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Medical Genetics-Mendelian Genetics
Robert F. Waters, Ph.D.
Preparation for Pathology
 Preparation for Immunology
 Preparation for Epidemiology
 Etc.
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Gametes
Spermatogenesis
 Oogenesis
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Chromosomes (Karyotype)
Classification of Chromosomes
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Centromeric Classification (Nuclear)
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Metacentric (mediocentric)
• Center (nearly)
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Submetacentric (submediocentric)
• Little off center
• q-long arm
• p-short arm
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Acrocentric
• Centromere at the terminus
Meiosis
First meiotic division
Meiosis
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Second meiotic division
Human Spermatogenesis
Human Oogenesis
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Intrauterine primary Oocyte
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First meiotic division
Second meiotic division
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12 to 50 years after start of meiosis
Ova (secondary Oocyte)
• Receives most of the cytoplasm
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Others become polar bodies
Longer prophase in meiosis in females
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Higher probability of meiotic non-disjunction
The Pedigree
Propositus
 P1 (Parental)
 F1, F2, etc. (Filial)
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Phenylthiocarbamide (PTC)
Taster vs. Non-taster
 Homozygous
 Heterozygous
 Complete dominance
 Punnett’s square
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Genotype and Phenotype
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Genotypic ratio and phenotypic ratio
Autosomal Dominant
Approximately 50% Males and
Females affected
 Dentinogenesis imperfecta
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Pediatric opalescent brown color
 Wear down easily
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Dentinogenesis imperfecta
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Approximately 1:8000
Criteria for Autosomal
Dominant
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Usually not fully expressed in
heterozygous state
Appears in every generation with no
skipping
Trait transmitted by affected person to
half the offspring (average)
Unaffected persons do not transmit the
disease (not carriers)
Occurrence and transmission of trait not
influenced by sex (males ~ females)
Autosomal Recessive
Cystic Fibrosis
 Consanguinity and Recessive
Inheritance
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Autosomal Recessive-Cont:
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Tay-Sachs Disease
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Ashkenazi Jews
• Neuro-degenerative disorder
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High frequency in North America
• Migrations
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Tyrosinemia
Usually lethal
 Hepatic lethal
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Autosomal Recessive-Cont:
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Criteria
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Carrier identification, if possible
Trait characteristically occurs in sibs, not in
parents, immediate offspring, and most other
close relatives
About 1 in 4 ratio at birth to have trait
Parents of affected child may be
consanguineous (unknowingly)
Males and females equally likely to be affected
Multiple Alleles
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ABO blood type system
Sex Linked Inheritance
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X-Linked
May be X-linked Recessive
 May be X-linked Dominant
 When X-Linked gene in male (y) is
considered hemizygous not
heterozygous
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X-Linked Recessive
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Follow a well defined pattern
Expressed always males and only in
females that are homozygous
Example (Hemophilia)
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Queen Victoria
• Classical Hemophilia A (XR)
• Deficiency in antihemophilic globulin
• Clinical features
• Severe arthritis’
• Internal joint hemorrhages
• Difficulty in healing after cuts or abrasions
X-Linked Recessive
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Normal Female
Hemophiliac male
OVA
Xh
y
XH
XH Xh
XHy
XH
XH Xh
XHy
Daughters: 100% carriers (heterozygotes)
Sons: 100% normal
X-Linked Recessive Cont:
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Carrier Female
Normal Male
ova
XH
Xh
XH
XH XH XH Xh
y
XHy
Xhy
Daughters: 50% normal, 50% carriers
Sons: 50% normal, 50% affected
Criteria for X-Linked
Recessive Inheritance
Incidence of trait much higher in
males
 Trait passed from affected man
through all his daughters to half
their sons
 Trait never passed directly from
father to son
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X-Linked Dominant
Inheritance
Traits occur approximately twice as
often in females
 Affected male transmits the trait to
ALL of his daughters and to NONE of
his sons
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X-Linked Dominant Cont:
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Example
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X-linked blood group system Xg
Xg/Xg x Xga/y Male has Dom. Marker
OVA
Xg
Xg
Xga
Xga/ Xg Xga/Xg
y
Xg/y
Xg/y
Daughters: Gen: Xga/ Xg Phen: Xg(a+) -- Like father
Sons: Gen: Xg/y Phen: Xg(a-) –- like mother
X-Linked Dominant Cont:
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Heterozygous female and Xg(a-)male
Cross is Xga/ Xg x Xg/y
Ova
Xg
y
Xga
Xg
Xga/ Xg Xg/Xg
Xga /y Xg/y
Daughters:Xga/ Xg Xg/Xg – 50% receive dominant allele
Sons: Xga /y Xg/y – 50% receive dominant allele
Criteria for X-Linked
Dominant Inheritance
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Affected males transmit trait to all of their
daughters but to none of their sons
Affected females who are heterozygous
transmit the gene to half the sons and
half the daughters
In X-Linked dominant disorders, affected
females are twice as common as affected
males but will express the condition
in a milder form (heterozygous)
Penetrance
Ability of any gene to be expressed
 When some individuals have the
gene but fail to express it are said to
have reduced penetrance
 Patients who have a gene and do
not express it are said to have a
nonpenetrant gene
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Expressivity
The degree of expression of a
penetrant gene
 Polymorphisms
 May be due to modifier genes
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E.g. oncorepressor genes repressing
oncogenes
Pleiotropy
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One gene, multiple effects
Stem cells
E.g. galactosemia
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Defect in galactose-1-phosphate uridyl
transferase
• Multiple effects
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Cirrhosis of liver
Cataracts
Galactosuria
Mental retardation
Reversed by galactose free diet
Sex-Limited and SexInfluenced Genes
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Sex-Limited Trait
Autosomally inherited trait expressed in
one sex (e.g., male only)
 X-linked ruled out because may be
transmitted by females
 Precocious puberty
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• Exhibit adolescent growth spurt around the
age of four years
Precocious Puberty Pedigree
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Autosomal dominant precocious
puberty
Sex-Limited Expression
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Testicular feminization
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XY males have testes but are also born
with female external genitalia and
raised as females (Some female
secondary sexual characteristics at
puberty)
Autosomal Phenotypes with Unequal Male
and Female Expression
Hemochromatosis
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May be less expression in young
females
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Menstrual cycle
Iron storage disease
 Different from Thalassemias
 Treatments
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Latent Genes (Delayed Onset)
Huntington’s Chorea
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Choreic movement
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Unpredictable, jerky, ballistic
Mental deterioration
 Dominantly inherited
 Gene remains in population
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After reproductive age
Variable onset
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Usually above 35