Patterns of inheritance
Suna Onengut-Gumuscu, PhD
Center for Public Health Genomics
• Email: so4g@virginia.edu
• Human Genetics and Genomics (2006), Korf, 3rd edition, ISBN 06320-456-2
• Thompson and Thompson Genetics in Medicine (2007), Nussbaum,
McInnes, Willard, 7th edition, ISBN 978-1-4160-3080-5
Patterns of inheritance
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Family history/ Pedigree
Autosomal recessive
Autosomal dominant
Sex-linked traits
Penetrance and Expressivity
Genetic imprinting
Genetic anticipation
Human genome
46 chromosomes
• 22 pairs of autosomes
• XY male
• XX female
Classification of Genetic Disorders
• Chromosomal disorders: Defect is due to an excess or
a deficiency in whole chromsomes or chromsome
segments (trisomy 21,Turner syndrome, Klinefelter
syndrome)
• Single gene defects: Caused by individual mutant
genes
• Multifactorial inheritance: Combination of multiple
genes and environmental factors. (Complex disease:
diabetes mellitus, Crohn’s disease, Multiple sclerosis)
Single gene disorders/ Common disease
• More then 3900 single gene defects have been
catalogued
• Rare single gene disorders: usually less then 1 in
100000 births
• Common diseases: determined by combinations of
genes interacting with one another and with the
environment. Do not fit the characteristic patterns of
inheritance observed in single gene defects.
Patterns of Inheritance
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Gregor Mendel (1822-1884) was the first person to describe how certain
traits are inherited from generation to generation.
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Early 20th century Archibald Garrod recognized the existence of families in
which traits segregated according to Mendel’s laws
Pedigrees in genetics
• Single-gene disorders show
patterns of transmission in families
• Family history: 1st step in
establishing pattern of inheritance
• Pedigree: A diagram of a family
history indicating the family
members, their relationship to the
proband, and their status with
respect to a particular heredity
condition
Family history
• In diagnosis
• To clarify pattern of inheritance
• Provide information if there is variation in expression
among family members
• Natural history of a disease
Main symbols used in pedigrees
Inheritance patterns
• Recessive: expressed only when both
chromosomes of a pair carry mutant alleles
at a locus (2 mutant copies)
• Dominant: expressed when one
chromosome of a pair carries a mutant allele
at a locus . (1 mutant copy)
Inheritance patterns
• Sex-linked: on the X or Y chromosomes
• Autosomal: on any of the other 22
chromosome pairs
Genetic Terms
• Allele: one variant of a gene or marker
• Genotype: genetic composition for a trait
• Phenotype: physical manifestation of a
trait
Inheritance patterns
• Autosomal recessive
Genotype and phenotype correlation with gene locus for an
autosomal recessive trait
A
a
Dominant allele
Recessive allele
Genotype:
Homozygous
Heterozygous
Homozygous
Phenotype:
unaffected
unaffected
affected
Autosomal Recessive Inheritance
• Autosomal recessive traits are only
expressed in individuals who carry
two mutant alleles inherited from each
parent.
• Autosomal recessive traits usually
arise in children of phenotypically
normal parents
Aa
Aa
eggs
A
a
A
AA
Aa
a
Aa
aa
sperm
Segregation of an autosomal recessive trait in a
pedigree
Autosomal recessive: increased incidence of parental
consanguinity
Autosomal Recessive Inheritance
• Usually parents are heterozygous carriers
• Affected individuals are usually born to unaffected
parents
• Affected children are homozygous for mutant gene
• In most autosomal recessive diseases males and
females are equally likely to be affected
• Carrier couple has a 1 in 4 chance of having
affected offspring
• There is an increased incidence of parental
consanguinity
Autosomal Recessive Inheritance
• These traits are only expressed in individuals
who carry two mutant alleles inherited from each
parent.
• Usually due to mutations that reduce or
eliminate the function of the gene product (lossof-function)
• In many cases: mutations that impair or
eliminate the function of an enzyme
Oculocutaneous Albinism
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Lack of pigmentation
Fair skin and hair
Decreased visual acuity
Lack of stereoscopic vision
Mutations in the gene encoding
Tyrosinase (lack of Melanin)
• Autosomal Recessive Genetic
Transmission
Metabolic pathways involving tyrosine
Most enzyme deficiencies are transmitted as
autosomal recessive
Mutations responsible for recessive traits
usually leads to:
• Lack of gene expression (eg: promoter
mutations)
• Lack of protein production (eg:mutations that
lead to premature termination of translation)
• Production of a protein with reduced or absent
function (eg: amino acid substitution)
Inheritance patterns
• Autosomal recessive
• Autosomal dominant
Genotype and phenotype correlation with gene locus for an
autosomal dominant trait
Genotype:
Phenotype:
A
a
Dominant allele
Recessive allele
Homozygous
Heterozygous
affected
Homozygous
unaffected
Phenotype expressed in both homozygotes and heterozygotes for a mutant allele
Pedigree illustrating autosomal dominant transmission
Autosomal Dominant Inheritance
• Expressed in heterozygous or homozygous individuals
• Affects an individual of either sex
• Transmitted by either sex
• An affected person usually has at least one affected
parent
• Transmitted to 50 % of offspring
Osteogenesis Imperfecta Type I
• Autosomal Dominant
• Marked by extreme fragility of bones
• Deficient production of the protein collagen
leading to abnormal bone matrix
• Muations in COL1A1 or COL1A2 lead to
reduced amounts of normal collagen
Autosomal Dominant inheritance/structural
gene mutations
Gain-of-function mutation is achondroplasia
p.Gly380Arg
• Mutation in the fibroblast growth factor type 3
receptor (FGFR3) leads to Achondroplasia (a form of
dwarfism)
• FGFR3 promotes differentiation of cartilage into bone.
• Gain-of-function mutation constitutively activates the
receptor causing premature conversion of the growth
plate into bone.
Inheritance patterns
• Autosomal recessive
• Autosomal dominant
• Sex-linked traits
X-linked inheritance
Male
X
Y
X
Unaffected
Y
Affected
Female
Homozygous
Wild-type
Heterozygous
Homozygous
mutant
X-linked recessive inheritance
• Affects mainly males
• Affected males are
usually born to unaffected
parents
• Females may be affected
if the father is affected
and the mother is a
carrier, or occasionally as
a result of nonrandom Xinactivation
X-linked dominant inheritance
• Affects either sex
• Females are often more mildly and
more variably affected than males
• The child of an affected female has
a 50 % chance of being affected
• For an affected male, all his
daughters but none of his sons are
affected
Y-linked inheritance
• Affects only males
• Affected males always have an affected father
• All sons of an affected man are affected
Mutations in Y-linked genes usually lead to male infertility therefore
usually not passed on to future generations.
Penetrance and Expressivity
Penetrance: The proportion of individuals of a specified
genotype who show the expected phenotype
aa
Aa
Aa
Aa
aa
aa
aa
- Autosomal dominant traits occasionally may skip a generation
-Rate of penetrance applies to a population not an individual
Age-related penetrance in late-onset diseases:
In late –onset disease although genotype is present at birth the
phenotype may not manifest until adult life (Huntigton disease,
progressive neurodegenaration)
Penetrance and Expressivity
Penetrance: The proportion of individuals of a specified
genotype who show the expected phenotype
Expressivity: The range of phenotypes expressed by a
given genotype
- Penetrance is high
Neurofibromatosis type 1
(Autosomal dominant)
-Tumors along peripheral nerves
-Patches of brown pigmentation on skin
-Bone deformities
-Learning disabilities
-Brain tumors
- Wide range of expressivity
Genomic Imprinting
• Certain genes are expressed only from the maternal or
paternal chromosome
• Genomic Imprinting: Differential expression of
maternally and paternally derived genes.
• Expression of the disease phenotype depends on
whether the mutant allele has been inherited from the
mother or the father.
Genomic Imprinting
- The specific gene copy to be
inactivated is always determined by the
parent of origin
-Is a dynamic process: the “imprint” has
to be erased and reset in each
generation
-The “imprint” is reset in germ cells
-If a mutant gene is imprinted, sex of the
parent it was inherited from plays a role
in the expression of the disease
phenotype
Deletions on chromosoome 15 can result in Prader-Willi or
Angelman syndrome
Prader-Willi Syndrome
-initial failure to thrive
-distinctive facial features
Paternal
-developmenta delay
-hypogonadism
Angelman Syndrome
-seizures
-jerky, uncoordinated movements
-unprovoked smiling/laughter
-lack of speech
-severe developmental delay
Maternal
Anticipation
• Symptoms in certain genetic disorders tend to be more severe and
have earlier age of onset from generation to generation.
• Unstable repeat expansions: characterized by expansion of a
segment of DNA consisting of repeating units of three or more
nucleotides in tandem
Slipped mispairing mechanism in the expansion of unstable
repeats
Unstable Repeat expansion Diseases
Repeat Numbers
Normal
Affected
Disease
Inheritance pattern
Repeat
Gene
Huntington Disease
Autosomal dominant
CAG
HD
<36
>40
X-linked
CGG
FMR1
<60
>200
Myotonic dystrophy
Autosomal dominant
CTG
DMPK
<30
80-2000
Friedrich ataxia
Autosomal recessive
AAG
FRDA
<34
36-100
Fragile-X
Huntington Disease
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Triplet repeat expansion (CAG
repeat leading to expansion of
polyglutamine)
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Autosomal dominant
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Progressive neurodegenerative
disorder
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Anticipation: there is an earlier and
earlier age of onset from generation
to generation
Age of onset/ number of CAG repeats
Pathogenesis of disease due to unstable repeat
expansions
• Expansion of noncoding repeats that cause a loss of
protein function by impairing transcription.
- Fragile X syndrome: Presence of more then 200 copies of CGG
repeat in the 5’ UTR of FMR1 leads to over methylation of cytosines
in the promoter
• Expansion of noncoding repeats that confer novel
properties on the mRNA.
- Myotonic dystrophy 1: (3’ UTR of DMPK) CTG >80 copies.
Excessive
splicing
binding of RNA-binding proteins quench normal RNA
mechanism in the cell
• Expansion of a codon leading to novel features
- Huntington Disease: CAG>40 long polyglutamine sequences,
damage specific neurons
Factors affecting pedigree patterns
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Penetrance
Expressivity
Age of onset
Imprinting
Anticipation
Occurrence of new mutations
X inactivation
OMIM
• Online Mendelian Inheritence in Man
• http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim
• A catalog of genes and human traits
• Each entry has a unique six-digit MIM number. Entries that
begin with
1
(100000- )
Autosomal loci or phenotypes (entries created before May 15, 1994)
2
(200000- )
3
(300000- )
X-linked loci or phenotypes
4
(400000- )
Y-linked loci or phenotypes
5
(500000- )
Mitochondrial loci or phenotypes
6
(600000- )
Autosomal loci or phenotypes (entries created after May 15, 1994)
-Mouse Genome informatics: http://www.informatics.jax.org/
-OMIA – Online Mendelian Inheritance in Animals: http://omia.angis.org.au/