20: Appendix- Muller’s Morphs

Another way to look at alleles is from a functional perspective. This was the approach taken by Herman J. Muller (1890-1967) in the 1920s and 30s. He exploited unique features of the fruit fly Drosophila. Geneticists had isolated a number of chromosomal duplications and deletions, something made possible by unique aspects of chromosome organization in the salivary glands of the fly (←). These cells are polyploid; each chromosome contains more than 1000 double-stranded DNA molecules lined up from end to end.^[627] Based on the analysis of various mutations he could place mutations into distinct functional (with respect to a particular phenotype) groups: they were either amorphic, hypomorphic, hypermorphic, antimorphic, or neomorphic compared to the wild type (“normal”) version of the gene. Note that a particular gene/gene product may have more than one functional role, and a particular mutation may influence its different functions differently. An allele could be hypomorphic for one trait and antimorphic for another. Here a note, all types of alleles can lead to complex, adaptive changes to the cellular system that can lead to phenotypic effects.
Neomorphic mutations (alleles) are particularly interesting. Such mutations (alleles) change the activity of the gene product, producing a new (neo-) function. As an example a mutation can change the specificity of an enzyme, something that can occur in the development of a cancer.^[628] As an illustration, consider the transcription factor MyoD, a protein that regulates the formation (differentiation) of skeletal muscle cells. There are mutant alleles of MyoD associated with an aggressive form of embryonal rhabdomyosarcoma, a cancer of skeletal muscle. One missense mutant allele changes the leucine present at position 122 of the wild type MyoD protein to an arginine.^[629] This change alters the DNA binding site preference of the MyoD protein. The wild type MyoD protein binds to a particular consensus sequence (top panel →); in contrast the consensus binding sequence for the mutant protein is altered (bottom panel →). The mutant MyoD protein's binding preference now closely resembles the sequences bound by the transcription factor Myc. Myc regulates genes associated with active cell division. The result is that a gene product that normally inhibits cell division and encourages the formation of non-dividing muscle cells (MyoD), now turns on a different set of genes inducing (aberrant) cell division – a key feature of cancer cells. The mutation is neomorphic because the mutated MyoD protein (known as MyoDAla₁₂₂→Arg) has a new function.^[630]

The relationship between the type of mutation (in Muller’s terminology) and recessivity or dominance is not simple. An amorphic allele can be dominant, a behavior known as halpoinsufficiency, if a single wild type copy of a gene may not produce a sufficient amount of gene product. If recessive, a single functional copy of the gene is sufficient to produce a wild type phenotype. There are mutations that do not change the amino acid sequence of the encoded polypeptide, but change the DNA sequence – these are known as synonymous mutations. Such mutations result in what are known as single nucleotide polymorphisms (SNPs), a feature in the DNA that can be detected by various molecular methods. SNPs are often used in the analysis of genomic similarities and differences, including human ancestry.

Finally, remember essentially all traits are dependent upon a number of gene products, and so are polygenic, while a particular gene product can influence a number of traits - it can be pleiotrophic.^[631]

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