C

1. Principle of segregation- allele pairs separate or segregate during gamete formation

(meiosis), and randomly unite at fertilization

Segregation of alleles in the production of sex cells

According to the principle of independent assortment, different pairs of alleles are passed to
offspring independently of each other.

2. Punnet square- used to predict an outcome of a particular cross or breeding experiment

B b

B BB Bb

B bB Bb

This cross yeilds three possible genotypes in the offspring - BB, Bb, and bb. The punnett square
also indicates how likely a particular child of this mating is to have a given genotype. In this
case, there is a one in four (25%) chance that the child would be BB, two in four (50%) that it
would be Bb and one in four (25%) that it would be bb. On average only 25 % will be bb.
However, remember that this is a separate combination of egg and sperm. It is possible to get
four out of four bb children from this cross. It is simply less probable than one out of four
having a genotype of bb.

Punnett Square for a dihybrid cross (two traits):

Gene 1: A-dominant, a-recessive
Gene 2: C-dominant, c-recessive
Parents are heterozygous for both genes
Parent 1: Genotype=AaCc
Parent 2: Genotype=AaCc
Gene 1 A A a a
Gene 2 C c C c
A AA AA Aa Aa
C CC Cc CC Cc
A AA AA Aa Aa
c Cc cc Cc cc
a Aa Aa aa aa
C CC Cc CC Cc
a Aa Aa aa aa
c Cc cc Cc cc
3. Multiplication rule: estimates the probability that two independent events will occur
together. Blank event “AND” blank event.
Say a couple wants to know the probability all of their planned kids will be girls. Mating of eggs
and sperm is an independent event: ½ x ½ x ½ = 1/8
If couple already has one girl and wants to know the probability of having two more. ½ x ½ = ¼

Addition rule: wish to know the probability of either one outcome “OR” another, add the
probabilities.
Example: the probability of producing three girls or three boys: 1/8 + 1/8, or 1/4. The
probability of having some combination of boys and girls is 3/4, because the sum of all
possibilities must equal 1.

4. Genotype is the genetic makeup of an organism

phenotype -physical or clinical characteristics

5.List the characteristics of dominant phenotype and genotype

A dominant phenotype is the result of either homozygous for dominant gene or heterozygous
genotype.
In pedigrees . . .
-the first two sexes exhibit the trait in approximately equal proportions, and males and females
are equally likely to pass the trait (this tells you it is Autosomal and not x-linked).
-trait shows up in each generation (no skipping) called vertical transmission
-if neither parent has the trait – none of the children will have it
-father son inheritance may occur (rules out x-linked)

6. Describe the recurrence risks of dominant and recessive disorders

Recurrence risk is given to parents who have conceived two or more diseased children. The
recurrence risk is the probability that subsequent children will have the disease.

Occurrence risk is when parents who are known to have a risk have not yet had any children.

Autosomal dominant diseases: occur 1/200 individuals, they are rare. The most common
diseases have frequencies of 0.001. Mating is usually between affected and normal, and their
offspring have a probability of 0.5 that they will be affected. Each birth is an independent
event, so even if the parents have already had a child or several children with the disease, their
recurrence risk remains 50%.

Autosomal recessive inheritance – rare, heterozygous carriers for recessive disease genes are
much more common than affected homozygotes. Parents of affected kids with autosomal
recessive diseases are usually heterozygous carriers.
In pedigree chart . . .
-observed in one or more siblings but not in earlier generations
-males and females affected in equal proportions (ruling out x-linked)
-if two affected individuals (who have a recessive disease) mate, all offspring will be affected
The recurrence risk for Autosomal recessive diseases is usually 25 % when both parents are
heterozygous. If a heterozygous individual mates with an individual who is homozygous for the
recessive disease gene, the recurrence risk is 50% - this is also called quasidominant
inheritance.

7. New mutaions: an alteration in DNA sequence that appears for the first time in a family as
the result of a mutation in one of the parents’ germ cells. A gene transmitted by one of
the parents DNA mutated to a disease-causing allele. Especially likely if the disease in
question is autosomal dominant. Recurrence risk for the parents’ subsequent offspring
would not be elevated; however, offspring of the affected child may have high risk (50 %
if autosomal dominant).

Germline mosaicism: during embryonic development of one of the parents, a mutation

occurred that affected all or part of the germ line, but few or none of the somatic cells
of the embryo contain mutated DNA. Parent carries the mutation in germ line, but
doesn’t have the disease. A mosaic parent usually has more than one affected child.
Delayed age of onset: don’t have disease symptoms until adulthood. The delay of onset
reduces natural selection against a disease gene. Huntington’s disease, a neurological
disorder resulting in adult dementia and uncontrolled limb movement. Those who get it
usually have already had children. This is bad because Huntington’s is an Autosomal
dominant disorder – so 50 % of kids will get it.
Reduced Penetrance: describes the situation in which individuals who have a disease-causing
genotype do not develop the disease phenotype. So not all individuals with a mutant
genotype show the mutant phenotype. They can transmit the disease gene to the next
generation. In retinoblastoma, an Autosomal dominant disorder, 10% of the obligate
carriers (who have parents and kids with it) do not have the disease. Thus, the
penetrance is 90%.
Variable expression: a trait in which the same genotype may produce phenotypes of varying
severity or expression. Realize that penetrance is an all-or-none phenomenon: you have
a disease phenotype or you do not. Variable expression refers to the extent of
expression of the disease phenotype. (ex: neurofibromatosis type 1). The causes of
variable expression are not known. In the absence of certain environmental factors the
gene is expressed less. Also modifier genes may interact with the disease gene.
Consanguinity: mating of related individuals. More often in autosomal recessive diseases.
Pleitrophy: describes genes that have multiple phenotypic effects (examples: Marfan
syndrome, cystic fibrosis)
Heterogeneity, allelic: describes conditions in which different alleles at a locus can produce
variable expression of a disease. Depending on phenotype definition, allelic
heterogeneity may cause two distinct diseases, as in Duchenne’s and Becker muscular
dystrophy.
Heterogeneity, locus: mutations at two distinct loci can produce the same disease phenotype
(examples: osteogenesis imperfect; retinitis pigmentosa; polycystic kidney disease).
D
1,2,3. Look up the following in figure 4.5 and in the hand out.
Male
Female
Affected
Carrier
Deceased
Lines for mating
Lines for parentage
Lines for offspring
Consanguinity
Identical twins
Fraternal twins

4. Autosomal Dominant:

 50% recurrence risk

 Vertical transmission pattern (no generation
skips)
 Males and females affected equally (usually)
 Father-son transmission

Autosomal Recessive Pedigree: Affected individual has two

copies of the mutant allele. When just one copy of the
mutant allele is present, an individual is a carrier of the
mutation, but does not develop the condition. Females and
males are affected equally. When two carriers mate, each
child has a 25% chance of being homozygous wild-type Affected individuals are
(unaffected); a 25% chance of being homozygous mutant indicated by solid black
(affected); or a 50% chance of being heterozygous symbols and unaffected
(unaffected carrier). Horizontal transmission; seen in carriers are indicated by
multiple siblings, but not in earlier generations. the half black symbols.

5. Distinguish the circumstances in which carriers will or will not be indicated on a pedigree
that you must interpret.
Carriers are indicated by half-filled symbols. Female carriers of x-linked recessive gene have a
dot in the center. Carriers are not always included in pedigrees that you will analyze – say they
have not yet been genetically tested, ect. Only info that is accurate is in the pedigree.

6. Use a pedigree to determine the coefficient of relationship of individuals.

Coefficient of relationship is a measure of the proportion of genes that are shared by two
related individuals. Look at blue box 4.2 in detail.
E Sex-Linked and Nontraditional Inheritance
1. Describe the key characteristics of the Lyon hypothesis with regard to X chromosome
inactivation that is random, fixed (permanent), and incomplete.
Lyon hypothesis: one X chromosome is randomly inactivated in each somatic cell of the normal
female embryo (lionization). This ensures that females, who have two copies of the X
chromosome, make X-linked gene products in quantities similar to those produced in males –
process called dosage compensation. mRNA is only transcribed from one X chromosome in each
cell. The inactive X chromosome is observed as a Barr body in the somatic cells of females.
Inactivation occurs early in female embryonic development where the X from the father is
inactivated in some cells and the X from the mother is inactivated in other cells (random
process so about half of each). Once an X chromosome is inactivated, it stays inactive in all
descendants of that cell. Thus X inactivation is randomly determined, but fixed. Females are
mosaics of the two populations. Males have one copy of the X and are hemizygous for the X
chromosome (hemi = half).

X-linked recessive albinism is an example. Males with mutation in their X show uniform lack of
melanin, but females with the mutation have alternating patches of pigment and non-
pigmented areas.

Inactivation is permanent with one exception. Inactive X chromosome gets reactivated in the
female’s germ line so each egg cell receives one active copy of the X chromosome.

If the extra X chromosomes are no longer active then why are people with extra or missing X
chromosomes phenotypically still messed up? X inactivation is incomplete, about 15 % of the X
genes stay active, the majority of these are on the short arm of the X an area which has many
genes homologous to the Y chromosome.

2. Describe the pedigree of X-linked recessive and dominant disease with regard to
inheritance in males and females.
X-linked recessive disorders in females: generally carriers
-in most cases must have both mutated genes in order to have the disorder
-disease frequency of q2
-heterozygotes is able to produce about 50 % of the normal level of gene product –
usually enough for a normal phenotype.
- rarely heterozygous females can be affected. This is because X inactivation is a random
process, some female heterozygotes may experience inactivation of most of the normal
X chromosomes in their cells- these individuals are called manifesting heterozygotes.
Usually only mildly affected.
X-linked recessive disorders in males: if recessive disease gene on the X is inherited, he will be
affected because the Y does not carry a normal allele to compensate.
-gene frequency of q
Pedigrees for X-linked recessive diseases
-trait is seen much more frequently in males
 - X linked genes are not passed from father to son.
-X-linked disease allele can be transmitted through a series of phenotypically normal
heterozygous females – skipping generations.
-an affected father passes the gene to all of his daughters, who as carriers, give it to half
of their sons, who are affected.
-fig 5.5

X-linked dominant disease in females:

-have one mutant X chromosome
-milder expression of X-linked dominant traits
Males: get the disorder less often
-inheritance of X-linked dominant gene is lethal in some diseases
X-linked dominant pedigree:
-an individual need inherit only one copy of an X linked dominant disease gene to be
affected.
-women are twice as likely to have the disease. Females have two X chromosomes,
either which can carry the disease gene.
-affected fathers cannot transmit the trait to their sons, but all daughters have the
disease gene and are affected.
-affected females have a 50% chance of passing the disease allele to their kids.
-usually no generation skipping
-fig 5.9
Example: hypophospatemic rickets, Rett syndrome, incontinentia pigment type 1 disorder
3. Describe Barr bodies in female somatic cells with regard to the XIST gene product (RNA),
methylation of CG dinucleotides, and the number in normal females and aneuploid
females, e.g. XXX.
XIST gene is located in the X inactivation center and is required for X inactivation. It codes an
RNA product that coats the inactive X chromosome. X inactivation is also associated
with methylation of the inactive X chromosome – to ensure long-term stability of
inactivation.
Barr body: the inactive X chromosome, visible as a densely staining chromatin mass in the
somatic cells of normal females. Also called sex chromatin. It is noticeable because its
DNA is replicated later in the S phase as compared to other chromosomes. The number
of Barr bodies in somatic cells is always one less than the number of X chromosomes.
Normal females have one Barr body. Aneuploid females XXX have two Barr bodies.

4. Describe the father-son transmission of a disease gene in X-linked and Y-linked traits.
X linked genes are not passed from father to son.
Y-linked or holandric transmission of a disease gene only occurs from father to son.

5. Describe the symptoms and molecular defects for the X-linked disorders Hemophilia A,
Duchenne’s muscular dystrophy and color blindness

Hemophilia A: X –linked recessive. Females are carriers. Males are affected. Deficiency of
factor VIII, defects in intrinsic coagulation cascade lead to increased PTT.
Macrohemorrage – hemarthroses (bleeding in joints), and easy bruising.

Duchenne’s muscular dystrophy: X – linked recessive frame-shift mutation deletion of

dystrophin gene accelerated muscle breakdown. Weakness starts in pelvic girdle
muscles and progresses superiorly. Pseudohypertrophy of calf muscles due to fibrofatty
replacement of muscle; cardiac myopathy; respiratory compromise. Use of Gowers’
maneuver, kids walk up with their hands to stand. Onset is before 5 years of age.
Diagnose by increased CPK and muscle biopsy.

Trichromatic - normal color vision - requires rod cells (contain light absorbing rhodopsin) and all
three classes of cone cells (contain light absorbing opsins that react to red, green, and
blue)
These genes have been mapped:
-Rodopsin gene (chrom 3)
-Blue opsin gene (chrom 7)
-To have normal red –green color vision – need one red and one to several green
genes located on the X chromosome
Monochromacy – true colorblindness, the ability to only perceive one color. Two forms:
1. Rod monochromacy –autosomal recessive condition which all visual function is
carried out by the rods. Missing all opsin genes.
2. Blue cone monochromacy – X-linked recessive, both red and green cones are absent.
The red and green genes located on the X chromosome are so similar that they get mixed up
during meiosis, a process called unequal crossover. The result is loss of chromosome material
on one homolog and a gain of material on the other. One gene can flip with another or with
two. Also crossover can occur within the red and green genes, yielding new gene hybrids called
fusion genes – give rise to perception changes. This leads to many different ranges of color
deficits. Red green perception changes are the most common defects.
Dichromatic – can’t perceive one primary color
Deuteranopia – can’t perceive green
Protanopia- can’t perceive red
Deuteranomalous – altered perception of green
Protanomalous-altered perception of red

6. Describe the basis for Fragile X syndrome and explain the unusual inheritance pattern
seen in some individuals
Fragile X syndrome: X linked defect affecting the methylation and expression of the FMR1
gene. Trinucleotide repeat disorder (CGC)n. Associated with chromosomal breakage.
The 2nd most common cause of genetic mental retardation (after down syndrome).
Findings: macro-orchidism (enlarged testies), long face with a large jaw, large everted
ears, autism. Affects males more. Has less penetrance in females, as well as variability
in expression bc females have 1 normal chromosome and variation in X-inactivation.
The inheritance is unusual: mothers of transmitting males had lower proportion of affected
sons than did the daughters of these males. Daughters of transmitting males were never
affected, but their sons could be. This is called the Sherman paradox as it doesn’t follow
typical X-linked inheritance rules. The permutations of the gene worsen with each
generation. Generation I transmitters might have 50-55 CGC repeats, with each
generation there are more repeats. Finally at generation V affected individuals have
>230 CGC repeats and have full blown Fragile X syndrome.

7. Describe the unique features of mtDNA with regard to the following:

-Shape & Size: double-stranded circular
-MtRNAs: mitochondrial genome makes 22 transfer RNAs
-Respiratory proteins subunits (oxidative phosphorylation): are a combination of 13
mitochondrial genome derived polypeptides and about 90 nuclear DNA derived
polypeptides (transferred into mitochondrial matrix).
-mtDNA transcription occurs in mitochondria
-mtDNA mutation rate: 10 X higher than nuclear DNA. Reasons: no DNA repair mechanisms in
the mtDNA and lots of free oxygen radicals released by oxidative phosphorylation.
-Introns: mtDNA has none
-Several copies per organelle.
-Mt DNA’s hetero- & homoplasmy: Each cell has a population of mtDNA. One cell can have
some mutated and some normal mtDNA molecules. Results in variable expression in
mitochondrial diseases where greater mutated population of mtDNA leads to more
severe disease phenotypical expression.
-mtDNA is inherited maternally only
8. Describe what effects heteroplasmic mtDNA and nuclear DNA have on the phenotypic
expression of mtDNA. Described above.

9. mitochondrial disorders
LHON-leber hereditary optic neuropathy
mutation type: missense mutation in protein coding mtDNA
presence of heteroplasmy: rare, expression is uniform
symptoms: rapid loss of vision in central visual field as a result of optic nerve death,
begins when individual is about 30 years old.
MERRF –myoclonic epilepsy with ragged-red fiber syndrome
mutation type: single base mutations in a tRNA gene
presence of heteroplasmy: yes, highly variable in expression
symptoms: epilepsy, dementia, ataxia (uncoordinated muscle movement), and
myopathy (muscle disease).
MELAS – mitochondrial encephalomyopathy and stroke-like episodes
mutation type: single base tRNA mutation
presence of heteroplasmy: yes, highly variable in expression
symptoms: encephalomyopathy, stroke-like episodes.

10. Describe the inheritance pattern of a mutation where genomic imprinting occurs and
the features expected in a pedigree of such a disorder
In most cases the phenotype is the same no matter if a gene was paternally or maternally
inherited. But in some cases a “critical region”, which codes for several genes, is only active on
the chromosome inherited from the father and not active on the chromosome inherited from
the mother (and the other way around). If the single copy on the active gene is lost, then the
disease occurs. Thus, disease genes can be expressed differently depending on whether it was
inherited maternally or paternally – process called genomic imprinting. Inactive gene is
“imprinted”. Look at pedigree diagram for Prader-Willi syndrome and angelman syndrome.

11. Explain triplet repeat expansion and its relation to genetic disorders and the
phenomenon of “anticipation”.
Anticipation – progressively earlier or more severe expression of a disease in more recent
generations. Triplet repeat expansion has been shown to cause anticipation. Myotonic
dystrophy, an autosomal disease, results from a mutation of the expanded CTG trinucleotide
repeat. # repeats increases with each generation. The severity of the disease increased with
the # of repeats – expanded repeats decrease production of protein kinase (resulting in cardiac
conduction defects) and expanded repeats mess up RNA binding proteins producing myotonic
myopathy.