Extensions to Mendelian Analysis

In Principle

Mendel's rules assume two alleles per locus
                                           complete dominance
                                           independent loci
                                           independent phenotypes

But there are multiple alleles per locus
                       intermediate dominance relationships among alleles
                       interactions among two (or more) loci (Epistasis)
                       complex phenotypes with contributions from several loci (Quantitative genetics)
                            
Multiple alleles
    Many traits exists in multiple phenotypic variants
        Many of these are due to allelic series
    More than two alleles may be present in a cross
    Ex.: coat-colour dilution variants in cats and other mammals
        C (or c+) (full colour) > cb (burmese) ~ cs (siamese) > c (albino)
         Note: superscript "+" designates "wild type":
                     most common character state seen in nature: "typical," "standard," "normal"

    Ex.: ABO blood types in humans (OMIM 110300)
        Isoagglutinin locus (I) on Chromosome 9 has three alleles: IA , IB , IO
              IA , IB create different cell-surface antigens; IO makes no antigen
                     IA:  alpha 1,3-N-acetylgalactosaminyl transferase
                     IB:  alpha 1-3-Galactosyl transferase

         Matings ("marriages") between males & females produce  
Genetics of ABO genotypes
 
IA
IB
IO
IA
AA
AB
AO
IB
AB
BB
BO
IO
AO
BO
O

           six genotypes (AA, AO, BB, BO, AB, & OO)
                  [There are > 83 alleles at the DNA sequence level for this locus]

    Most or all gene loci exist in multiple allelic forms: variation is the rule
             "Wild type" allele is a myth
             Most allelic variants produce indistinguishable physical / biochemical phenotypes

Semi-dominance & Co-dominance
    Some phenotypes result from the expression of both alleles
       semi-dominance: phenotype is an equal blend or combination
             Ex.: RR red flower x rr white flower Rr pink flowers
                     Semi-dominant phenotype ratio: 1 red : 2 pink :1 white
                     Clue: phenotype ratio same as genotype ratio
             AKA incomplete dominance: heterozygous phenotype is intermediate bx two homozygotes [IG1 15.4]
                                                                    or, alleles contribute unequally to phenotype
             Ex.: [PAH] in blood is not the sum of contributions of PKU and 'standard' alleles

       co-dominance: phenotype is a consequence of simultaneous expression [IG1 15.6]
              Ex.: Most protein loci express both products; one may be 'null'
                     HbS / HbA globins are both present in electrophoresis of sickle-cell trait

             Ex.: ABO blood types: A or B dominant to O, but A & B co-dominant 
                        Six genotypes reduce to four phenotypes: AA = AO, BB = BO
                         Phenotype determined by presence and/or absence of A and/or B antigens
  
ABO phenotypes
 
IA
IB
IO
IA
A
AB
A
IB
AB
B
B
IO
A
B
O
                 


       Note: distinguish pink [left] versus "red + white" [right] (cf. IG1 15.6)
                  former is semi-dominant, latter is co-dominant


                  pinkred & white
Modified Mendelian ratios: interactions between two loci

Ordinary Mendelian case: two loci affect two different traits:
Ex.: A [Colour] = Green, a = white
        B [Font] = Roman, b = bold italic
      Four phenotypes in ratio 9 : 3 : 3 : 1


 AB
 Ab
 aB
 ab
AB
 AABB
 AABb
 AaBB
 AaBb
Ab
 AABb
 AAbb
 AaBb
 Aabb
aB
 AaBB
 AaBb
 aaBB
 aaBb
ab
 AaBb
 Aabb
 aaBb
 aabb

But suppose both loci affect same trait ?

14 classes of non-Mendelian interactions recognized: we'll talk about four
Interaction
 A-B-
 A-bb
 aaB-
 aabb
 Phenotype
Ratio
Independent loci (Mendelian assortment)
 9
 3
 3 1
 9 : 3 : 3 : 1
Dominant Epistasis
 9
 3
 3
 1
 12 : 3 : 1
Recessive Epistasis
 9
 3
 3
 1
 9 : 3 : 4
Complementary loci (Duplicate dominant loci)
 9
 3
 3
 1
 15 : 1
Supplementary loci (Duplicate recessive loci)
 9
 3
 3
 1
 9 : 7

 Epistasis: alleles at one locus affect expression of alleles at another locus 
          or, two (or more) loci interact to influence one phenotypic character
          not "dominance," which occurs only between alleles at the same locus
          Extremely common, probably the norm for most phenotypes
               Simple metabolic pathways (cf. Phenylalanine) metabolic pathway
               Complex gene regulations patterns

1. Dominant epistasis: dominant allele at "A" locus is epistatic to "B" locus
                              Thus A- shows a constant phenotype irrespective of -B
                               B is expressed only in aa genotypes, and
                                   B- and bb differ phenotypically     12 : 3 : 1 

Ex.:   A = Colourless [epistatic to B], a = colour
          B = Yellow, b = green

AB
 Ab
 aB
 ab
AB
 AABB
 AABb
 AaBB
 AaBb
Ab
 AABb
 AAbb
 AaBb
 Aabb
aB
 AaBB
 AaBb
 aaBB
 aaBb
ab
 AaBb
 Aabb
 aaBb
 aabb

Epistasis is observed in A- genotypes [colourless];
    B is expressed only in aa genotypes [yellow or green] (IG1 15.12,13)

AB
 Ab
 aB
 ab
AB
 +
 +
 +
 +
Ab
 +
 Ab
 +
 Ab
aB
 +
 +
 aB
 aB
ab
 +
 Ab
 aB
 ab


 
2. Recessive epistasis: recessive allele at "D" locus is epistatic to "E"
       E is expressed, except in dd         9: 3 : 4

Ex.: D = Pigmented, d = albino [epistatic to E]
        E = Yellow, e = green

DE
 De
 dE
 de
DE
 DDEE
 DDEe
 DdEE
 DdEe
De
 DDEe
 DDee
 DdEe
 Ddee
dE
 DdEE
 DdEe
 ddEE
 ddEe
de
 DdEe
 Ddee
 ddEe
 ddee

Epistasis is observed only in dd genotypes;
    E locus is expressed in any D- genotype

DE
 De
 dE
 de
DE
 +
 +
 +
 +
De
 +
 De
 +
 De
dE
 +
 +
 dE
 dE
de
 +
 De
 dE
 de

cf. Arginine biosynthesis pathway in diploid organisms (IG1 15.11)

Duplicate loci: two loci function interchangeably to affect one trait
                               Ex.: occurs in "diploidization" of a polyploid

3. Complementary genes:
        either "A" or "B" is sufficient for wildtype function (AKA duplicate dominant)
         [OR: aa and bb together block wildtype function]
        15 A- or B- : 1 aa and bb

A is epistatic to bb; B is epistatic to aa

AB
 Ab
 aB
 ab
AB
 +
 +
 +
 +
Ab
 +
 +
 +
 +
aB
 +
 +
 +
 +
ab
 +
 +
 +
 aabb


4. Supplementary genes:
        either "aa" or "bb" blocks wildtype function (AKA duplicate recessive)
        [OR: both "A" and "B" are required for wildtype function ]
        9 A and B : 7 aa or bb

aa is epistatic to B; bb is epistatic to A

AB
 Ab
 aB
 ab
AB
 +
 +
 +
 +
Ab
 +
 AAbb
 +
 Aabb
aB
 +
 +
 aaBB
 aaBb
ab
 +
 Aabb
 aaBb
 aabb
 

Additivity: two (or more) genes contribute quantitatively to a single trait

        Ex.: One allele contributes 1 unit of colour, alternative allele contributes 0 units
                dihybrid genotype ratio 1:4:6:4:1 expresses 4, 3, 2, 1, & 0  phenotype units

AB
 Ab
 aB
 ab
AB
 4
 3 3 2
Ab
 3
 2 2 1
aB
 3 2 2 1
ab
 2 1
 1
 0

  Thresholds of phenotypic expression occur at various levels. (IG1 15.9,10)
    Some of these resemble conventional epistatic ratios

    4       vs 3,2,1,0         15 : 1  [same as complementary genes]
     4, 3     vs  2,1,0           5 : 11 
    4, 3, 2  vs    1,0         11 : 5
    4, 3  vs 2,1 vs 0           5 : 10 : 1
    and so on

  With multiple loci quantitative genetics
Expressivity & Penetrance
    Phenotype is not directly predictable from genotype
         Genotype variably expressed in phenotype: low expressivity
             Ex.: Same PKU genotype produces variable elevated blood [Phe] among individuals
           
         Special extreme case: expected phenotype not seen at all = low penetrance
             Ex.: Temperature sensitivity of point colour (ears, paws, tails) in mammals
            Ex.: Predisposition to cancer manifested in some persons with genotype, but not others
                          environment: diet may reduce likelihood of colon cancer
                          chance: "two-hit" cancer models require two somatic mutagenic events,
                                            or one inherited mutation, plus one random mutagenic event
                           epistasis: inefficient DNA repair fails to correct mutation (e.g., xeroderma pigmentosum)

Pleiotropy
    Single locus has multiple phenotypic effects
       Ex.: HbS mutation produces anemia and multiple organ damage
               Tailless (T) locus in Manx cats & mice affects axial skeleton (hindquarters) generally

See also
    Polygenic (quantitative) inheritance
    physical linkage of loci on chromosomes

Homework: iGen2 Chapter 12: ## 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34
         
All text material ©2012 by Steven M. Carr