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Human Biology Lecture

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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?

    #

    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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