Name: __________________________________________________________ Date: __________ Pd: ___
Genetics – Ms. Mullin
Chapter 5 (Extensions and Exceptions to Mendel’s Laws) Notes
5.1 When Gene Expression Appears to Alter Mendelian Ratios…
 Exceptions to Mendel’s Law
 Mendel chose traits in peas that showed two distinct forms
 Not all genes exhibit such simple inheritance.
 Genotypic ratios persist but phenotypic ratios may vary due to “outside-the-gene” influences
o
Alleles interact
o
Genes interact
o
Non-nuclear genes
o
Segregation of genes on same chromosome
o
Gene Linkage
o
Environment
 Lethal alleles
o
Some allele combinations are lethal.
o
Early acting lethal alleles are responsible for spontaneous abortions in humans
o
Homozygous recessive or dominant lethal alleles eliminate a progeny class
o
Mexican hairless dogs result from a mutation in a gene that shows lethality
o
hh
hairy
the wildtype trait
Hh
hairless
one mutation present creates a visible phenotype
HH
dies
two mutation are lethal
This Mexican hairless dog has inherited a dominant allele that makes it hairless. Inheriting two such
dominant alleles is lethal during embryonic development.
o
Some combinations of alleles cause problems so severe that the fetus ceases to develop. Such lethal
allele combinations appear to alter Mendelian ratios because homozygotes do not appear as a progeny
class
o
Looking at how to avoid the lethal alleles
o
Breeders cross Mexican hairless dogs to hairy (powderpuff) dogs to avoid dead embryos and stillbirths
that represent the HH genotypic class
o
Another example = Achondroplastic dwarfism
 Multiple Alleles
o
A gene may exist in more than two allelic forms in a population
o
Genes can mutate in many ways at any nucleotide in their DNA sequence.
o
An individual carries two alleles for each autosomal gene
o
However, a gene can have multiple alleles because its sequence can deviate in many ways
o
Different allele combinations can produce variations in the phenotype
o

PKU gene has hundreds of alleles resulting in four basic phenotypes

CF gene has over 1500 alleles
Multiple alleles: coat color in rabbits

Grey
= ____________________

Chinchilla
= ____________________

Himalayan
= ____________________

Light Grey
= ____________________

Albino
= ____________________
o
Predicting phenotypes based on genotype information can be difficult.
o
Different allele combinations can produce different phenotypes and different severities of symptoms

Cystic fibrosis phenotypes

Same genotype -> same degree of pancreatic insufficiency

Same genotype -> different lung phenotype mild to severe

PKU (phenylketonuria) phenotypes

Four different phenotypes cause by 300 mutant alleles

Classic PKU (with profound mental retardation)

Moderate PKU

Mild PKU

No symptoms, just secreting excess of the amino acid in urine
 Incomplete dominance
o
Indicates the heterozygous phenotype is distinct from either homozygous phenotype
o
The heterozygous phenotype is typically intermediate to the homozygous phenotype
o
Example: Familial hypercholesterolemia (FH)

A heterozygote has approximately half the normal number of receptors in the liver for LDL
cholesterol

A homozygous for the mutant allele totally lacks the receptor, and so their serum cholesterol
level is very high
o
A cross of pure breeding red snapdragons with pure breeding white snapdragons always produces
plants with pink flowers
o
You cannot produce a pure breeding line of pink snapdragons
o
If allele T (long tongue) exhibits incomplete dominance over the recessive allele t (short tongue) a
heterozygote for this tongue gene would most likely have a tongue of intermediate length
 Codominant alleles are observed simultaneously
o
The heterozygous phenotype results from the expression of both alleles
o
The ABO gene encodes a cell surface protein
o

Allele A makes A protein

Allele B makes B protein

Allele O makes no protein
Alleles A and B can be present on the cell surface at the same time

Alleles A and B are codominant

Allele O is recessive to both A and B alleles
o
Different alleles that are both expressed in a heterozygote are condominant
o
The IA and IB alleles of the I gene are codominant, but they follow Mendel’s law of segregation. These
Punnett squares follow the genotypes that could resuld when a person with type A blood produces
offspring with a person with type B blood
 Epistasis
o
The phenomenon where one gene affects the expression of a second gene
o
Example: Bombay phenotype

TheHgene is epistatic to the Igene

H protein places a molecule at the cell surface to which the A or B antigens
are attached

hhgenotype = no H protein

Without H protein the A or B antigens can not be attached to the surface of
the RBC

All hhgenotypes have the phenotype of type O, although the ABO blood
group can be anything (A, B, AB, or O)
o
H gene is epistatic to the ABO gene.
o
H protein attaches the A or B protein to the cell surface All ABO genotypes appear as type O
o
Can a woman with blood type A have a child with blood type O with a man who is AB? Yes, because of
epistasis between the I and H genes
 Variable expressivity & Incomplete Penetrance
o
Penetrance refers to the all-or-none expression of a single gene
o
Expressivity refers to the severity or extent
o
A genotype is incompletely penetrant if some individuals do not express the phenotype
o
A phenotype is variably expressive is symptoms vary in intensity among different people
o
A phenotype that varies in intensity shows variable expressivity

o
FF or Ff all show mild, moderate or profound deafness
Penetrance occurs when the disease phenotype is not always observed among individuals carrying the
disease-associated genotype.

DD or Dd
80% polydactyly

o
DD or Dd
20% no polydactyly
A family has an autosomal dominant condition where the second toe is attached by webbing to the third
toe and is longer than the big toe. Only some family members who inherit the mutant gene have the
odd toe, and the extent of webbing varies. This phenotype is incompletely penetrant and variably
expressed
o
Enamel hypoplasis is an autosomal dominant disorder that results in holes and cracks around the
crowns of baby teeth. Some individuals are apparently unaffected but transmit the trait to their
offspring. Individuals with the trait also vary in the number of teeth affected. This trait is an example of
variable expressivity and incomplete penetrance
 Pleiotropy
o
Phenomenon where one gene controls several functions or has more than one effect
o
Example: Porphyria variegata

Affected several members of European Royal families, including Kg George III

The varied illnesses & quirks appeared to be different unrelated disorders

Diseases that result from deficiencies of any of several enzymes required to make
heme

In each disease, an intermediate biochemical builds up

It may be excreted in urine, or accumulate in tissues causing symptoms

These symptoms, including reddish teeth and photosensitivity, may have inspired the
vampire and werewolf legends

King George III suffered from the autosomal dominant disorder porphyria variegata – and so did
several other family members. Because of pleiotrophy, the family’s varied illnesses and quirks
appeared to be different, unrelated disorders. In King George, symptoms appeared every few
years in a particular order
o
One gene controls or influences the expression of many symptoms in a disorder. These symptoms may
be variably expressed
o
A Mendelian disorder that has many associated symptoms is pleiotropic
o
Marfan Syndrome is another example
 Phenocopy
o
A trait that appears inherited but is caused by the environment
o
May have symptoms that resemble an inherited trait or occur within families
o
Exposure to teratogens

o
Thalidomide causes limb defects akin to rare inherited phocomelia
Infection

Rubella in pregnant mothers causes deafness mimicking inherited forms of deafness

AIDS virus can be passed from mother to child, looking like it is inherited
 Genetic heterogeneity
o
o
Individuals with identical phenotypes may reflect different genetic causes.

Deafness

Albinism

Cleft palate

Poor blood clotting
Genetic disorders such as deafness, cleft palate, and albinism that may be caused by different genes
that produce similar phenotypes are examples of genetic heterogeneity
o
o
Examples…

Hearing loss –132 autosomal recessive forms

Osteogenesis imperfecta –At least two different genes involved

Alzheimer disease –At least four different genes involved
Genes may encode enzymes that catalyze the same biochemical pathway, or different proteins that are
part of the pathway
o
A man with a recessive deafness allele on chromosome 17 marries a woman who also has a recessive
deafness allele, but on chromosome 3. Based on this, the probability that their children will be deaf is
closest to 0%
o
Of nearly 200 forms of hereditary deafness, 132 are autosomal recessive, 64 autosomal dominant, and
X-linked recessive. Hereditary deafness is genetically heterogeneic.
 The Human Genome Sequence Adds Perspective
o
The Human Genome Project has revealed that complications to Mendelian inheritance are more
common than originally thought
o
Thus terms like epistasis and genetic heterogeneity are beginning to overlap and blur

o
Example: Marfan syndrome
Interactions between genes also underlie penetrance and expressivity

Example: Huntington disease
5.2 Maternal Inheritance and Mitochondrial Genes
 Done via mitochondrial genes (found within mitochondria)
 Only females transmit mitochondrial genes, in the oocyte cytoplasm
 In maternal inheritance, a trait passes from females to offspring of both sexes, but NOT from males
 Mitochondrion
o
Organelle providing cellular energy
o
Contains small circular DNA called mtDNA
o
No crossing over or DNA repair
o
Many copies of the mitochondrial genome per cell
o
37 genes, no histones, no introns
o
Mutation rate = greater than nuclear DNA
o
Maternal inheritance
o
A mitochondrion contains several rings of DNA; different alleles can reside on different copies of
mitochondrial chromosomes
 Mitochondrial Inheritance
o
Mitochondria and their genome are transmitted from a mother to all of her offspring
o
Mothers pass mitochondrial genes to all offspring, fathers do not transmit mitochondrial genes because
sperm only very rarely contribute mitochondria to fertilized ova
o
Mitochondrial DNA differs from nuclear DNA in that it lacks repair mechanisms, introns, and does not
cross over
 Mitochondrial Disorders
o
Mitochondrial genes encode proteins that participate in protein synthesis and energy production
o
Several diseases result from mutations in mtDNA
o
Examples:
o

Mitochondrial myopathies –Weak and flaccid muscles

Leber optical atrophy –Impaired vision
Ooplasmic transfer technique can enable woman to avoid transmitting a mitochondrial disorder
 Heteroplasmy
o
There are many copies of the mitochondrial DNA; Thus, a mitochondrion will have different alleles for
the same gene
o
Heteroplasmy is the condition in which mitochondrial DNA sequence is not the same in all copies
o
The presence of two different alleles in mitochondria within the same cell is called heteroplsmy
o
At each cell division, the mitochondria are distributed at random into daughter cells
o
If an oocyte is heteroplasmic, differing number of copies of a mutant mtDNA may be transmitted

The phenotype reflects the proportion of mitochondria bearing the mutation
 Mitochondrial DNA reveals the past
o
mtDNA provides a powerful forensic tool used to:

Link suspects to crimes

Identify war dead

Support or challenge historical records

o
Example: Identification of the son of Marie Antoinette and Louis XVI
mtDNA is more likely to survive extensive damage and cells have many copies of it
5.3 Linkage
 Linkage
o
Is the term indicating that two genes are not transmitted independently.
o
Why? Two genes physically near each other on a chromosome will not assort randomly in meiosis
o
Genes that are close on the same chromosome are said to be linked
o
Linked genes do not assort independently in meiosis

Rather, they are usually inherited together when the chromosome is packaged into
a gamete

Therefore, they do not produce typical Mendelian ratios
Unlinked; 4 type of gametes (PL, Pl, pL, pl)
Tightly linked: 2 types of gametes (PL and pl)
 When genes are not linked, they assort independently; the gametes then represent all possible allele
combinations; the expected phenotypic ratio of a dihybrid cross is 9:3:3:1
 If genes are linked on the same chromosome, only two allele combinations are expected in the gametes; the
phenotypic ratio is 3:1 the same as for a monohybrid cross
 Recombination
o
When chromosomes recombine new combinations of alleles are created
o
Parental chromosomes have the alleles present in the original configuration
o
Recombinant chromosomes have new combinations of alleles
o
Crossing over disrupts linkage. The linkage between two genes may be interrupted if the chromosome
they are located on crosses over with its homolog at a point between the two genes. Crossing over
packages recombinant arrangements of the genes into gametes.
o
1) cis = Two dominant or two recessive alleles are on each chromosome
o
2) Trans = One dominant and one recessive allele are on each chromosome
o
Geneticists construct linkage maps of chromosomes by calculating the percent recombination between
two linked genes

A and B are linked genes. In a study of 100 offspring, 94 had parental genotypes for A and B,
while 6 were recombinants. A and B are 6 map units apart

A,B, and C are linked genes. Recombination between A and B is 3%; between A and C is 6%
and between B and C is 9%. What is the order of these genes on the chromosome?
o
The frequency of recombination between two genes is directly related to the physical distance between
the genes.
o
In a heterozygote for two linked genes, when both dominant alleles are on one chromosome and both
recessive alleles are on the other, the genes are in coupling
o
Crossing over is more likely to occur between the widely spaced linked genes A and B, or between A
and C, then between the more closely spaced linked genes B and C, because there is more room for an
exchange to occur
 Inheritance of linked genes
o
The genes for Rh factor (R) and anemia (E) are linked, but some recombination occurs between the two
genes
o
Parent 2 (mother) produces 4% recombinant gametes, therefore the Rh factor gene and the anemia
gene are 4 map units or 4 cM apart.
 Linkage map
o
A linkage map is a diagram indicating the relative distance between genes.
o
1% recombination = 1 map unit = 1 centiMorgan (cM)
o
Map distances are additive
 Solving Linkage Problems
o
The genes for Nail-patella syndrome (N) and the ABO blood type (I) are 10 map units apart on
chromosome 9
o
Greg and Susan each have Nail-patella syndrome.
o
Greg has type A and Susan type B blood
o
What is the probability that their child has normal nail and knees and type O blood?
o
The ni sperm would have to fertilize the nioocyte
o
Using the product rule, the probability of a child with nnii genotype is 0.45 x 0.05 = 0.0025 or 2.25%
 Linkage Disequilibrium
o
The non-random association between alleles at two locations on a chromosome is called linkage
disequilibrium
o
The human genome consists of many “LD” blocks where alleles stick together

o
These are interspersed with areas where crossing over is prevalent
Two genes, A and B, exist in a population

If the frequency of chromosomes with AB=Ab=aB=ab then the genes are in equilibrium

If the frequency of one allele of gene A is seen more frequently with a particular allele of gene
B, then the genes are in linkage disequilibrium
 LOD score
o
Is the logarithm of the odds ratio
o
Is a statistical measure of likelihood that two genes are linked at a particular distance
o
LOD scores of 3 or greater are considered significant and indicate the data would be observed by
chance 1 in 1000 times
 Haplotype
o
A haplotype is the set of alleles inherited on one chromosome
o
Each number indicates the allele present for one of 5 genes A-E
o
Make it possible to track specific chromosome segments in pedigrees

o
Disruptions of a marker sequence indicate crossover sites
Examples…
Diseases to know from the Chapter…
 Alkaptonuria (OMIM 203500)
o
Back spasms, spine degeneration, cartilage loss, dark stained diapers, inborn error of metabolism,
pleiotrophic, deficiency of enzyme homogentistic acid oxidase
o
Blackened nails are just one sign of alkaptonuria, an inborn error of metabolism
o
It is pleiotropic
o
Deficiency of the enzyme homogentisic acid oxidase leads to buildup of melanin pigment in urine, nails,
skin and cartilage
 Phenylketonuria PKU (OMIM 261600)
o
Autosomal recessive
o
Unable to breakdown phenyalanine
o
Mental retardation
o
Fair skin
o
Test at birth
o
Special diet
 Porphyria variegata (OMIM 176200)
o
Autosomal dominant
o
Red urine, fever, abdominal pain, headache, insomnia, visual delirium, convulsions, coma, death
o
Variegate porphyria (VP) is an inherited disorder of porphyrin-heme metabolism arising from mutations
of the gene encoding the enzyme protoporphyrinogen oxidase.
o
Manifestations of VP in any given individual may include cutaneous photosensitivity, systemic
symptoms arising from neurologic dysfunction, or both.
o
Pleiotropic
o
Inborn error of metabolism
 Marfan Syndrome (OMIM 154700)
o
Autosomal dominant
o
Flo Hyman was a 6’5” star on the U.S. women’s volleyball team that won a silver medal in the 1984
Olympics. Two years later, at the age of 31, she died in a volley ball game from a ruptured aorta
caused by Marfan Syndrome.
o
The gene responsible for Marfan Syndrome is located on chromosome 15.
o
The normal gene codes for fibrilin, which is part of connective tissue.
o
1 in 10,000 individuals
o
It has been suggested that Abraham Lincoln had Marfan.
o
Long limbs, sucken chest, lens dislocation, spindly fingers, weakened aorta
o
pleiotropy
 Leber Optic atrophy (OMIM 535000)
o
Energy related genes can cause fatigue
o
Mitochondrial disorder
o
A painless loss of central vision between 12 and 30 years of age. Both eyes are affected at the same
time. Males will not pass the gene to any of their children, but females with the mutation will pass it to all
of their children, regardless of whether they are sons or daughters.
 MELHS Mitochondrial myopathy (OMIM 540000)
o
Encephalopathy lactic acidosis syndrome
o
Neuromuscular disorders that all result in a decrease in energy production in the body’s tissues.
o
Short statue
o
Seizures; Stroke-like episodes with focused neurological deficits
o
Recurrent headaches
o
Cognitive regression
o
Disease progression
o
Ragged-red fibers
 Enamel hypoplasia (OMIM 600907)
o
Holes and cracks in baby teath
o
Autosomal dominant
o
Incomplete penetrance and variable expressivity
o
Epidermolysis bullosa (OMIM 226500, 226650, 131750)
o
Intermediate filaments are abnormal
o
Epidermolysis Bullosa (EB) is a rare genetic disease characterized by extremely fragile skin and
recurrent blister formation.
o
An afflicted person's skin is so fragile, that it can tear or blister from what is normally routine activity or
contacts.
o
Approximately 2 out of 100000 Americans are afflicted with this disease.
o
This disease in typically inherited as autosomal dominant.