Extensions to Mendelian Analysis


In Principle

Mendel's Laws 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
  
  Up to four distinct alleles may be present in a 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)
         Note: superscript "+" designates "wild type":
                     Character state seen most often 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
                    
IAalpha 1,3-N-acetylgalactosaminyl transferase
                     IB alpha 1-3-Galactosyl transferase

Allele Combinations 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 (DNA sequence variants) for this locus]

 
Most or all gene loci exist in multiple allelic form: variation is the rule
            "Wild type" allele is a myth
            Most genotype variants produce indistriguishable physical / biochemical phenotypes       
 
Matings ("marriages") between males & females produce

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


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


       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)
               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 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 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


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
 


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 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
 
        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
                          BRCA expressed as breast cancer in women, less so in men
                          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
            Ex.: epistasis: inefficient DNA repair at one locus 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

        

All text material 2013 by Steven M. Carr