Molecular Basis of Dominant & Recessive patterns of inheritance

    Consider patterns of gene expression at three different loci:

Recessive expression at the A (Xase) locus
Genotype
[ Xase ]
Phenotype
++
100 %
 
+a
 50 %
 
aa
  0 %
 

    The standard + allele produces a functional Xase enzyme; the a allele produces a non-functional enzyme.  The +a heterozygote produces half the typical concentration of enzyme made by a ++ homozygote. This is sufficient for standard phenotypic expression ("green") [haplosufficiency], and the phenotype of the +a heterozygote resembles that of the ++ homozygote. The variant allele a is therefore described as recessive to the wild-type + allele (or, + is dominant to a; this may also be written a+ is dominant to a).


Dominant expression at the B (Yase) locus
Genotype
[ Yase ]
Phenotype
++
100 %
 
+B
50 %
 
BB
0 %
 

    The standard + allele produces a functional Yase enzyme; the B allele produces a non-functional enzyme. The +B heterozygote produces half the typical concentration of enzyme. So far this is exactly the same pattern as at the Xase locus. However, the amount of enzyme produced by the +B heterozygote is not enough to produce standard phenotypic expression [haploinsufficiency], and the phenotype of the +B heterozygote resembles that of the BB homozygote ("pink"). The variant allele B is therefore described as dominant to the wild-type + allele  (or, + is recessive to B, or B is dominant to b+). Even though the recessive ++ homozygote produces more enzyme, this does not make the + allele "dominant" to the B allele.


Recessive expression at the D (Zase) locus
Genotype
[ Zase ]
Phenotype
++
100%
 
+d
120%
 
dd
140%
 

    The standard + allele produces a functional Zase enzyme; the d allele results in overproduction of the enzyme, which results in an exaggerated phenotype ("dark blue"). The phenotype of the +d heterozygote is the same as the ++ homozygote ("light blue"): the variant d allele is therefore described as recessive to the wild type + allele (or, d+ is dominant to d). Note that the higher level of enzyme production and the exaggerated phenotype produced by the d allele do not make it dominant to the + allele.



    At the three loci described above, the biochemical expression of the alleles in the heterozygote is exactly intermediate between the two homozygotes.  However, in each of the cases the resultant pattern of phenotypic expression is different. The variant alleles are described as dominant or recessive, depending on the phenotype of the heterozygote relative to that of the two homozygotes.  The level of enzyme activity relative to the ++ "wildtype", or the nature of the phenotype (in these examples, 'darker' or 'lighter') are irrelevant.

    Intermediate biochemical expression in the heterozygote is most simply modeled as the additive result of two alleles that each produce 50% of the enzyme activity. The standard phenotype results from a homozygous genotype with two fully functional alleles that each produce 50% + 50% = 100% of the standard activity. A heterozygous genotype with a functional allele and a non-functional allele produces 50% + 0% = 50% of the standard activity. The phenotype of the heterozygote will then depend on the degree of haplosufficiency of the single functional allele. Typically, the functional allele provides sufficient catalytic activity that a standard phenotype is obtained. Where the non-standard allele contributes some degree of activity, the heterozygote will also exhibit standard function. Thus is most cases, the functional allele can be described as "dominant" to the non-functional allele.

    Other circumstances affect the expression of heterozygous genotypes. "Up-regulation" of gene expression may result in an increase in the amount of enzyme from the standard functional allele that approaches that of the homozygous genotype. Contrariwise, the presence of a defective protein produce may interfere with the activity of the standard protein, for example, by competitively binding substrate such that the net activity of the standard enzyme is reduced. If this reduction falls below the critical point for standard function, the result is haploinsufficiency, and the non-standard allele will be called dominant. We will also see circumstances where the presence of a defective protein itself produces a phenotypic effect, notably the tri-nucleotide repeat diseases.




Homework
Expression at the E (Ease) locus
Genotype
[ Ease ]
Phenotype
50 %
 
$
 100 %
 
$ $
  150 %
 

Based on the phenotypic expression patterns for the genotypes involving alleles and $, which of the two alleles is dominant to the other? Explain.
Explain the genetic and molecular basis of the phenotypes.


All text material 2013 by Steven M. Carr