Alteration & Variation in the Genetic Code

 

Central Dogma

 

Remember: DNA genotypes produces phenotypes indirectly
    DNA genes contain information necessary for production of proteins,
        expressed biochemically through an RNA Genetic Code
           DNA is a coding molecule, but not "the Genetic Code"


Alternative alleles of genes arise by mutations
     which alter DNA sequences of genes  
         which may result in amino acid substitutions in proteins
             which may affect function of those proteins
     which appear in populations as Single Nucleotide Polymorphisms (SNPs)
         Most genes are highly polymorphic

Mutations & SNPs

    Mutations - interchanges of one base type for another
       transitions   - alternative pyrimidines [ C T ]  or purines [ A G ]
       transversions -  purines pyrimidines [C / T A / G]

     Recognized in individuals & populations as SNPs ("snips": single nucleotide polymorphisms)
                [ SNPs, Mutations, & Mutants: a note on terminology & some lessons from history ]

        Alternative nucleotide sequences of a gene correspond to alternative alleles
             or: a single gene occurs in variant forms (alleles)

  Single-base mutations
        Consequences of exon SNPs depend on position in triplet
            3rd position
                 typically a silent mutation - if 2- or 4-fold degenerate "wobble", no change to amino acid
                 sometimes a mis-sense mutation - results in different amino acids

           2nd position - always mis-sense mutation
           1st position - almost always mis-sense replacement
                                      six-fold degenerate Leu codons the exception
            Stop Codon mutations may occur at any position: coding  non-coding triplet
                non-sense (termination) mutations terminate polypeptides prematurely

                HOMEWORK: Identify all codons one step away from a termination codon

        Mutations in non-coding DNA have variable effects
               Ex.: mutations in promoter regions
                      mutations at intron / exon splice junctions

Mis-sense mutations in DNA cause amino acid substitutions in protein
   Proteins do not mutate!
      Consequences depend on position of substitution in polypeptide
        none:  substitution not in active site or binding site
        minor: substitution of same type (synonymous substitution)
             Allozyme: variant enzyme arising from allele variation
                               Charge of enzyme modified: (-)  (0)  (+)
         major: substitution affects structure / function (nonsynonymous substitution)
             Ex.: Glu Val   in beta-globin  produces Sickle-cell hemoglobin (HbS)
                         HOMEWORK: What is the DNA mutation involved?

     Insertion / Deletion ("indel") mutations
        gain or loss of one or two nucleotides alters reading frame
        frameshift mutations  (examples)
              single & double nucleotide indel downstream amino acids change
                    non-sense mutation eventually (quickly) produced
              triplet indel - insertion / deletion of single amino acid
                   typically milder consequences
                   multiple triplet insertions produce major effects
                       Ex.: CGG repeats in "Fragile X" Syndrome
         length mutations - very large indels (102~6 bps)

Genes highly polymorphic (multiple alleles) due to SNP variation

        Phenylalanine Hydroxylase (PAH) (OMIM citation 261600)
             has 14 exons, encodes 2.4kb mRNA for 452 amino acid protein

        Among 68 alleles that affect PAH enzyme activity [GenBank List: 1,228 in 2026]
                68% mis-sense SNPs (many produce Phenylketonuria (PKU))
                13% non-sense SNPs (premature termination)
                  9% indel SNPs (single base 1~5 triplets whole exon)
                10% splice-site SNPs (including most common variant allele)
              
        Most SNP variants of PAH locus are 3rd position silent:
                no affect on PAH expression
                & therefore undetected

Homework:
     (1) "What is a Gene?" Write a one-paragraph essay that that distinguishes Gene, Allele, and Locus
     (2) Critique the following statements:
            "PAH is the gene for Phenylketonuria (PKU)."
            "PKU is a genetic disease caused by absence of the PAH gene."
    (3) Take the first three pages (4 x 30 = 120) of GenBank variants: count current mutational types.

Text material ©2026 by Steven M. Carr