Extensions to Mendelian Analysis

In Principle

Mendel's Laws explain 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
                       complex phenotypes with contributions from several loci
                            
Multiple alleles
    Many traits exists in multiple phenotypic variants
        Many of these are due to allelic series: dominance runs A > B > C > D
    Up to four distinct alleles may be present in any cross [ AB x CD ]
    Ex.: coat-colour dilution variants in cats and other mammals
        C (or c+) (full colour) > cb (burmese) ~ cs (siamese) > c (albino)
                 superscript "+" designates top-dominant "wild type":

    Ex.: ABO blood types in humans (OMIM 110300)
        Isoagglutinin locus (I) classically has three alleles: IA , IB , IO
              IA  & IB create different cell-surface antigens
                   IA:  alpha 1,3-N-acetylgalactosaminyl transferase (A3GALNT)
                     IB:  alpha 1,3-galactosyl transferase (A3GALT1)
                   IO: no antigen
 
         Combinations of three alleles produce six genotypes:
 
ABO Genotypes
 
IA
IB
IO
IA
AA
AB
AO
IB
AB
BB
BO
IO
AO
BO
O

Matings ("marriages") between males & females produce 1 ~ 4 phenotypes @:

ABO matings 
HOMEWORK: Determine the proportions of each ABO phenotype produced by each mating type

Transfusion compatibility: Type O is "universal donor", Type AB is "universal recipient"
                                              Type A & Type B require identical donor, or Type O

Hemolytic Disease of Newborns (HDN)
     Type A / B /AB father x Type O mother: mother generates anti-A & anti-B IgG antibodies
          Antibodies cross placenta, hemolyse RBCs of A, B, or AB fetus
     Rh-factor incompatibility: Rh+ father x Rh- mother: D-antibodies attack Rh+ fetus
2016: There are 100s of alleles (DNA variants) at the ABO locus [1,000 genomes project]
   Most or all gene loci exist in multiple allelic form:
        variation is the rule, "wild type" allele is a myth
            Most genotype variants produce indistinguishable physical / biochemical phenotypes
            Frequencies of alleles may vary among continental & sub-continental groups             

Semi-dominance & Co-dominance
    Some phenotypes result from the expression of both alleles

       semi-dominance: phenotype is an equal blend or combination of alleles
             Ex.: RR red flower x rr white flower Rr pink flowers
                     Semi-dominant phenotype ratio: 1 red : 2 pink :1 white
                     Clue: phenotype ratio = 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 of alleles [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
                     DNA sequences identify both sequences

             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 / absence of A & B antigens
ABO Phenotypes
 
IA
IB
IO
IA
A
AB
A
IB
AB
B
B
IO
A
B
O


            Ex.: X-linked co-dominance in tortoiseshell & calico cats         

       Note: distinguish pink versus "red + white" (cf. IG1 15.6)
                  ZOOM IN: Left panel shows semi-dominant, right panel shows 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 between two loci : 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
          Probably the norm for most phenotypic traits
               Simple metabolic pathways (cf. Phenylalanine)
               Complex interactions between multiple genes in regulatory pathways

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 diploids (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 wild-type function (AKA duplicate dominant)
         [OR: aa and bb together block wild-type 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

Evolution by Gene Duplication : duplicate locus can diverge in function without affecting phenotype

4. Supplementary genes:
        either "aa" or "bb" blocks wild-type function (AKA duplicate recessive)
        [OR: both "A" and "B" are required for wild-type 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
 
Multiple critical gene loci
Additivity: two (or more) genes contribute quantitatively to a single trait

        Ex.: One allele at each of two loci contributes 1 unit of colour, alternative allele contributes 0 units
                dihybrid 1:4:6:4:1 genotype ratio 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
         variable expressivity: genotype variably expressed in phenotype
             Ex.: Same PKU genotype produces variable elevation of blood [Phe] among individuals
             Ex.: Severity of Huntington disease not strictly correlated with # CAG repeats
           
         low penetrance: genotype does not "penetrate" through to the phenotype
                                       expected phenotype may not be seen at all [~ special case of variable expressivity]
             Ex.: Temperature sensitivity of point colour (ears, paws, tails) in mammals
            Ex.: Predisposition to cancer associated with same genotype presents clinically in some but not others
                          BRCA expressed as breast cancer in women, less so in men
                           environment: smoking increases likelihood of lung cancer
                          chance: "two-hit" model requires two random mutational event ("sporadic"),
                                        "one-hit" model requires one inherited allele ("hereditary"), plus one random event
             Ex.: epistasis: inefficient DNA repair at one locus fails to correct mutation (e.g., xeroderma pigmentosum)

Pleiotropy
    Single locus has multiple phenotypic effects
       Ex.: Beta-Globin gene mutation produces sickle-cell anemia & multiple organ damage
       Ex.: T locus hinders development of posterior axial skeleton
                    tailless Manx cats have multiple defects of hindquarters
                    T alleles cause segregation distortion: Tt genotype produces >> 50% T alleles
        
All text material © 2016 by Steven M. Carr