Advanced Qualitative Genetics

BIOLOGY 230
DEPARTMENT OF BIOLOGY
GRADUATE SCHOOL
CENTRAL MINDANAO UNIVERSITY
THINGS STUDIED IN QUALITATIVE
GENETICS
1. WAYS BY WHICH GENE AND
GENE PRODUCTS INTERACT
2. INTERPRETATION OF GENETIC
RATIOS BASED ON HOW GENE
PRODUCTS INTERACT IN A
BIOCHEMICAL WAY
3. HOW GENE AFFECTS THE
PHENOTYPE
GENES OF VARIABLE
EXPRESSION
GENETIC CONSTITUTION
= SPECIFIES ORGANISM’S
POTENTIAL TO DEVELOP AND
FUNCTION
ENVIRONMENT
= INFLUENCES GENE
EXPRESSION
1. Pleiotropy
Condition in which a single
mutation simultaneously
affects several characters
Several phenotypes can be
observed
1. Sickle-cell anemia
 Anemia
 Physical weakness
 Heart failure
 Mental retardation
 Brain damage
 Pnemonia
 Rheumatism
 Kidney failure
 Spleen damage
 Increased resistance to one type of malaria (Plasmodium
falciparum)
2. Meckel Syndrome
Rare autosomal recessive lethal
gene
Malformation in the CNS
Polydactyly
Multicystic kidney dysplasia
Ductal changes in the liver
2. Phenylketonuria(PKU)
2. Phenylketonuria(PKU)
Homozygous recessive
No phenylalanine hydroxylase
Mental retardation
Albinism
Excretion of phenylalanine the urine
Lower IQ
Smaller head size
Lighter hair color – low synthesis of melanin
PENETRANCE
Frequency in which a dominant or
recessive gene manifests itself in
individuals in a population
Number of individuals expressing
the gene in a population
Types of penetrance
1. Complete penetrance – 100% of the
population with the allele show the
phenotype
Ex.
 Polydactyly
 short vestigial wings
in Drosophila
 Osteogenesis imperfecta
Types of Penetrance
2. Incomplete Penetrance – not all
individuals positive for the gene show
the phenotype
Ex.
a. Harelip – 50% penetrant
b. Dominant retinoblastoma – 90%
-cancer of the eye in children; if affecting optic
nerve, brain will be affected->early death
Types of Penetrance
2. Incomplete Penetrance
Ex.
a. Brachydactyly-50-80% penetrant
- Shortening of index fingers and toes
- Autosomal dominant
b. Neurofibromatosis -50-80%
penetrant
EXPRESSIVITY
Degree to which a particular
phenotypic effect is exhibited in an
individual
The degree of expression of a
genetically controlled trait
Types of expressivity
1. Constant expressivity
- Phenotypes exhibited by individuals
positive for the gene is identical.
2. Variable expressivity
- Phenotypes exhibited by individuals
positive for the gene is not identical.
Examples of variable expressivity
Polydactyly (autosomal dominant)
– different location of extra fingers
Neurofibromatosis
Café-au-lait spot (color of coffee
with milk)
Freckling
Neurofibromas
Examples of variable expressivity
Osteogenesis imperfecta (autosomal
dominant)
Blue sclerae (whites of the eye)
Very fragile bones
deafness
Hapsburg jaw - Mandibular prognathism
Protrusion of the mandible
Dominant
Started in Austria, moved to Spain due to arranged
marriage of Kings
PHENOCOPY
Environmental mimic of gene
action
Environmentally induced
phenotype which closely resemble
the phenotype produced by a
known gene
Examples of phenocopy
Noselift
Breast augmentation
Curly/straight hair
Diabetic individuals with
normal glucose due to insulin
shots
Examples of phenocopy
babies with short limb
– Phocomelia – rare genetic disorder
_ due to thalidomide drug for
morning sickness (1960s)
Sun red cord
Due to 3 genes: A-B-plpl
Pigmentation only in parts exposed
to the sun
Examples of phenocopy
Photosynthetic genes
Expressed only in the presence of
light
Blistering of feet
Due to single dominant gene
Gene alone cannot cause blistering,
hot weather or winter
Tail feather pattern
Examples of phenocopy
Cataracts, deafness, heart defects
in children with mothers infected
with rubella or German measles
Also caused by recessive genes
Yellow fat in rabbits
yy – supposed to be yellow fat; with
no xanthophyll in the diet, colorless
fats are observed
CAUSES OF INCOMPLETE
PENETRANCE AND VARIABLE
EXPRESSIVITY
1. Environmental factors
External enviroment
alleles of other genes
Internal environment
 age of onset
Sex
External environment
Drosophila: genes for viability
 >28oC – lethal
Low temperature: little or no effect
Primrose flower color
Red flower – 24oC
White flower – 32oC
Siamese cats/Himalayan rabbits
Darker color in paws, ears, nose
Due to low body temperature in the extremities
Internal environment
Age
Reflects internal environment
Can affect gene function
Some genes require programmed
activation and deactivation
Examples
Pattern baldness – 30-40 y.o.
Duchenne muscular dystrophy – 2 to 5
y.o.
Internal environment
Sex
Influences expression of particular
genes
Sex-linked genes = genes of sex
chromosomes
Hemophilia
 colorblindness
Internal environment
Sex-limited traits = appear only in one
sex
Feathering pattern in chicken
Female=short tail
Male= long tail
Milk production in dairy cattle
Formation of breasts and ovaries in human
females
Ability to produce egg or sperm
Causes of incomplete penetrance and
variable expressivity
2. Alleles of the other genes
Modifier genes: have secondary effect on
the trait
Ex. 1. gene diluting intensity of
pigmentation in animals : black to gray
2. tailless in Manx cat – no tail to
small no. of fused vertebrae
Detecting Patterns of Gene Expression
Haploid Vs. Diploid
Tetrad Analysis
For haploid
Arrangement of Spores in an ascus
Random meiotic products (gametes)
Use of punnetsquare
Pedigree analysis in humans
Method of detecting gene products
1. Electrophoresis –charged molecule in solution
migrate in response to electrical field
 Rate of migration depends on strength of field, net
charge, size and shape of molecules as well as
viscosity, ionic strength and temperature of medium
 Low molecular weight – faster migration
 Positively charged proteins – migrate towards
negative electrode (cathode)
 Negatively charged proteins – migrate towards the
positive electrode (anode)
Method of detecting gene products
1. Electrophoresis
 Supporting media – silica gel, alumina,
cellulose, cellulose acetate,agarose gel,
starch gel, polyacrylamide, buffered
aqueous solutions
 Factors considered in electrophoresis:
buffer pH, length of running time,
strength of electric field, nature of
substrate
Detection of protein
Chromatography
Electrophoresis (SDS-PAGE)
Use of stains: Coomassie blue
Detection of enzymes
Use of a substrate specific for an
enzyme
Product-enzyme substrate reaction
forms a distinct band
Score for the presence of a band
Band indicates genes are expressed
Detection of enzymes
 Use of a substrate specific for an enzyme
Example:
lactate dehydrogenase(LDH)
Lactic acid+ NAD  pyruvic acid +NADH

Test for LDH

1. Add substrate to gel (lactic acid, NAD)
2. Use suitable stain specific for the product
NitroBlue tetrazolium – reduced by NADH forming
formazan (blue precipitate) indicates presence of LDH
Definition of terms
Allele: alternate forms of a gene
Equivalent to a band with its own characteristic
mobilities
Genotype: genetic constitution of an individual
Isozyme: different molecular forms of an enzyme
with similar enzymatic activities
Can show single or multiple bands
Can be coded for one locus or more
Locus : single zone of isozyme activity scored to
measure genetic variation
Definition of terms
Monomer: protein with single polypeptide
Absence of variation= single band
More than one allele = two bands
Dimer: protein with two subunits/polypeptides
Absence of variation= single band
More than one allele = three bands
Monomorphism: absence of any variation in a
locus
Polymorphism : presence of more than 2 alleles
in a locus
Variation at a locus
Monomorphic locus
only one allele is responsible for a particular
gene product
No allelic variation
Single band
Polymorphic locus
Due to change in DNA sequence, two alleles are
responsible for a gene product
Two bands (electrophoretically distinguishable)
Monomeric protein

AA AA’ A’A’

▬A’ ▬A’

▬A ▬A
Dimeric protein

AA AA’ A’A’

▬A’A’ ▬A’

▬AA’
▬A ▬AA
Finding the expected number of bands
and relative band densities
Formula: binomial expansion

(a+b)n, where n is the no. of polypeptides

Ex. (a+b)4 = a4+4a3b+6a2b2+4ab3+b4

Number of bands : 5

Relative band intensities-

1:4:6:4:1
 (a+b)4
AA AA’ A’A’

▬▬A’A’A’A’ ▬A’A’A’A’

▬AA’A’A’
▬AAA’A’
▬AAAA’
▬ AAAA ▬▬AAAA
MODES OF GENE EXPRESSION
AND INTERACTION
•FUNDAMENTAL RATIOS AND MODIFIED RATIOS
•INTERPRETATION WILL BE BASED ON GENE PRODUCT INTERACTION
•HOW THE GENE PRODUCTS ARE INVOLVED IN A BIOCHEMICAL
PATHWAY
1. SIMILAR GENES SPECIFYING
A TRAIT
1. ALLELIC INTERACTIONS
Allelic genes = similar genes specifying a trait
Genes in the same locus but specifying for alternative forms
of a trait
Ex. Color of seed: Yellow (Y-), green (yy)
Type of seed: Smooth (S-), wrinkled ( ss)
A. COMPLETE DOMINANCE
Wild type allele- codes for normal functional protein
Mutant allele- encodes defective protein
Nonsense mutation
Decrease or eliminate functional activity of protein
AA = Aa (same phenotype)
Why?
 Aa enzyme
Present but half (50%)
adequate to provide a normal phenotype
Complete dominance (examples)
Phenylketunoria (PKU) – absence of
phenylalanine hydroxylase
Albinism – absence of tyrosinase so no melanin
synthesis
Tay Sachs disease – absence of hexosaminidase A
Defect in lipid metabolism: paralysis, blindness,
early death
Lesch Nyhan Syndrome – absence of HPRT
(hypoxanthine-guanine RT); self-mutilation
CODOMINANCE
Each allele has equal contribution
Examples:
1. Blood type AB
2. Esterase in Drosphila = Aa= 2 bands (fast
and slow bands)
3. Amylase in corn = Aa = amylase 1 and
amylase 2*
Incomplete Dominance
Heterozygote has intermediate phenotype
Example: (Color of Four-o’clock flower)
Rr = pink = 50%of normal protein is not
enough to produce red colot
Mutant allele (rr) – white phenotype = no
functional protein for pigmentation
Overdominance
Heterozygote is superior than
homozygote.
Some proteins are composed of
subunits.
2 subunits –dimer
Homodimer protein- both units are
encoded by the same gene
Example of overdominance
A exists in two alleles
A1 = polypeptide A1
A2 = polypeptide A2

A1A1 A1A1
A2A2A2A2
A1A2 A1A1,A1A2, A2A2 (3 forms of homodimer)
A1A2 homodimer
 better functional activity
 Can function under a wide range of condition
 Superior compared tohomozygote
Example of overdominance
A1 = enzyme functioning at low temp
A2 = enzyme functioning at high temp

A1A2 - better enzyme; wide range of temp

Example of overdominance
Pigmentation in the eyes of Drosophila
w+w+ = red
ww = white
w+w = higher flourescence pigments
o (sepiapterideine and himmelblaus)
Allelic complementation
A – product
a- product produces a hybrid
protein
Example:
acid phosphatase in nematodes
Alcohol dehydrogenase in tomato
Allelic complementation:
Acid phosphatase in nematodes

++ +l ll

▬ ▬ Hybrid
protein
▬
▬ ▬
Allelic complementation:
Alcohol dehydrogenase in tomato

Adh+ Adh+l Adhll

▬ ▬ Hybrid
protein
▬
▬ ▬
Similar genes specifying a trait
2. Isoloci interaction
Isoloci :
nucleotide sequence in two or more loci
Specifying for an isozyme
Isozyme :
different molecular forms of an enzyme
Similar enzymatic activity
AA Aa aa Allelic
complementation/
Incomplete
dominance/
codominance

Aa
AA aa Complete
dominance

Aa AA aa Overdominance

AA aa Aa Overdominance
Genetic Mechanisms of Isozyme
Formation
 Multilocus system I
Different genes would be coding for independent proteins
with the same enzymatic activity
 Multilocus system II
Enzymes involved are polymeric; subunits coded by more
than one locus
 Multilocus polymeric system
Enzymes are polymeric composed of nonidentical subunits
Isozymes are combination of subunits
 Allozyme system
Encoded by allelic gens; hence, called allozymes
Testing gene mutations for allelism
(same locus)
Do crosses
New recessive mutation x recessive mutation of
known gene
Principle of the test:
If two mutations are combined, the organism will be
abnormal for this function.
A mutant phenotype will be exhibited. Thus, two
genes are allelic.
If wild type is obtained. Then the two genes are not
allelic.
Example
c-c- x aa  wild type ( 2 genes are not allelic)
c-c- x cc  mutant type ( 2 genes/mutations are
not allelic)

New mutation x tester genotype

c-c- x bb  wild type
c-c- x cc  mutant type*
c-c- x dd  wild type
c- and c are allelic
Classification of isoloci
 Clustered isoloci
Due to duplication
Closely linked genes
Example: mouse esterases: Est1, Est2, Est3
 Dispersed isoloci
Due to translocation (duplication happened beforehand)
Distributed in the genome
Example: catalase in corn
 Cat1 – 5S
 Cat2 - 1S
 Cat 3 – 1L
2. DISSIMILAR GENES
SPECIFYING A TRAIT
NON ALLELIC GENES
I.Genes of the immune system
Gene families : genes or nucleotide
sequences with the following characteristics:
Multiplicity
Close linkage
Sequence homology
Related or overlapping phenotypic functions
Duplications of ancestral sequence brings
about duplication of function
I.Genes of the immune system
Gene families :examples
rRNA gene = produced rRNA
Histocompatibility genes = organ transplant
rejection
Genes for hemoglobin
Humans: 7 distinct polypeptide chains encoded by
separate genes
Adult Hb: α2β2 - tetramer
Fetal Hb: α2γ2
Immunoglobulin genes = antibody genes
I.Genes of the immune system

Immunoglobulin or
antibody structure

= 2 heavy chains and 2

light chains
The immune response
Humoral – β lymphocytes  produce antibodies or Ig
Cellular – T lymphocytes  bursting of cells

Types of antibodies:
1. IgM
2. IgD
3. IgG
4. IgA
5. IgE

IgM
Constant and variable
regions of immunoglobulin chains.
Mechanisms of antibody diversity
1. Germline theory
 functional antibody genes are encoded in the
germline or zygote
Mechanisms of antibody diversity
2. Somatic mutation
Mechanisms of antibody diversity
3. Multispecificity or cross reactivity

 Single antibody molecules may combine

with a spectrum of different antigens
 Overlapping functions of different
antibodies
 Can respond to completely new antigens
Somatic Recombination or DNA
rearrangement
1. Light chain
 Random combination of V, J, and C genes (variable,
joining, constant)
Example: k light chain in mouse
Vk = 1-300 variable genes
Jk = 1-4 joining genes
Ck = 1 constant gene
 Single DNA recombination (V-J joining)
 300 Vk x 4 Jk = 1200 Vk exons
 Final k light chain: Vk+Jk+Ck
The V–J joining process involved in
making a human k light chain.
Somatic Recombination or DNA
rearrangement
2.Heavy chain : V+D+J+C
 D-J joining
 V-DJ joining
 splicing
Example: IgM heavy chain
V = 1-200 variable genes
D = 1-12 diversity genes
J = 1-4 joining genes
C = 1-8 constant gene
Somatic Recombination or DNA
rearrangement
Example: 300 Ig genes = 18B antibodies
Source Factor
Light chains
V 150x
J 5x
V-J recombination 10 x = 7500x
Heavy chains
V 80x
D 50x
J 6x
V-D, D-J 100x = 2,400,000x
recombination
II. Heteroloci
2 or more genes at different loci coding for different
nucleotide gene sequences
Classification of Heteroloci
1. Clustered heteroloci – different genes on the same
chromosome
Examples:
1. Gene clusters in fungi
2. Complex loci in Drosophila
3. Bacterial operon – lac operon
2. Dispersed heteroloci – genes on nonhomologous
chromosomes
Examples of clustered heteroloci
Gene clusters in yeast
Cluster Enzymes encoded
His4 1. Dehydrogenase
2. Cyclohydrolase
3. Pyrophosphorylase

Aro2 1. dihydroquinase
2. Dihydroquinic acid
synthetase
3.Dihydroshikinic acid
reductase
4. Shikimic acid kinase
Examples of clustered heteroloci
Lac operon in Escherichia coli
Mode of interaction between
dispersed heteroloci
1. Gene products specify a protein
 Example: Tryptophan in Neurospora

2. Gene products control a reaction sequence

Mode of interaction between
dispersed heteroloci
1.Gene products specify a protein
 Example: Tryptophan in Neurospora
 Controlled by dispersed genes
 specify subunits of the same gene
 Dispersed genes: trp1 and trp2
 Trp1: codes for 4 subunits with 2 enzymatic functions
 Phosphoribosyl anthranilic acid isomerase
 Indole 3 glycerol P synthetase
 Trp2: codes for 2 subunits responsible for anthranilate
synthetase
Mode of interaction between
dispersed heteroloci
2.Gene products control a reaction sequence
 Gene product governs a step in a biochemical
pathway
Gene A Gene B Gene C
↓ ↓ ↓

Enzyme Enzyme Enzyme

A B C
↓ ↓ ↓

A → B → C → D
Example
Arginine biosynthesis in E. coli
Collection of mutants that cant synthesize
arginine

RULE: If the mutants grow in the presence

of a certain precursor, they must suffer a
genetic mutation affecting a step before the
synthesis of that precursor
 How to determine the site of
mutation of different mutants.
Mutant Minimum + + +
strain Medium Ornithine Citrulline Arginine
1 - - - +
2 - - + +
3 - + + +

Arrange the table columns from the least number of + in a column

to the greatest number of +. You can determine the steps of the
pathway. Consider the rule.. You can determine the site of mutation
 How to determine the site of
mutation of different mutants?
Mutant Minimum + + +
strain Medium Ornithine Citrulline Arginine
1 - - - +
2 - - + +
3 - + + +
N-acetyl → Ornithine → Citrulline → Argino → Arginine
ornithine -
succini
c acid
↑ ↑ ↑
M M2 M1
 Seatwork/ assignment
A number of mutant strains was isolated from wild type Neurospora
that responded to the addition of certain supplement in culture medium
by growth(+) or no growth (-). Considering the responses of single mutants
(as shown in Table 1), diagram the metabolic pathway that could exist in the
Wild type strain consistent with the data. Indicate which part in the pathway
Is blocked in each mutant strain

Mutant Supplements added to the minimal culture medium

strain Glutamic Arginine Glutamic Ornithine Citrulline
acid semialdehyd
e
1 - + - - +
2 - + + + +
3 - + - + +
4 - + - - -
 Your answer

Precursor → Glutamic → Glutamic → Ornithine → Citrullin → Arginine

acid semialdehy e
de
↑ ↑ ↑ ↑
M M M M
2 3 1 4
Segregation of dispersed heteroloci
Law of Independent Assortment
ALLELIC PAIR  single trait
Non-allelic gene interactions
Recessive epistasis = 9:3:4
Dominant epistasis = 12:3:1
= 13:1
Complementary gene action (double epistasis) = 9:7
Duplicate gene action = 15:1
Novel phenotypes = 9:3:3:1
Analyze the pathway…
Complementary gene action (double epistasis)
= complementary because in order to produce purple,
both P and C must be present.

P- :purple P1: x ppcc

C- : color PPCC
pp: white
F1: PpCc x PpCc
F2: 9 P-C- 9 purple:
cc: no color
3 P-cc 7 white
3ppC-
1 ppcc
The biochemical pathway involved

White → White → purple

precursor precursor
1 2
↑ ↑
Enzyme Enzyme P
C
↑ ↑
Gene C Gene P
Seatwork…
Recessive epistasis black x albino
P1: x AAcc
aaCC
A- :agouti dominant
to black (a)
C- : color dominant to F1: AaCc x AaCc
color inhibition (cc)
cc is epistatic to C F2: 9 A-C- 9 agouti:
3 A-cc 3 albino
3aaC- 3 black
1 aacc 1 albino

9 agouti: 3 black: 4 albino

The biochemical pathway involved

Albino → black → agouti

↑ ↑
Enzyme Enzyme A
C
↑ ↑
Gene C Gene A
Dominant epistasis
3 types of onion
R- : pigment production (red pigments)
rr (slight amount of pigments to form yellow
I- : dominant inhibitor

F2: 9 R-I- 9 white:

3 R-ii 3 red
3 rrI- 3 white
1 rrii 1 yellow

12 white: 3 red: 1 yellow

Dominant epistasis in onion color

white → yellow → red

↑ ↑
Inhibitor Enzyme R
I
↑ ↑
Gene I Gene R
 White x White
Dominant epistasis leghorn Wyandotte
P1: x iicc
IICC
I- : color inhibition
dominant over color F1: IiCc x IiCc
allele
white white
C- : color dominant to
F2: 9 I-C- 9 white:
white(cc)
cc is epistatic to C 3 I-cc 3 white
3 iiC- 3 colored
1 iicc 1 white

13 white: 3 colored
Dominant epistasis in chicken
feather color

White → colored → white

precursor
↑ ↑
Enzyme Inhibitor I
C
↑ ↑
Gene C Gene I
Duplicate genes
2 dominant alleles at
loci A and B
Encode same product

Growth pattern in
F2: 9 A-B- 9 spring:
wheat
A = spring 3 A-bb 3 spring:
B = spring
3 aaB- 3 spring:
1 aabb 1 winter

15 spring : 1 winter
Growth pattern in wheat

Substrate → → → Spring
wheat
↑ ↑
Enzyme Enzyme
A B
↑ ↑
Gene A Gene B
Duplicate genes
Shape of capsules of
shepherd’s purse

A = triangular is
dominant over ovoid
B = triangular is F2: 9 A-B- 9 triangular
dominant over ovoid 3 A-bb 3 triangular
3 aaB- 3 triangular
1 aabb 1 ovoid

15 triangular : 1 ovoid
Growth pattern in wheat
Gene A
↓
Enzyme triangular
A
↓

Precursor

↑ triangular

Enzyme
B
↑
Gene B
Novel Phenotypes rose x pea
P1: x rrPP
When both genes are RRpp
dominant or both are
recessive F1: RrPp x RrPp
Comb in chicken
R- rose dominant
F2: 9 R-P- 9 walnut
over nonrose (rr)
3 R-pp 3 rose
P- pea dominant over
3 rrP- 3 pea
nonpea (pp)
1 rrpp 1 single

9 walnut: 3rose:3pea:1 single

Comb in Chicken
Gene P
↓
Enzyme pea
P
↓

Single walnut

↑ rose

Enzyme
R
↑
Gene R
Novel phenotypes
Color of corn snake
(Elaphe guttata)
F2: 9 O-B- 9 natural
3 O-bb 3 orange
3 ooB- 3 black
1 ooabb 1 albino
Color of corn snake
Gene O
↓
Enzyme orange
O
↓

Albino natural

↑ black

Enzyme
B
↑
Gene B
LETHAL GENES
LETHAL GENES
Changes in nucleotide sequences
Changes in protein
Death
Modification of zygotic ratio
Differential mortality
LETHAL ALLELE IN RATS
Abnormal
Cartilage

Narrowed Thickened Abnormal

trachea ribs nasal passage

Abnormal Other
chest organs anomalities

Diseased
lungs

Breathing Enlargement Arrested

difficulties of the heart development

Heart failure Lung Difficulties in

hemorrhage eating

DEATH
How do lethal alleles kill?
Allele causes a deficiency of some essential
chemical reactions
Allele causes structural defect
Types of lethal alleles
1. Produces a recognizable phenotype in the heterozygote
 Yellow mouse (yy) –die before birth
 Manx cat (no tail)
 MlMl : severe external dev’t abnormaltity: death
 MLMl : absence of a tail
 Dexter in cattle – bulldog calves; aborted before birth
 Xeroderma pigmemtosum (humans) –sensitive to UV light
 Lacks DNA repair enzymes  Skin cancer
 Infantile amaurotic idocy (human) – Tay Sach’s disease
 No hexosaminidase A acummulation of gangliosides (300x) in
the brain
 Death before 4 y.o.
Types of lethal alleles
2. Fully dominant and kill in one dose in the heterozygote
(AA/Aa = death)
 Epiloia or tuberous sclerosis
 Tumor-like formation in skin and organs
 Severe mental defects
 Huntington’s disease
 Involuntary movements
 Progressive degeneration of CNS
 Symptom: 30 y.o.
 Death: 40 y.o.
3. Confer no detectable effect on the heterozygote
 Lethality is recessive (aa= death)