Factors affecting Mendelian genetics

▶ GENETICS – branch of biology that deals with heredity and

variation of organisms.
▶ Genotype – the genetic makeup of an organisms
▶ Phenotype – the physical appearance
of an organism (Genotype + environment)

▶ Monohybrid cross: a genetic cross involving a single pair of

genes (one trait); parents differ by a single trait.
▶ P = Parental generation
▶ F1 = First filial generation; offspring from a genetic cross.
▶ F2 = Second filial generation of a genetic cross

▶ Dihybrid crosses
▶ Matings that involve parents that differ in two genes (two
independent traits)
1. Describe Mendel’s conclusions about how traits are
passed from generation to generation?

2. What is the chromosome theory of inheritance and

how is it related to Mendel’s finding?

3. Define genotype and phenotype and describe how

they are related?
Homozygous – having identical genes (one from each parent) for a particular
characteristic.

Heterozygous – having two different genes for a particular characteristic.

Dominant – the allele of a gene that masks or suppresses the expression of

an alternate allele; the trait appears in the heterozygous condition.

Recessive – an allele that is masked by a dominant allele; does not appear in

the heterozygous condition, only in homozygous.

Allele – two genes that occupy the same position on homologous

chromosomes and that cover the same trait (like ‘flavors’ of a trait).
 Mendel’s Garden Peas
➢ Mendel observed seven characteristics of pea plants:
1. Plant height (traits: long and short);
2. Flower position along stem (traits: axial and terminal);
3. Pod color (traits: green and yellow);
4. Pod appearance (traits: inflated and constricted);
5. Seed texture (traits: round and wrinkled);
6. Seed color (traits: yellow and green);
7. Flower color (traits: purple and white).
Mendel’s Principles
1. Principle of Dominance:
One allele masked another, one allele was dominant over
the other in the F1 generation.

2. Principle of Segregation:
When gametes are formed, the pairs of hereditary factors
(genes) become separated, so that each sex cell (egg/sperm)
receives only one kind of gene.

3. Principle of Independent Assortment:

“Members of one gene pair segregate independently from
other gene pairs during gamete formation”
Recessive allele - Represented with lowercase latter (r)
- Both recessive alleles must be present (rr) for the
expression of the trait.
Recessive allele: An allele which is expressed only in
homozygotes, but remains unexpressed in heterozygotes.
rr --------- Recessive trait expressed
(white flower)
Rr ------ Recessive trait NOT expressed
(purple flower)
When you have an individual with an unknown genotype,
you do a test cross.

Test cross: Cross with a homozygous recessive

individual.

For example, a plant with purple flowers can either be

PP or Pp… therefore, you cross the plant with a pp
(white flowers, homozygous recessive)
P ? × pp
 Mendel’s experiments

➢ Experiments involved crossing varieties of pea plants that differed from one
another in a single characteristic - trait

The first thing Mendel did was create a “pure” generation or true-breeding
(plants that self­pollinate and all of their offspring are homozygous) generation

True-breeding plants receive only the dominant factors or the reccessive

factors from each of their parents

Non-true-breeding plants were hybrids, which received the dominant and the
recessive factors in equal shares

➢ He made sure that certain pea plants were able to self pollinate (Pollination is
the act of transferring pollen grains from the male anther of a flower to the
female stigma), eliminating unwanted traits.
 Analyzing results of Mendel’s dihybrid crosses
Mendel also made experiments observing two characters
simultaneousely – two-factor cross or dihybrid cross.

The contrasted alleles for the genes of seed shape and seed
color assort independently from one another during gamete
formation

Mendel’s law of independent assortment

The distribution of alleles for one trait into the gametes

does not affects the distribution of alleles for other traits
 Allele interactions:
Incomplete dominance and Codominance
Codominance occurs when two versions, or “alleles,” of the same gene are
present in a living thing, and both are expressed.
Some alleles are neither dominant nor recessive (incomplete dominance
and co-dominance)
1. Incomplete/partial dominance - When the phenotype of a heterozygous
(Tt) offspring differs from either homozygous parent (TT & tt)
There is “blending” of phenotypes

2. Co-dominance – when two different alleles are fully and

simultaneously expressed in a heterozygote.
Ex: Human MN blood groups. Antigen called glycoprotein (L) is present
on the RBC membrane.
The blood type is due to a glycoprotein present on the surface of red blood
cells, which behaves as a native antigen. 

 
Incomplete dominance : dominance is not necessarily all-
or-none phenomenon
Polymorphism
When more than two distinct phenotypes are present in a population due to multiple
allelism, the trait is polymorphic

Genetic polymorphism - is the occurrence in the same population of two or more

alleles at one locus, where the minimum frequency is more than 1%.

Polymorphism is NOT a mutation!

Hair color
Eye color

Tissue type (HLA alleles) -The human leukocyte antigen (HLA) system or complex is

a gene complex encoding the major histocompatibility complex (MHC) proteins in
humans. These cell-surface proteins are responsible for the regulation of the immune
system in humans.
 Pleiotropy

When expression of a single gene has multiple phenotypic effects

A gene that influences many traits is said to be pleiotropic

1 gene has greater than 1 effect on phenotype!

Ex: Marfan syndrome
Polygenic traits

Polygenic traits – when several genes influence one particular

trait/characteristic.

Each gene adds a small amount to the value of the phenotype

Ex: Skin color (3 major genes), Eye color (~15 genes, 2

most important), Hereditary deafness (over 50 genes involved
in the ability to discern sound)

Epistasis - the expression of a gene or gene pair masks or

modifies/changes the expression of another gene.
Expressivity and penetrance
1. Penetrance – is the % of individuals that express phenotype
for a particular genotype. Influenced both by genetic and
environmental factors. Full penetrance – 100%, Reduced
penetrance – less than 100%

Ex: Osteogenesis imperfecta (OI) – disorder characterized by

bones that easily break, because of a deficiency of Type-1-collagen
caused by mutations in the COL1A1 and COL1A2 genes.  70%
penetrated & 30% normal.

2. Expressivity – the degree for which a phenotype for a

given trait is expressed (the severity of a condition).
Expressivity is measured only when there is 100% penetrance.

Ex: Neurofibromatosis (NF1)

Pedigrees

Single-gene disorders are characterized by their patterns of

transmission in families.

To establish the pattern of transmission, a usual first step is to

obtain information about the family history of the patient and
to summarize the details in the form of a pedigree, a graphical
representation of the family tree.
 Chromosomal Theory of Inheritance

▪ In 1888 scientists gave the name chromosomes to the discrete

threadlike bodies that forms as nuclear material condenses during
these processes of cell division (mitosis and meiosis)
▪ Sutton suggested that if Mendel’s hypothesis were correct , then
each gamete must make equal hereditary contributions
▪ He noted that chromosomes are in pairs and segregate during
meiosis
▪ Behavior of chromosomes during meiosis paralleled the behavior
of the hereditary factors
▪ Mendel’s factors were located on chromosomes.
 MENDELIAN INHERITANCE

The patterns shown by single-gene disorders in pedigrees

depend chiefly on two factors:

1. whether the phenotype is dominant (expressed when only

one chromosome of a pair carries the mutant allele and
the other chromosome has a wild-type allele at that locus)
or recessive (expressed only when both chromosomes of a
pair carry mutant alleles at a locus);
2. the chromosomal location of the gene locus, which may be
on an autosome (chromosomes 1 to 22) or on a sex
chromosome (chromosomes X and Y).

The majority of loci on the X show X-linked inheritance

because they participate in meiotic recombination only during
female gametogenesis, when there are two X chromosomes,
but cannot recombine with the Y during male gametogenesis.
Autosomal and X-Linked Inheritance

Whether an abnormal gene is on an autosome or is X-linked has a profound

effect on the clinical expression of the disease.

First, autosomal disorders, in general, affect males and females equally.

For X-linked disorders, the situation is quite different.
Males have only a single X and are therefore hemizygous with respect to X-
linked genes;
46,XY males are never heterozygous for alleles at X-linked loci, whereas
females can be heterozygous or homozygous at X-linked loci.

Second, to compensate for the double complement of X-linked genes in

females, alleles for most X-linked genes are expressed from only one of the
two X chromosomes in any given cell of a female.
Dominant and Recessive Inheritance

Recessive Inheritance As classically defined, a phenotype expressed only in

homozygotes (or, for X-linked traits, male hemizygotes) and not in
heterozygotes is recessive.

Most of the recessive disorders described to date are due to mutations that
reduce or eliminate the function of the gene product, so-called loss-of-
function mutations.
For example, many recessive diseases are caused by mutations that impair or
eliminate the function of an enzyme.
These are usually inherited as recessive diseases because heterozygotes, with
only one of a pair of alleles functioning and the other (abnormal) allele not,
can typically make sufficient product (∼50% of the amount made by wild-type
homozygotes) to carry out the enzymatic reaction required for normal
physiological function, thereby preventing disease.
Dominant Inheritance

A phenotype expressed in both homozygotes and heterozygotes

for a mutant allele is inherited as a dominant.

Dominant disorders occur whether or not there is normal gene

product made from the remaining normal allele.

In a pure dominant disease, homozygotes and heterozygotes for

the mutant allele are both affected equally.

Pure dominant disorders rarely if ever exist in medical genetics.

On occasion, phenotypic expression of two different alleles for a

locus occurs, in which case the two alleles are termed codominant.
One well-known example of codominant expression is the ABO blood
group system.
Most commonly, dominant disorders are more severe in
homozygotes than in heterozygotes, in which case the disease is
called incompletely dominant (or semidominant).

However, mutant alleles are often referred to as dominant or

recessive on the basis of whether they can cause a change in
phenotype in the heterozygous or homozygous state, respectively.

Consequently, the terms dominant allele or gene and recessive

allele or gene are widely used.
FACTORS AFFECTING PEDIGREE PATTERNS

Penetrance and Expressivity

Many genetic conditions segregate sharply within families; that is,

the abnormal phenotype can be readily distinguished from the
normal one.

Phenotypic expression of an abnormal genotype may be modified

by the effects of aging, other genetic loci, or the effects of
environment.

These differences in expression can often lead to difficulties in

diagnosis and pedigree interpretation.
There are two distinct ways in which such differences in
expression can occur: reduced penetrance and variable
expressivity.

Penetrance is the probability that a gene will have any phenotypic

expression at all.

When the frequency of expression of a phenotype is less than

100%—that is, when some of those who have the appropriate
genotype completely fail to express it—the gene is said to show
reduced penetrance.
Penetrance is an all-or-none concept.

It is the percentage of people with a predisposing genotype

who are actually affected, at least to some degree.

Expressivity is the severity of expression of the phenotype

among individuals with the same disease causing genotype.

When the severity of disease differs in people who have

the same genotype, the phenotype is said to have variable
expressivity.
Some of the difficulties raised by age-dependent penetrance and variable
expressivity in understanding the inheritance of a disease phenotype are
demonstrated by the autosomal dominant disease neurofibromatosis (NF1).

NF1 is a common disorder of the nervous system, the eye, and the skin that
occurs in approximately 1 in 3500 births.

NF1 is characterized by
growth of multiple benign fleshy tumors,
neurofibromas, in the skin;
presence of multiple flat, irregular pigmented skin lesions known as café au lait
spots;
growth of small benign tumors (hamartomas) called Lisch nodules on the iris of
the eye;
and less frequently, mental retardation, central nervous system tumors, and the
development of cancer of the nervous system or muscle.
NF1 was first fully described by the physician von Recklinghausen
in 1882, but the disease has probably been known since ancient
times.

Although adult heterozygotes almost always demonstrate some

sign of the disease (penetrance is therefore said to be 100% in
adults), some may have only café au lait spots, freckles on the
axillary skin, and Lisch nodules, whereas others may have life-
threatening benign tumors involving the spinal cord or malignant
sarcomas of an extremity.
Diagnosis is further complicated in children because the signs
develop gradually during childhood. For example, in the
newborn period, less than half of all affected newborns show
even the most subtle sign of the disease, an increased
incidence of café au lait spots.

Penetrance, therefore, is age dependent.

Many different mutations have been found in the NF1 gene, all
of which appear to cause loss of function of its gene product,
neurofibromin.
Approximately half the cases of NF1 result from a new rather
than an inherited mutation.
The chief genetic problem in counseling families of patients with NF1 is to
decide between two equally likely possibilities:

Is the disease in the proband (the member through whom a

family with a genetic disorder is first brought to the attention of
the geneticist is the proband) sporadic, that is, due to new
mutation,or has the patient inherited a clinically significant
form of the disorder from a parent in whom the gene is
present but only mildly expressed?

If the proband has inherited the defect, the risk that any of his or her sibs
will also inherit it is 50%; but if the proband has a new mutant gene, there is
very little risk that any sib will be affected.

Significantly, in either case, the risk that the patient will pass the gene on to
any one of his or her offspring is 50%.
In view of these uncertainties, it is reassuring to families of
patients with NF1 to know that the disorder can be detected
presymptomatically and even prenatally by molecular
genetic analysis.

Except for the association of complete gene deletions with

dysmorphic features, mental retardation, and increased
number of neurofibromas at an early age, there is no
correlation between severity of the phenotype and particular
mutant NF1 alleles.
Another example of an autosomal dominant malformation with reduced
penetrance is the split-hand deformity, a type of ectrodactyly (Fig. 7-5).

The malformation originates in the sixth or seventh week of development, when

the hands and feet are forming.

The disorder demonstrates locus heterogeneity, with at least five loci recognized,
although the actual gene responsible has been identified in only a few.

Failure of penetrance in pedigrees of split-hand malformation can lead to

apparent skipping of generations, and this complicates genetic counseling
because an at-risk person with normal hands may nevertheless carry the gene for
the condition and thus be capable of having children who are affected.