 2nd ed. All rights reserved. View Terms of Use

Sturtevant Uses Crossing-Over Data to Construct the First Genetic Map

Soon after Morgan presented his hypothesis, Alfred Henry Sturtevant, a 19-year-old Columbia University undergraduate who was working with Morgan, realized that if the frequency of crossing over was related to distance, one could use this information to map out the genes on a chromosome. After all, the farther apart two genes were on a chromosome, the more likely it was that these genes would separate during recombination. Therefore, as Sturtevant explained it, the "proportion of crossovers could be used as an index of the distance between any two factors" (Sturtevant, 1913). Collecting a stack of laboratory data, Sturtevant went home and spent most of the night drawing the first chromosomal linkage map for the genes located on the X chromosome of fruit flies (Weiner, 1999).

A linear gene map shows the arrangement of six traits along a chromosome. The chromosome is represented by a long, thin, black, horizontal line, and the traits are shown as short, thin, black, vertical lines that cross the chromosome line at different numbered points along its length. Trait B (yellow) is for yellow body color, is located at the far left of the gene map at position 0.0. Traits C and O (blue) are for white eyes and are both located 1.0 map unit to the right of trait B. Traits P (red) and R (green) are for vermilion eyes and miniature wings, respectively, and are located in the middle of the gene map, to the right of traits C and O. Trait P is located 30.7 map units away from trait B, and trait R is located 33.7 map units away from trait B. At the far right side of the gene map, trait M (purple) is for rudimentary wings and is located 57.6 map units away from trait B.
Figure 3: Sturtevant's Drosophila gene map.
In Sturtevant's gene map, six traits are arranged along a linear chromosome according to the relative distance of each from trait B. Traits include yellow body (B), white eyes (C, O), Vermillion eyes (P), miniature wings (R), and rudimentary wings (M).
© 2013 Nature Education Adapted from Pierce, Benjamin. Genetics: A Conceptual Approach, 2nd ed. All rights reserved. View Terms of Use

When creating his map, Sturtevant started by placing six X-linked genes in order. B was a gene for black body color. C was a gene that allowed color to appear in the eyes. Flies with the P gene had vermilion eyes instead of the ordinary red, and flies with two copies of the recessive O gene had eyes that appeared a shade known as eosin. The R and M factors both affected the wings. Sturtevant placed C and O at the same point because they were completely linked and were always inherited together — in other words, he never saw any evidence for recombination between C and O. Sturtevant then placed the remainder of the genes in the order shown in Figure 3 (Sturtevant, 1913). Crossover events were tracked by examining the F2 progeny in crosses for "new" phenotypes.

A diagram with letters and arrows shows the phenotypes of two fruit flies that were crossed to determine the distance between genes. The phenotypes of the two types of flies used in Sturtevant's crosses are shown at the top of the diagram. The phenotypes are uppercase M (long wings), lowercase p (vermillion eyes) and lowercase m (rudimentary wings), uppercase P (red eyes). The letter X after both genotypes indicates that the genes are present on the X chromosome. Arrows point from both the first and second fly's phenotypes to their phenotypic descriptions.
Figure 4: Phenotypes used in Sturtevant's cross.
Sturtevant crossed flies with long wings (M) and vermillion eyes (p) with flies with rudimentary wings (m) and red eyes (P). These traits are X-linked.
© 2008 Nature Education All rights reserved. View Terms of Use

For example, to find the distance between P (vermilion eyes) and M (long wings), Sturtevant performed crosses between flies that had long wings and vermilion eyes and flies that had small wings and red eyes. These crosses resulted in F1 flies that either had long wings and red eyes or long wings and vermilion eyes. Sturtevant then crossed these two types of F1 flies and analyzed the offspring for evidence of recombination. Unexpected phenotypes observed in the male F2 progeny from this cross were then examined. (Because very little recombination occurs in the male germ line of Drosophila, only the female F1 chromosomes are considered for predicting phenotypes [Figure 4].) Sturtevant noted four classes of male flies in this F2 generation, as shown in Table 1.

The two additional classes of flies that appeared in this generation (long wings with red eyes and rudimentary wings with vermilion eyes) could only be explained by recombination occurring in the female germ line.

Phenotype Number of Flies Nature of Related Gametes
Long wings, red eyes 105 Recombinant
Rudimentary wings, red eyes 33 Nonrecombinant
Long wings, vermilion eyes 316 Nonrecombinant
Rudimentary wings, vermilion eyes 4 Recombinant
Table 1: Class of male files in the F2 generation

Sturtevant then worked out the order and the linear distances between these linked genes, thus forming a linkage map. In doing so, he computed the distance in an arbitrary unit he called the "map unit," which represented a recombination frequency of 0.01, or 1%. Later, the map unit was renamed the centimorgan (cM), in honor of Thomas Hunt Morgan, and it is still used today as the unit of measurement of distances along chromosomes.

In addition to describing the order of the genes on the X chromosome of fruit flies, Sturtevant's 1913 paper elucidated a number of other interesting points, including the following:

  • The relationship between crossing over and genetic map distance
  • The effects of multiple crossover events
  • The fact that a first crossover can inhibit a second crossover (a phenomenon called interference, which is described later in this article)

Mapping Genes Using Recombination Frequency

To better understand how Sturtevant arrived as his results, let's take a closer look at the process he followed. In Figure 5, the gray-eosin and yellow-red flies are the parental lines, and all the alleles for these traits are linked on the X chromosome. Therefore, any gray-red or yellow-eosin male offspring are recombinants. As you can see, two recombinants result from the cross. We count only the male progeny because the males have one X chromosome and dominance will not obscure any phenotypes (Robbins, 2000). Of course, crossing over can occur only in the female fruit flies, which have two X chromosomes. Thus, in this cross, the female F1 gametes provide the parental and recombinant gametes that we observe in the F2 progeny.

A diagram shows genotypes of the parental, F1, and F2 generations in Sturtevant's cross. Chromosomes are represented as thick, vertical black lines. The lines are intersected in two places by short, thin, horizontal black lines that mark two genes located along the length of the chromosomes. The genes are for body color (gray or yellow) and eye color (eosin or red). The parental generation begins with homozygous females for gray body color and eosin eye color and males with one X chromosome containing genes for yellow body color and red eye color. Mating between these two parental flies may yield two genotypes in the F1 generation, gray-red females and gray-eosin males. A cross between these two F1 generation genotypes may yield four male genotypes in the F2 generation: gray-red, gray eosin, yellow-red, and yellow-eosin.
Figure 5: An illustration of Sturtevant's cross, showing the chromosomes, illustrates his logic
Sturtevant illustrated the crosses and offspring resulting from a parental strain of gray-eosin female flies and yellow-red male flies. He followed this cross to the F2 generation.
© 2008 Robert J. Robbins. All rights reserved. View Terms of Use

In order to calculate the recombination frequency we use the following formula:

Substituting the values from our data set, we arrive at the following:

Therefore, the two genes are 0.5 map units apart.

Deviations from Expected Results Revealed Genetic Interference

Sturtevant also described the fact that, for genes that were distant from one another, there was a discrepancy in the predicted number of crossovers. For example, the distance between B and M on his map was 57.6. His recombination data using those two genes, however, did not suggest this distance. Instead, Sturtevant found 260 recombinants in 693 male progeny, which, when plugged into the equation, produced a result of 37.6. How, then, did Sturtevant explain the deviation?

In short, Sturtevant realized that double recombination events could occur if genes were far apart. Moreover, not only did Sturtevant's data suggest that double-crossing over occurred, but it also suggested that an initial crossover event could inhibit subsequent events by way of a phenomenon Sturtevant referred to as interference.

To understand how Sturtevant arrived at this conclusion, take a look at the data shown in Figure 6 (Sturtevant, 1913). As you can see, Sturtevant examined recombination events between B (body color), CO (two eye color genes that were closely linked), and R (rudimentary wings), and compared the frequencies of crossover events. When B and CO did not separate, Sturtevant noticed that the "gametic ratio," or presence, of CO/R recombinants was approximately 1:2 (3,454:6,972). However, when a crossover between B/CO (N = 60) occurred, there was a much lower likelihood (approximately 1:6.5) of a crossover between CO/R (N = 9). This finding is indicative of interference.

Three of Sturtevant's fly traits are organized in a three-column table in various combinations. The first column shows a single combination of the three traits that does not involve a cross-over event. The middle column shows two combinations of the three traits involving a single cross-over event. The rightmost column shows a single combination of the three traits involving a double cross-over event. The gametic ratio, or presence of recombinants, is shown below each combination of traits.
Figure 6: Data collected by Sturtevant
Number of possible combinations in forms having from 2 to 36 chromosomes in the pre-synaptic cells.
© 2008 Robert J. Robbins. All rights reserved. View Terms of Use

Interference phenomena are still being studied today, and research has shown that interference can act over extremely large distances of the genome. For example, Kenneth J. Hillers and Anne M. Villeneuve recently demonstrated that in Caenorhabditis elegans, interference can actually occur over half the genome of the organism. They demonstrated this by fusing multiple chromosomes together and observing that crossovers still occurred a single time (Hillers & Villeneuve, 2003).

Complete and Incomplete Linkage

When Sturtevant drew his chromosomal map, he placed the C and O genes at the same location because they were always inherited together (Figure 3; Sturtevant, 1913). Genes that are so close together on a chromosome that they are always inherited as a single unit show a relationship referred to as complete linkage. In fact, two genes that are completely linked can only be differentiated as separate genes when a mutation occurs in one of them. There is no other way to identify genes with complete linkage from single genes that show multiple phenotypes.

On the other hand, the phenomenon known as incomplete linkage occurs when two genes show linkage with a recombination level greater than 0% and less than 50%. In incomplete linkage, all expected types of gametes are formed, but the recombinant gametes occur less often than the parental gametes.

In addition, if two genes are on the same chromosome and are far enough apart that they undergo recombination at least 50% of the time, the genes are independently assorting and do not show linkage. Genes independently assort at a distance of 50 cM or more apart. This means that no statistical test would allow researchers to measure linkage.

Finally, linked genes that do not independently assort show statistical linkage. Statistical linkage is detected as deviation from independent assortment that favors the parental gametes. Syntenic genes are genes that are physically located on the same chromosome, whether or not the genes themselves exhibit linkage (Passarge et al., 1999). Therefore, all linked genes are syntenic, but not all syntenic genes show genetic linkage.

References and Recommended Reading

Blixt, S. Why didn't Gregor Mendel find linkage? Nature 256, 206 (1975) doi:10.1038/256206a0 (link to article)

Bridges, C. B. Salivary chromosome maps with a key to the banding of the chromosomes of Drosophila melanogaster. Journal of Heredity 26, 60–64 (1935)

———. A revised map of the salivary gland X chromosome. Journal of Heredity 29, 1113 (1938)

Hillers, K., & Villeneuve, A. Chromosome-wide control of meiotic crossing over in C. elegans. Current Biology 13, 1641–1647 (2003) doi:10.1016/j.cub.2003.08.026

Morgan, T. H. Random segregation versus coupling in Mendelian inheritance. Science 34, 384 (1911)

Passarge, E., et al. Incorrect use of the term "synteny." Nature Genetics 23, 387 (1999) (link to article)

Pierce, B. Genetics: A Conceptual Approach. (New York, W. H. Freeman & Co., 2005)

Punnett, R. C. Linkage in the sweet pea (Lathyrus odoratus). Journal of Genetics 13, 101–123 (1923)

———. Linkage groups and chromosome number in Lathyrus. Proceedings of the Royal Society of London: Series B, Containing Papers of a Biological Character 102 236–238. (1927)

Robbins, R. J. Introduction to sex-limited inheritance in Drosophila. Electronic Scholarly Publishing Foundations of Classical Genetics Project. (2000) (accessed May 19, 2008)

Sturtevant, A. H. The linear arrangement of six sex-linked factors in Drosophila, as shown by their mode of association. Journal of Experimental Zoology 14, 43–59 (1913)

Weiner, J. Time, Love, Memory: A Great Biologist and His Quest for the Origins of Behavior (New York, Random House, 1999)


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