A mutation is discovered that causes diabetes

in individuals that are either heterozygous or

homozygous for the mutation. When the gene
was characterized, it was found that
heterozygotes have only 1% of the active
enzyme observed in wild-type homozygotes.
What is this mutation best described as?
A) recessive
B) haplosufficiency
C) haploinsufficiency
D) dominant negative

-this is the correct answer, the dominant negative interferes with the product quantity of the
normal(wild type)

HMB265: Human & General Genetics

Lecture 4: Mendelian Traits in
Humans & Human Pedigree
Analysis

Prof. Stephen Wright

Lecture Outline
! Mendelian traits in humans
! Autosomal dominant traits
! Autosomal recessive traits
! Anatomy of a pedigree
! Human pedigree analysis & genetic testing
Reading:
! Hartwell et al, first Canadian Edition, Chapter 2
(emphasis on pages 29-33)

What Makes a Good

Genetic Model Organism?

rapid generation time

easy to grow/breed

can examine large numbers of offspring

can self-fertilize


Arabidopsis thaliana

!"
!"
!"
!"

-weed, used by many geneticists for the genetics of every plant. This is the model
organism for plants

What Makes a Good

Genetic Model Organism?

rapid generation time

easy to grow/breed

can examine large numbers of offspring

can self-fertilize

Caenorhabditis elegans

!"
!"
!"
!"

-model organism for animals. Its a nemotoad. It can also self-fertilize, very rare in animals

What Makes a Good

Genetic Model Organism?

rapid generation time

easy to grow/breed

can examine large numbers of offspring

can self-fertilize


Drosophila melanogaster

!"
!"
!"
#"

-fruit fly, major genetic model system for comparison to humans. Can't self fertilize.
Get inbred lines by incest.

What Makes a Good

Genetic Model Organism?

rapid generation time

easy to grow/breed

can examine large numbers of offspring

can self-fertilize


Mus musculus page 772

!"
!"
!"
#"

-even closer to humans is the mouse. It cannot self-fetilize. Not as fast a

generation time and not as many offspring but they are a good model for
mammanls.

Humans Are TERRIBLE

Genetic Model Organisms!

rapid generation time

easy to grow/breed

can examine large numbers of offspring

can self-fertilize

#"

#"
#"
#"
#"

-Humans are not good genetic model systems. We do

not have rapid genertion time, and easy to breed,
cannot self-fertilize and can't have many offspring. can't
self-fertlize.

Humans are NOT Genetic

Models- Solutions
1) Use other organisms as models:
-to understand our own genetics we use other model systems
to compare to our own genetics.

Humans are NOT Genetic

Models- Solutions
1) Use other organisms as models
2) follow pedigrees

The other solution: use pedigrees:what

happens to traits in families(observe this), can
track how genetics are displayed in humans.

Using Pedigrees to Follow

Genetics
1) Use other organisms as models
2) follow pedigrees

male
female
deceased
affected/
diseased
mating

siblings

How is this disease inherited?

-the disease is recessive, since mom and dad are
heterozygous for the disease but is 50% in the offspring

Mendelian inheritance and humans:

Same principles apply
to a single mendilian gene. If you have two copies of
Albinism -due
little a, you get inactive of tyrosinase enzyme therefore
giving albino for heterozygous.

-Heterozygous is enough for getting pigmented phenotype - haplosufficient.

-two normal A, homozygote, gives proper pigmented gene

Mendelian inheritance and humans:

Same principles apply
Some human traits are simple mendilian gentics

Mendelian inheritance and humans:

Same principles apply
-Mendilian genetic disease.

-Dominant allele

Some diseases are mendilian genetics also, simple(black and white)

Thousands of examples are described in the database:

Online Mendelian Inheritance in Man
www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

Mendelian inheritance and humans:

Autosomal inheritance

Autosomal Inheritance
-Autosomal: non sex chromosomes. Normal Mendelian genetics

! Human autosomal traits are located on the non sex

chromosomes (1-22)
! They may be inherited as:
! Autosomal dominant or
! Autosomal recessive

Mendelian inheritance and humans:

Autosomal inheritance

Autosomal Dominant
affected parent

Aa

unaffected parent

aa

affected, unaffected progeny

-affected parent is usually heterozygous and unaffected is homozygous giving 50/50 progeny.

-unaffected is homozygous not

heterozygous

! Homozygous dominant and heterozygotes exhibit the affected

phenotype
! Males and females are equally affected and may transmit the trait
! Affected phenotype does not skip a generation -if its dominant, it will not be masked in a generation.
-How is individual hetero or homo for the disease: assume that individual with dominant disease(rare in pop'n) that the individual is heterozygous and not
homozygous. The prbobabbility will be the product of the two events(product rule)

Mendelian inheritance and humans:

Autosomal inheritance

Autosomal Recessive
unaffected parent

Aa

unaffected parent

Aa

1/4 affected, 3/4 unaffected progeny

! Only homozygous recessive individuals exhibit the affected
phenotype If both parents are heterozygotes, they are unaffected but carry the disease silenty therefore lead to 1/4 progeny affected.
! Males and females are equally affected and may transmit the
trait
! May skip generations

Mendelian inheritance and humans

Pedigrees are used to study human genetics
! Cannot do controlled breeding experiments on humans,
use model organisms and human pedigrees to dissect
Mendelian traits of interest
! Pedigrees are an orderly diagram of a family s relevant
genetic features extending through multiple generations
! Pedigrees help us infer if a trait is from a single gene
and if the trait is dominant or recessive

Anatomy of a pedigree

-this is something figured out in the pedigree,

carriers of recessive disease.

-mating amongst relatives. The expresson of rare

genetic disase comes up when there is inbredding
event

Mendelian Inheritance of Huntington s Disease

-Dominant allele disorder - Huntingstons, but shows up in individuals later in life.

Anatomy of a pedigree

Huntington s disease: A rare dominant trait

It shows up in most generations since the disease is dominant. The inbred generation got 14 unaffected kids even though the parents were affected. This
means the parents were heterozygous.

Recognizing dominant & recessive traits in pedigrees

Dominant Traits
! Affected children always have at least one affected
parent -cant skip generations
! the trait tends to show up every generation
! Two affected parents can produce unaffected children,
if both parents are heterozygotes like in the inbred case.

Recognizing dominant & recessive traits in pedigrees

Recessive Traits
! Affected individuals can be the children of two unaffected
carriers, particularly as the result of consanguineous
matings -carrier = heterozygote not expressing the disease.
! All the children of two affected parents should be affected
-both parents are homozygous therefore children should have the disease, purebred

Recognizing dominant & recessive traits in pedigrees

Recessive Traits
-non tasting is recessive and tasting is dominant.

Recognizing dominant & recessive traits in pedigrees

-cystic fibrosis, rare recessive disease

-for rare recssive, we assume individuals are homozygous for non
disease allele.e
-7-1, the parents must be heterozygous since they did not express the
disease but the 7-1 did.
-5-1, and 5-2 both got their recessive alele from shared ancestors. The
1-1 or 1-2 must have had the reessive allele since only at least 50% did
not have the recessive allele.

Consangineous mating

A Pedigree with Consanguinuity

(inbreeding)
Frequently uncovers traits that
are recessive
Can give rise to inbreeding
depression - offspring that are
less fit than their parents

Solving pedigrees - deducing mode of

inheritance and associated genotypes

Solving pedigrees - deducing mode of

inheritance and associated genotypes

Solving pedigrees - deducing mode of

inheritance and associated genotypes

6-4, means that this parents must be heteroygous for the diseae

Solving pedigrees - deducing mode of

inheritance and associated genotypes

Solving pedigrees - deducing mode of

inheritance and associated genotypes

-Cystic fibrosis was heterozygous reessive in the pedirgree

Solving pedigrees - deducing mode of

inheritance and associated genotypes
or

Solving pedigrees - deducing mode of

inheritance and associated genotypes

2- unaffected individuals
gives rise to 2 afffected
individuals due to
inbreding

Solving pedigrees - deducing mode of

inheritance and associated genotypes

Solving pedigrees - deducing mode of

inheritance and associated genotypes

Solving pedigrees - deducing mode of

inheritance and associated genotypes

-unaffected offspring means that they can be

hetero or homo, we need to see their offspring to
know.

Fig 2-21

Solving pedigrees - deducing mode of

inheritance and associated genotypes

Fig 2-21

Solving pedigrees - deducing mode of

inheritance and associated genotypes

Fig 2-21

Solving pedigrees - deducing mode of

inheritance and associated genotypes

Fig 2-21

Solving pedigrees - deducing mode of

inheritance and associated genotypes

-individuals in generation 3 can be

Big A little a or big A big A.

Fig 2-21

Solving pedigrees - deducing mode of

inheritance and associated genotypes

-patrents in generation 1, one must be

heterozygous

Fig 2-21

Solving Genetics Problems

! List genotypes and phenotypes for the trait

! Determine the genotypes of the parents
! Determine the parents possible gametes
! Determine the possible genotypes of offspring
! Repeat for successive generations
! is the trait rare or common in the population?
rare = random individuals will not have the disease, but if its common, a random will have it.

Genetic Predictions
Can make predictions based on
Mendelian Laws
Example:
Ellen s brother Michael has cystic fibrosis, an
autosomal recessive disease. No other family members have
the disease
What is the probability that Ellen s child has a
cystic fibrosis-causing allele?

-Child can be heterozygous

Genetic Predictions

Ellen and Michael s parents must be

heterozygous
ellen is either heterozygous or homozygous

Probability Ellen is a carrier = 2/3

-probability that she is heterozygous

Probability child inherits cystic fibrosis allele =

Probability child carries cystic fibrosis allele from Ellen
= 2/3 x 1/2 = 1/3
ss

-product rule, both of these things have to happen.

Genetic Predictions = Genetic Counseling

Genetic counseling sessions:
! Family history
! Pedigree construction
! Information provided on specific disorders, modes of
inheritance, tests to identify at-risk family members
! Testing arranged, discussion of results
! Links to support groups, appropriate services
! Follow-up contact

Issues associated with genetic screening

! Why carry out genetic screening at all?
! When is a test accurate and comprehensive enough to
be used as the basis for screening?
! Once an accurate test becomes available at reasonable
cost, should screening become required or optional?
! If a screening program is established, who should be
tested?
! Should private companies and insurance companies
have access to employee and client test results?
! What education needs to be provided regarding test
results?

Questions 1 and 2 are based on the Kirk family pedigree

shown below. This family is affected by the disease,
Tay-Sachs. It is a recessive trait that is rare in most
populations, so assume that individual II-3 is
homozygous dominant.

II

III

1) What is the probability that the first child of III-1 and III-2
is affected by Tay-Sachs disease?

A) 1/12
B) 1/6
C) 1/4
D) 1/8

-Correct answer,whats the probability that both parents will be heterozygous, then look t probabbility of child having the disease.
Assume random individual is Dominant(AA) since the disease is rare. Mom (3-1) is 1/2 x1/2 and te dad is 2/3 x 1/2 = 1/12
II

III

2) If the first child of III-1 and III-2 is affected, what is the

probability that the second child is a girl and is also
affected by Tay-Sachs disease?

A) 1/8
B) 1/4

-correct answer, we already know that they have an infectd kid. We alredy know that the parennts are heterozygous therefore its a
1/4 chance that the child has the disease and 1/2 chance thats its a girl. Product rule

II

C) 1/12
D) 1/6

III