of 50
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A mutation is discovered that causes diabetes
in individuals that are either heterozygous orhomozygous 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) haplosufficiencyC) haploinsufficiency
D) dominant negative -this is the correct answer, the dominant negative interferes with the product quantity of thenormal(wild type)
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HMB265: Human & General Genetics
Prof. Stephen Wright
Lecture 4: Mendelian Traits in
Humans & Human Pedigree
Analysis
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Lecture Outline
Mendelian traits in humans
Reading:Hartwell et al, first Canadian Edition, Chapter 2
(emphasis on pages 29-33)
Autosomal dominant traits
Autosomal recessive traits
Anatomy of a pedigree
Human pedigree analysis & genetic testing
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rapid generation time
easy to grow/breed
can examine large numbers of offspring
can self-fertilize
What Makes a Good
Genetic Model Organism?
Arabidopsis thaliana -weed, used by many geneticists for the genetics of every plant. This is the modelorganism for plants
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rapid generation time
easy to grow/breed
can examine large numbers of offspring
can self-fertilize
What Makes a Good
Genetic Model Organism?
Caenorhabditis elegans -model organism for animals. Its a nemotoad. It can also self-fertilize, very rare in animals
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rapid generation time
easy to grow/breed
can examine large numbers of offspring
can self-fertilize
What Makes a Good
Genetic Model Organism?
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Drosophila melanogaster -fruit fly, major genetic model system for comparison to humans. Can't self fertilize.Get inbred lines by incest.
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rapid generation time
easy to grow/breed
can examine large numbers of offspring
can self-fertilize
Humans Are TERRIBLE
Genetic Model Organisms!
#
#
#
#
#
-Humans are not good genetic model systems. We donot have rapid genertion time, and easy to breed,cannot self-fertilize and can't have many offspring. can't
self-fertlize.
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1)Use other organisms as models:
Humans are NOT Genetic
Models- Solutions
-to understand our own genetics we use other model systemso compare to our own genetics.
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1) Use other organisms as models
2) follow pedigrees
Humans are NOT Genetic
Models- Solutions
The other solution: use pedigrees:whathappens to traits in families(observe this), canrack how genetics are displayed in humans.
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male
female
deceased
affected/
diseased
mating
siblings
Using Pedigrees to Follow
Genetics
1) Use other organisms as models
2) follow pedigrees
How is this disease inherited?-the disease is recessive, since mom and dad areheterozygous for the disease but is 50% in the offspring
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Mendelian inheritance and humans:Same principles apply
Albinism -due to a single mendilian gene. If you have two copies oflittle a, you get inactive of tyrosinase enzyme thereforegiving albino for heterozygous.
-Heterozygous is enough for getting pigmented phenotype - haplosufficient.-two normal A, homozygote, gives proper pigmented gene
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Mendelian inheritance and humans:Same principles apply
Some human traits are simple mendilian gentics
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Mendelian inheritance and humans:Same principles apply
Thousands of examples are described in the database:
Online Mendelian Inheritance in Man
www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
Some diseases are mendilian genetics also, simple(black and white)
-Dominant allele
-Mendilian genetic disease.
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Human autosomal traits are located on the non sexchromosomes (1-22)
They may be inherited as:
Autosomal dominant or
Autosomal recessive
Mendelian inheritance and humans:Autosomal inheritance
Autosomal Inheritance-Autosomal: non sex chromosomes. Normal Mendelian genetics
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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
Mendelian inheritance and humans:Autosomal inheritance
Autosomal Dominant
Aa x aa
!affected, !unaffected progeny
affected parent unaffected parent
-affected parent is usually heterozygous and unaffected is homozygous giving 50/50 progeny.
-if its dominant, it will not be masked in a generation.
-unaffected is homozygous not
heterozygous
-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 nothomozygous. The prbobabbility will be the product of the two events(product rule)
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Mendelian inheritance and humans:Autosomal inheritance
Only homozygous recessive individuals exhibit the affected
phenotype
Males and females are equally affected and may transmit the
trait
May skip generations
Autosomal Recessive
Aa x Aa
1/4 affected, 3/4 unaffected progeny
unaffected parent unaffected parent
If both parents are heterozygotes, they are unaffected but carry the disease silenty therefore lead to 1/4 progeny affected.
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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 dissectMendelian traits of interest
Pedigrees are an orderly diagram of a familys relevantgenetic features extending through multiple generations
Pedigrees help us infer if a trait is from a single geneand if the trait is dominant or recessive
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Anatomy of a pedigree
-this is something figured out in the pedigree,carriers of recessive disease.
-mating amongst relatives. The expresson of raregenetic disase comes up when there is inbreddingevent
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Mendelian Inheritance of Huntington
s Disease
-Dominant allele disorder - Huntingstons, but shows up in individuals later in life.
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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. Thismeans the parents were heterozygous.
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Recognizing dominant & recessive traits in pedigrees
Dominant Traits
Affected children always have at least one affected
parent
the trait tends to show up every generation
Two affected parents can produce unaffected children,if both parents are heterozygotes
-cant skip generations
like in the inbred case.
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Recognizing dominant & recessive traits in pedigrees
Recessive Traits
Affected individuals can be the children of two unaffectedcarriers, particularly as the result of consanguineous
matings
All the children of two affected parents should be affected
-carrier = heterozygote not expressing the disease.
-both parents are homozygous therefore children should have the disease, purebred
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Recognizing dominant & recessive traits in pedigrees
-cystic fibrosis, rare recessive disease
-for rare recssive, we assume individuals are homozygous for nondisease allele.e
-7-1, the parents must be heterozygous since they did not express thedisease but the 7-1 did.-5-1, and 5-2 both got their recessive alele from shared ancestors. The1-1 or 1-2 must have had the reessive allele since only at least 50% did
not have the recessive allele.
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Consangineous mating
A Pedigree with Consanguinuity(inbreeding)
Frequently uncoverstraits that
are recessive
Can give rise to inbreeding
depression- offspring that areless fit than their parents
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
6-4, means that this parents must be heteroygous for the diseae
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
or
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
2- unaffected individualsgives rise to 2 afffected
individuals due toinbreding
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
Fig 2-21
-unaffected offspring means that they can behetero or homo, we need to see their offspring toknow.
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
Fig 2-21
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
Fig 2-21
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
Fig 2-21
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
Fig 2-21
-individuals in generation 3 can beBig A little a or big A big A.
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Solving pedigrees - deducing mode ofinheritance and associated genotypes
Fig 2-21
-patrents in generation 1, one must beheterozygous
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Solving Genetics Problems
List genotypes and phenotypes for the trait
Determine the genotypes of the parents
Determine the parentspossible gametes
Determine the possible genotypes of offspring
Repeat for successive generationsis 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.
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Genetic Predictions
Can make predictions based on
Mendelian Laws
Ellens brother Michael has cystic fibrosis, an
autosomal recessive disease. No other family members have
the disease
What is the probability that Ellens child has a
cystic fibrosis-causing allele?
Example:
-Child can be heterozygous
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Genetic Predictions
Ellen and Michael
s parents must beheterozygous
= 2/3 x 1/2 = 1/3
ss
Probability Ellen is a carrier = 2/3
Probability child inherits cystic fibrosis allele = !
Probability child carries cystic fibrosis allele from Ellen
ellen is either heterozygous or homozygous
-probability that she is heterozygous
-product rule, both of these things have to happen.
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Genetic Predictions = Genetic Counseling
Genetic counseling sessions:
Family history
Pedigree construction
Information provided on specific disorders, modes ofinheritance, tests to identify at-risk family members
Testing arranged, discussion of results
Links to support groups, appropriate services
Follow-up contact
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Issues associated with genetic screening
Why carry out genetic screening at all?
When is a test accurate and comprehensive enough tobe used as the basis for screening?
Once an accurate test becomes available at reasonablecost, should screening become required or optional?
If a screening program is established, who should betested?
Should private companies and insurance companieshave access to employee and client test results?
What education needs to be provided regarding testresults?
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Questions 1 and 2 are based on the Kirk family pedigreeshown 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.
I
II
III
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