Thomas Hunt Morgan's experiments. The fruit fly (Drosophila melanogaster) as a model system.

Key points:

  • Boveri and Sutton's chromosome theory of inheritance states that genes are found at specific locations on chromosomes, and that the behavior of chromosomes during meiosis can explain Mendel’s laws of inheritance.
  • Thomas Hunt Morgan, who studied fruit flies, provided the first strong confirmation of the chromosome theory.
  • Morgan discovered a mutation that affected fly eye color. He observed that the mutation was inherited differently by male and female flies.
  • Based on the inheritance pattern, Morgan concluded that the eye color gene must be located on the X chromosome.

Introduction

Where are genes found in a cell? Odds are, you've already heard the punchline: genes lie on chromosomes. You may have even have heard the second punchline, the one that ushered in the modern genetic era: genes are stretches of DNA that specify proteins.
However, these were not always things that you could look up on Khan Academy! When Gregor Mendel began studying heredity in 1843, chromosomes had not yet been observed under a microscope. Only with better microscopes and techniques during the late 1800s could cell biologists begin to stain and observe subcellular structures, seeing what they did during cell divisions (mitosis and meiosis).
Eventually, some scientists began to study Mendel’s long-ignored work and re-evaluate his model in terms of the behavior of chromosomes. Around the turn of the 20th century, the biology community started to make the first tentative connections between chromosomes, meiosis, and the inheritance of genes1^{1}.

The chromosome theory of inheritance

Who figured out that genes are on chromosomes? Walter Sutton and Theodor Boveri generally get credit for this insight. Sutton, an American, studied chromosomes and meiosis in grasshoppers. Boveri, a German, studied the same things in sea urchins.
In 1902 and 1903, Sutton and Boveri published independent papers proposing what we now call the chromosome theory of inheritance. This theory states that individual genes are found at specific locations on particular chromosomes, and that the behavior of chromosomes during meiosis can explain why genes are inherited according to Mendel’s laws2,3^{2, 3}.
Photographs of Walter Sutton, Theodor Boveri, and Thomas Hunt Morgan.
_Modified from "Chromosomal theory of inheritance: Figure 1," by OpenStax College, Biology (CC BY 3.0) and from "Thomas Hunt Morgan," (public domain)._
Observations that support the chromosome theory of inheritance include4^{4}:
  • Chromosomes, like Mendel's genes, come in matched (homologous) pairs in an organism. For both genes and chromosomes, one member of the pair comes from the mother and one from the father.
    Diagram comparing:
    1) paired gene copies in an organism (Aa), one from the mother and one from the father
    with
    2) paired homologous chromosomes in the same organism, one of which bears an A allele at a particular location, and the other of which bears an a allele at a corresponding location; one homologue came from the organism's mother, while the other came from its father
  • The members of a homologous pair separate in meiosis, so each sperm or egg receives just one member. This process mirrors segregation of alleles into gametes in Mendel's law of segregation.
    Diagram comparing:
    1) segregation of alleles into gametes: an Aa organism produces A gametes and a gametes
    with
    2) segregation of chromosomes into gametes during meiosis. One homologous chromosome bears an A allele, while the other bears an a allele at the corresponding location. During meiosis I, the homologous chromosomes separate. During meiosis II, the chromatids of each homologous chromosome separate. Ultimately, four gametes are produced: two containing a chromosome with an A allele, and two containing a chromosome with an a allele.
  • The members of different chromosome pairs are sorted into gametes independently of one another in meiosis, just like the alleles of different genes in Mendel's law of independent assortment.
    Diagram comparing:
    1) How an AaBb individual is proposed to make four equally common gamete types, AB, Ab, aB, and ab, in Mendelian genetics
    with
    2) The independent assortment of chromosomes in meiosis. The diagram depicts the relationship between chromosome configuration at meiosis I and homologue segregation to gametes for two pairs of homologous chromosomes. The larger chromosome pair bears the A gene and the smaller chromosome pair bears the B gene. The organism is heterozygous, so the larger homologous pair consists of one chromosome with an A allele and another with an a allele, while the smaller homologous pair consists of one chromosome with a B allele and another with a b allele.
    If the homologues bearing the A and B alleles are positioned on one side of the metaphase plate, the homologues bearing the a and b alleles will be positioned on the other side of the metaphase plate, and AB and ab gametes will ultimately be produced. If, on the other hand, the homologues bearing the A and b alleles are positioned on one side of the metaphase plate (and the homologues bearing the a and B alleles on the other), Ab and aB gametes will ultimately be produced.
The chromosome theory of inheritance was proposed before there was any direct evidence that traits were carried on chromosomes, and it was controversial at first. In the end, it was confirmed through the work of geneticist Thomas Hunt Morgan and his students, who studied the genetics of fruit flies5^5.

T. H. Morgan: Fun with fruit flies

Morgan chose the fruit fly, Drosophila melanogaster, for his genetic studies. What fruit flies may lack in charisma (depending on your taste in insects), they make up for in practicality: they're cheap, easy, and fast to grow. You can raise hundreds of them in a little bottle with sugar sludge at the bottom, and many geneticists still do this today!
Image of a fruit fly, photographed from the top.
Image credit: "Drosophila melanogaster - top," by André Karwath (CC BY-SA 2.5).
Morgan's crucial, chromosome theory-verifying experiments began when he found a mutation in a gene affecting fly eye color. This mutation made a fly's eyes white, rather than their normal red.
Unexpectedly, Morgan found that the eye color gene was inherited in different patterns by male and female flies6^6. Male flies have an X and a Y chromosome (XY), while female flies have two X chromosomes (XX). It didn't take Morgan long to realize that the eye color gene was being inherited in the same pattern as the X chromosome.
This may have come as a surprise to Morgan, who had been a critic of the chromosome theory7^{7}!

A "sex limited" inheritance pattern6^6

What made Morgan think that the eye color gene was on the X chromosome? Let's look at some of his data. The first white-eyed fly he found was male, and when this fly was crossed with normal, red-eyed female flies, the F1\text F_1 offspring were all red-eyed^*—telling Morgan that the white allele was recessive. So far, so good, no surprises there.
P generation: red-eyed wild type female crossed with white-eyed male.
F1 generation: all females and males are red-eyed. F1 flies are allowed to interbreed.
F2 generation: consists of flies in a ratio of 2 red eyed females : 1 red-eyed male : 1 white-eyed male.
_Image modified from "Drosophila melanogaster," by Madboy74 (CC0/public domain)._
But when the F1\text F_1 flies were crossed to each other, something strange happened: all of the female F2\text F_2 flies were red-eyed, while about half of the male F2\text F_2 flies were white-eyed. Clearly, the male and female flies were inheriting the trait in different patterns. In fact, they were inheriting it in the same pattern as a particular chromosome, the X.

X marks the spot

Let's see how inheritance of the X chromosome can explain what Morgan saw. Earlier, we said that female flies have an XX genotype and male flies have an XY genotype. If we stick the eye color gene on the X chromosome (writing it as a little subscript, w+w+ for red and ww for white), we can use a Punnett square to show Morgan's first cross:
Punnett square for mating of white-eyed male (XwY\text X^w\text Y) with red-eyed wild type female (Xw+Xw+\text X^{w+}\text X^{w+}).
Xw\text X^wY\text Y
Xw+\text X^{w+}Xw+Xw\text X^{w+}\text X^wXw+Y\text X^{w+}\text Y
Xw+\text X^{w+}Xw+Xw\text X^{w+}\text X^wXw+Y\text X^{w+}\text Y
Xw+Xw\text X^{w+}\text X^w - red-eyed F1 females Xw+Y\text X^{w+}\text Y - white-eyed F1 males
_Image modified from "Drosophila melanogaster," by Madboy74 (CC0/public domain)._
The predictions match the F1\text F_1 phenotypes, but this set of phenotypes could also be explained by a gene that is not on the X chromosome, since all the flies were red-eyed (regardless of sex). So the real test comes when the F1\text F_1 flies are mated to make the F2\text F_2 generation:
Punnett square for mating of red-eyed F1 male (Xw+Y\text X^{w+}\text Y) with red-eyed, heterozygous F1 female (Xw+Xw\text X^{w+}\text X^{w}).
Xw+\text X^{w+}Y\text Y
Xw+\text X^{w+}Xw+Xw+\text X^{w+}\text X^{w+}Xw+Y\text X^{w+}\text Y
Xw\text X^{w}Xw+Xw\text X^{w+}\text X^wXwY\text X^{w}\text Y
Xw+Xw+\text X^{w+}\text X^{w+}, Xw+Xw\text X^{w+}\text X^w - red-eyed F2 females
XwY\text X^{w}\text Y - white-eyed F2 males
Xw+Y\text X^{w+}\text Y - white-eyed F2 males
_Image modified from "Drosophila melanogaster," by Madboy74 (CC0/public domain)._
Here is where the X makes the difference. Our Punnett square with the eye color gene on the X chromosomes correctly predicts that all of the female flies will have red eyes, while half of the male flies will have white eyes. The male flies get their only X chromosome from their mother, who is heterozygous (Xw+Xw\text X^{w+}\text X^w), leading to the fifty-fifty split of phenotypes.

Confirming the model

Morgan did lots of other experiments to confirm an X chromosome location for the eye color gene. He was careful to rule out alternative possibilities (for instance, that it was simply impossible to get a white-eyed female fruit fly)6^6.
By mating the F2\text F_2 files from the cross above, Morgan was able to obtain white-eyed females, which he then crossed to red-eyed males. All the female offspring of this cross were red-eyed, while all the males were white-eyed8^{8}.
Punnett square for mating of red-eyed male (Xw+Y\text X^{w+}\text Y) with white-eyed female (XwXw\text X^{w}\text X^{w}).
Xw+\text X^{w+}Y\text Y
Xw\text X^{w}Xw+Xw\text X^{w+}\text X^{w}XwY\text X^{w}\text Y
Xw\text X^{w}Xw+Xw\text X^{w+}\text X^wXwY\text X^{w}\text Y
Xw+Xw\text X^{w+}\text X^{w} - red-eyed females
XwY\text X^{w}\text Y - white-eyed males
_Image modified from "Drosophila melanogaster," by Madboy74 (CC0/public domain)._
This result makes sense if the eye color gene is on the X chromosome. The white females (XwXw\text X^w\text X^w) provide the male offspring with their only X chromosome (leading to XwY\text X^{w}\text Y, or white, males). Female offspring, in contrast, get an additional X from their red-eyed fathers (Xw+Y\text X^{w+}\text Y), giving them an XwXw+\text X^w\text X^{w+} genotype and red eyes.
Pulling together all of his observations, Morgan concluded (correctly) that the gene must lie on, or be very tightly associated with, the X chromosome7,9^{7,9}. A strong confirmation of this conclusion came later, from Morgan's student Calvin Bridges. Bridges showed that rare male or female flies with unexpected eye colors were produced through nondisjunction (failure to separate) of sex chromosomes during meiosis—basically, the exception that proved the rule10,11^{10,11}.
Morgan also found mutations in other genes that were not inherited in a sex-specific pattern. We now know that genes are borne on both sex and non-sex chromosomes, in species from fruit flies to humans.

Attribution:

This article is a modified derivative of "Chromosomal theory and genetic linkage, by OpenStax College, Biology, CC BY 4.0. Download the original article for free at http://cnx.org/contents/185cbf87-c72e-48f5-b51e-f14f21b5eabd@10.53.
This article is licensed under a CC BY-NC-SA 4.0 license.

Works cited:

  1. Meiosis. (2015, December 6). Retrieved December 8, 2015 from Wikipedia: https://en.wikipedia.org/wiki/Meiosis.
  2. Hegreness, M. and Meselson, M. (2007). What did Sutton see? Thirty years of confusion over the chromosomal basis of Mendelism. Genetics, 176(4), 1939-1944. http://dx.doi.org/10.1534/genetics.104.79723.
  3. Baltzer, F. (1967). Theodor Boveri: The life of a great biologist 1862-1915. (D. Rudnick, Trans.). In Developmental biology companion website. Retrieved from http://10e.devbio.com/article.php?ch=7&id=75
  4. Boveri-Sutton chromosome theory. (2015, 31 October). Retrieved December 8, 2015 from Wikipedia: https://en.wikipedia.org/wiki/Boveri%E2%80%93Sutton_chromosome_theory.
  5. Bergmann, D. C. (2011). The chromosomal theory of heredity. In Genetics lecture notes. Biosci41, Stanford University, 21.
  6. Morgan, T. H. (1910). Sex-limited inheritance in Drosophila. Science 32, 120-122 (page 1 of reprint). Retrieved from http://www.esp.org/foundations/genetics/classical/thm-10a.pdf.
  7. Robbins, R. J. (2000). Introduction [to ESP edition of "Sex limited inheritance in Drosophila"]. In ESP foundations reprint series, v. Electronic Scholarly Publishing Project. Retrieved from http://www.esp.org/foundations/genetics/classical/thm-10a.pdf.
  8. Morgan, T. H. (1910). Sex-limited inheritance in Drosophila. Science 32, 120-122 (page 4 of reprint). Retrieved from http://www.esp.org/foundations/genetics/classical/thm-10a.pdf.
  9. Morgan, T. H. (1910). Sex-limited inheritance in Drosophila. Science 32, 120-122 (page 6 of reprint). Retrieved from http://www.esp.org/foundations/genetics/classical/thm-10a.pdf.
  10. Robbins, R. J. (2000). Introduction [to ESP edition of "Sex limited inheritance in Drosophila"]. In ESP foundations reprint series, vi. Electronic Scholarly Publishing Project. Retrieved from http://www.esp.org/foundations/genetics/classical/thm-10a.pdf.
  11. Hartwell, L. H., Hood, L., Goldberg, M. L., Reynolds, A. E., Silver, L. M., and Veres, R. C. (2008). Analysis of rare mistakes in meiosis provided further support for the chromosome theory. In Genetics: From genes to genomes (3rd ed., pp. 109-110). Boston, MA: McGraw-Hill.
^* Actually, not 100% true! If you look at reference 6, Morgan's original paper, you'll see that out of 1,1,240240 F1\text F_1 flies, there were actually 33 white-eyed males. The original white-eyed male was bred to his sisters to produce the F1\text F_1 generation, and there may have been a few other copies of the same mutation running around in the gene pool. This doesn't change Morgan's result, but is a good example of how biology is not always as neat and tidy as it looks in a textbook.

Additional references:

Bergmann, D. C. (2011). The chromosomal theory of heredity. In Genetics lecture notes (pp. 21-26). Biosci41, Stanford University.
Genome News Network. (2004). Theodor Boveri (1862-1915) and Walter Sutton (1877-1916) propose that chromosomes bear hereditary factors in accordance with Mendelian laws. In Genetics and genomics timeline. Retrieved from http://www.genomenewsnetwork.org/resources/timeline/1902_Boveri_Sutton.php.
Genome News Network. (2004). 1910: Thomas Hunt Morgan (1866-1945) establishes the chromosomal theory of heredity. In Genetics and genomics timeline. Retrieved from http://www.genomenewsnetwork.org/resources/timeline/1910_Morgan.php.
Griffiths, A. J. F., Miller, J. H., Suzuki, D. T., Lewontin, R. C., and Gelbart, W. M. (2000). Historical development of the chromosome theory. In An introduction to genetic analysis. New York, NY: W. H. Freeman. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK22088/.
Hemizygous. (2015). In The free dictionary. Retrieved from http://medical-dictionary.thefreedictionary.com/hemizygous.
Meiosis. (2010, August 1). In New world encyclopedia. Retrieved from http://www.newworldencyclopedia.org/entry/Meiosis.
Morgan, T. H. (1910). Sex-limited inheritance in Drosophila. Science 32, 120-122. Retrieved from http://www.esp.org/foundations/genetics/classical/thm-10a.pdf.
OpenStax College, Biology. (2015, May 13). Chromosomal theory and genetic linkage. In OpenStax CNX. Retrieved from http://cnx.org/contents/185cbf87-c72e-48f5-b51e-f14f21b5eabd@9.85:64/Chromosomal-Theory-and-Genetic.
Reece, J. B., Urry, L. A., Cain, M. L., Wasserman, S. A., Minorsky, P. V., and Jackson, R. B. (2011). The chromosomal basis of inheritance. In Campbell biology (10th ed., pp. 292-311). San Francisco, CA: Pearson.
Robbins, R. J. (2000). Introduction [to ESP edition of "Sex limited inheritance in Drosophila"]. In ESP foundations reprint series, i-vii. Electronic Scholarly Publishing Project. Retrieved from http://www.esp.org/foundations/genetics/classical/thm-10a.pdf.
Thomas Hunt Morgan. (2015, November 18). Retrieved December 8, 2015 from Wikipedia: https://en.wikipedia.org/wiki/Thomas_Hunt_Morgan.
Tobin, A. J. and Dusheck, J. (2005). From meiosis to Mendel. In Asking about life (3rd ed., pp. 162-191). Belmont, CA: Thomson.
X chromosome. (2015, December 1). Retrieved December 8, 2015 from Wikipedia: https://en.wikipedia.org/wiki/X_chromosome.
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