One gene-one enzyme hypothesis

SIGNIFICANCE: The formulation of the one gene-one enzyme hypothesis in 1941, which simply states that each gene gives rise to one enzyme, was foundational to understanding the molecular basis of gene action. With a more detailed understanding of how genes work, geneticists now consider the original hypothesis an oversimplification and have reformulated it as the “one gene-one polypeptide” hypothesis. Even in its new form, however, there are exceptions.

Genetics Meets Biochemistry

In the early part of the twentieth century, genetics was becoming an established discipline, but the relationship between genes and how they are expressed as phenotypes was not yet understood. Biochemistry was also in its infancy, particularly the study of the enzyme-catalyzed chemical reactions of metabolic pathways. In 1902, a British medical doctor named Archibald Garrod brought genetics and biochemistry together in the discovery that a human disease called alkaptonuria—which causes individuals with the disease to accumulate a black pigment in their urine—was inherited as a recessive trait. Equally important, however, was Garrod’s observation that alkaptonurics were unable to metabolize alkapton, the molecule responsible for the black pigmentation, an intermediate in the degradation of amino acids. Garrod’s conclusion was that people with alkaptonuria lack the enzyme that normally degrades alkapton. Because it thus appeared that a defective gene led to an enzyme deficiency, Garrod predicted that genes form enzymes. This statement was the precursor of what came to be known as the one gene-one enzyme hypothesis.

Formation of the Hypothesis

Garrod’s work went largely ignored until 1941, when George Beadle and Edward Tatum, geneticists at Stanford University, used bread mold (Neurospora crassa) to test and refine Garrod’s theory. Wild-type Neurospora grows well on minimal media containing only sugar, ammonia, salts, and biotin because it can biosynthesize all other necessary biochemicals. Beadle and Tatum generated mutants that did not grow on minimal media but instead grew only when some other factor, such as an amino acid, was included. They surmised that the mutant molds lacked specific enzymes involved in biosynthesis. With several such mutants, Beadle and Tatum demonstrated that mutations in single genes often corresponded to disruptions of single enzymatic steps in biosynthetic metabolic pathways. They concluded that each enzyme is controlled by one gene, a relationship they called the “one gene-one enzyme hypothesis.” This time, the scientific community took notice, awarding a Nobel Prize in Physiology or Medicine to Beadle and Tatum in 1958, and the hypothesis served as the basis for biochemical genetics for the next several years.

Modifications to the Hypothesis

The one gene-one enzyme hypothesis was accurate in predicting many of the findings in biochemical genetics after 1941. It is now known that DNA genes are often transcribed into messenger RNAs (mRNAs), which in turn are translated into polypeptides, many of which form enzymes. Thus, the basic premise that genes encode enzymes still holds. On the other hand, Beadle and Tatum had several of the details wrong, and now the hypothesis should be restated as follows: Most genes encode information for making one polypeptide.

There are at least three reasons that the original one gene-one enzyme hypothesis does not accurately explain biologists’ current understanding of gene expression. First of all, enzymes are often formed from more than one polypeptide, each of which is the product of a different gene. For example, the enzyme ATP synthase is composed of at least seven different polypeptides, all encoded by separate genes. Thus, the one-to-one ratio of genes to enzymes implied by the hypothesis is clearly incorrect. This fact was recognized early and led to the theory’s reformulation as the “one gene-one polypeptide” hypothesis. However, even this newer version of the hypothesis has since been shown to be inaccurate.

Second, several important genes do not encode enzymes. For example, some genes encode transfer RNAs (tRNAs), which are required for translating mRNAs. Thus, clearly even the one gene-one polypeptide hypothesis is insufficient since tRNAs are not polypeptides.

Finally, further deviation from the original one gene-one enzyme hypothesis is required when one considers that several modifications to RNAs and polypeptides occur after gene transcription and can do so in more than one way. Thus, a single gene can give rise to more than one mRNA and potentially to numerous different polypeptides with varying properties. Post-transcriptional variation in gene expression occurs first during RNA processing, when the polypeptide-encoding regions of mRNA are spliced together. It is important to note that the exact splicing pattern can vary depending on the exact needs of the cell. One example of a gene that undergoes differential mRNA processing leading to two dramatically different phenotypes is the fruit fly gene sex-lethal (sxl). A long version of sxl mRNA is generated in developing male flies and a shorter one in female flies. Because the sxl protein regulates sexual development, mutant female flies that mistakenly splice sxl mRNA display male sexual characteristics.

Like differential mRNA processing, post-translational protein modification varies by cellular context, allowing a single gene to generate more than one kind of enzyme. However, unlike mRNA processing, protein modification is often reversible. For example, liver cells responding to insulin will chemically modify some of their enzymes by way of a process called signal transduction, thereby changing their enzymatic properties, often essentially making them into different enzymes. Once insulin is no longer present, the cell can undo the modifications, returning the enzymes back to their original forms.

Key Terms

• messenger RNA (mRNA) processingchemical modifications that alter messenger RNAs, often resulting in more than one gene product formed from the same gene
• metabolic pathwaya series of enzyme-catalyzed reactions leading to the complete breakdown or synthesis of a particular biological molecule
• polypeptidea complex molecule encoded by the genetic code and composed of amino acids; one or more of which compose a protein
• post-translational modificationchemical alterations to proteins that alter their properties as enzymes

Bibliography

"1941: One Gene, One Enzyme." National Human Genome Research Institute. National Institutes of Health, 23 Apr. 2013. Web. 27 Jan. 2016.

Beadle, G. W., and E. L. Tatum. “Genetic Control of Biochemical Reactions in Neurospora.” Proceedings of the National Academy of Sciences 27 (1941): 499–506. Print.

Berg, Paul, and Maxine Singer. George Beadle, an Uncommon Farmer: The Emergence of Genetics in the Twentieth Century. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 2003. Print.

Bonasio, Roberto. "Emerging Topics in Epigenetics: Ants, Brains, and Noncoding RNAs." Annals of the New York Academy of Sciences 1260.1 (2012): 14–23. Print.

Chhetri, Divyash. "George W. Beadles"s One Gene-One Enzyme Hypothesis." Embryo Project Encyclopedia. Arizona State U, School of Life Sciences, Ctr. for Biology and Soc., 23 May 2014. Web. 27 Jan. 2016.

Davenport, Sadie. "The 'One Gene--One Enzyme' Hypothesis." California Northstate University, 14 Dec. 2022, cnsu.libguides.com/blog/The-one-gene-one-enzyme-hypothesis. Accessed 4 Sept. 2024.

Davis, Rowland H. Neurospora: Contributions of a Model Organism. New York: Oxford University Press, 2000. Print.

DeBerardinis, Ralph J, et al. "Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?" Cell 148.6 (2012): 1132–44. Print.

"Experimental Basis for the One-Gene, One-Protein Hypothesis." The Rockefeller University, 2022, centennial.rucares.org/index.php?page=one-gene‗one-enzyme. Accessed 4 Sept. 2024.

Hartl, Daniel L. Essential Genetics: A Genomics Perspective. 6th ed. Burlington: Jones & Bartlett Learning, 2014. Print.

Hickman, Mark, and John Cairns. “The Centenary of the One-Gene One-Enzyme Hypothesis.” Genetics 163, no. 3 (March, 2003): 839. Print.

Karp, Gerald. “Gene Expression: From Transcription to Translation.” InCell and Molecular Biology: Concepts and Experiments. 5th ed. Chichester, England: John Wiley and Sons, 2008. Print.

Science 291, no. 5507 (February 16, 2001). Print.

Snustad, D. Peter, and Michael J. Simmons. “Evolution of the Concept of the Gene.” In Principles of Genetics. 5th ed. Hoboken, N.J.: John Wiley and Sons, 2009.Print.

Weaver, Robert F. Molecular Biology. 4th ed. Boston: McGraw-Hill Higher Education, 2008. Print.