7.5 Mutations Without Detectable Phenotypes
Not all DNA sequence changes result in mutant phenotypes — the various reasons are described below.
After mutagen treatment, the vast majority of base pair changes (especially substitutions) have no obvious effect on the phenotype. Often, this is because the change occurs in the DNA sequence of a non-coding region of the DNA, such as in intergenic regions (between genes) or within an intron where the sequence does not code for protein and is not essential for proper mRNA splicing. Also, even if the change affects the coding region, it may not alter the amino acid sequence (recall that the genetic code is degenerate; for example, GCT, GCC, GCA, and GCG all encode alanine) and is referred to as a silent mutation. Additionally, the base substitution may change an amino acid, but this does not quantitatively or qualitatively alter the function of the product, so no phenotypic change would occur.
Watch the video, Silent (Synonymous) Mutations of a Gene Explained, by Nikolay’s Genetics Lessons (2020) on YouTube, which further discusses silent gene mutations.
Environment and Genetic Redundancy
There are situations where a mutation can cause a complete loss-of-function of a gene, yet not produce a change in the phenotype, even when the mutant allele is homozygous. The lack of a visible phenotypic change can be due to environmental effects: the loss of that gene product may not be apparent in that specific environment, but might be in another. An example, is an auxotrophic mutant on complete medium. Conversely, researchers can alter the environment to reveal such mutants (e.g., auxotrophs on minimal media).
Alternatively, the lack of a phenotype might be attributed to genetic redundancy. That is. the mutant gene’s lost function is compensated by another gene, at another locus, encoding a similarly functioning product. Thus, the loss of one gene is compensated by the presence of another. The concept of genetic redundancy is an important consideration in genetic screens. A gene whose function can be compensated for my another gene, cannot be easily identified in a genetic screen for loss of function mutations.
Essential Genes and Lethal Alleles
Some mutant maybe required to reach a particular developmental stage before the phenotype can be seen or scored. For example, flower color can only be scored in plants that are mature enough to make flowers, and eye color can only be scored in flies that have developed to the adult stage. However, some mutant organisms may not develop sufficiently to reach a stage that can be scored for a particular phenotype. Mutations in essential genes create recessive lethal alleles that arrest or derail the development of an individual at an immature (embryonic, larval, or pupal) stage. This type of mutation may, therefore, go unnoticed in a typical mutant screen because they are absent from the progeny being screened. Furthermore, the progeny of a monohybrid cross involving an embryonic lethal recessive allele may all be of a single phenotypic class; giving a phenotypic ratio of 1:0 (which is the same as 3:0). In this case, the mutation may not be detected. Nevertheless, the study of recessive lethal mutations (those in essential genes) has elucidated many important biochemical pathways.
The identification of whole classes of genes involved in early embryonic development, is one example. Three Drosophila geneticists, Eric Wieschaus, Edward Lewis, and Christiane Nüsslein-Volhard, who were awarded a Nobel Prize in Physiology or Medicine in 1995 (Nobel Prize Outreach, n.d.), identified pair-rule, gap, and segment polarity genes that have corresponding homologs in all segmented organisms, including humans.
Many genes are first identified in mutant screens and, so, they tend to be named after their mutant phenotypes — not the normal function or phenotype. This can cause some confusion for students of genetics. For example, we have already encountered an X-linked gene named white in fruit flies. Null mutants of the white gene have white eyes, but the normal white+ allele has red eyes. This tells us that the wild type (normal) function of this gene is required to make red eyes. We now know its product is a protein that imports a colourless pigment precursor into developing cells of the eye. Why don’t we call it the “red” gene, since that is what its product does? Because there are more than one-dozen genes that, when mutant, alter the eye colour: violet, cinnabar, brown, scarlet, etc. For all of these genes, their function is also needed to make the eye wild-type red, and not the mutant colour. If we used the name “red” for all these genes, it would be confusing. So we use the distinctive mutant phenotype as the gene name. However, this can be problematic, as with the “lethal” mutations described above. This problem is usually handled by giving numbers or locations to the gene name, or making up names that describe how they die (e.g., even-skipped, hunchback, hairy, runt, etc.).
Nikolay’s Genetics Lessons. (2020, October 20). Silent (synonymous) mutations of a gene explained (video file). YouTube. https://www.youtube.com/watch?v=H-B9KIkYldY
Nobel Prize Outreach. (n.d.). The nobel prize in physiology or medicine 1995. NobelPrize.org. https://www.nobelprize.org/prizes/medicine/1995/summary/