single gene mutations and inheritance i april 3, 2008 lisa schimmenti, m.d
TRANSCRIPT
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Single Gene Mutations and Inheritance I
April 3, 2008
Lisa Schimmenti, M.D.
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Objectives
• Understand the basic types of single gene mutations
• Understand how mutations lead to abnormal protein expression
• Understand how a dominant mutation is passed from parent to child (inherited)
• Know retinoblastoma genetics: dominant inheritance, but recessive on the cellular level.
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Mutations are a change in DNA sequence that leads to a change in protein expression
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ASCO
The genetic code
A codon is made of 3 base pairs
64 codons total
1 codon (AUG) encodes 1 codon (AUG) encodes methionine methionine andand starts starts
translation of all proteinstranslation of all proteins
3 codons stop 3 codons stop protein translationprotein translation
60 codons encode 20 60 codons encode 20 amino acidsamino acids
(redundant code)(redundant code)
U A A
A U G
Met
G C A
Ala
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Genetics Vocabulary
• Allele: refers to different forms of the same gene
• Example: – wildtype allele– mutant allele– null allele
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More new words
• Phenotype: the physical appearance of a trait
• Genotype: the allele associated with a trait
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ASCO
Disease-Associated Mutations
A mutation is a change in the normal base pair sequence that has been proven to associate with a disease state
Commonly used to define DNA sequence Commonly used to define DNA sequence changes that alter protein functionchanges that alter protein function
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ASCO
Disease-Associated Mutations Alter Protein
Function
Functional proteinFunctional protein Nonfunctional or Nonfunctional or missing proteinmissing protein
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Classes of Mutations
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Type of mutations
• Missense: nucleotide change leads to amino acid change
• Nonsense: change leads to stop codon• Insertion: addition of nucleotides that
lead to frameshift• Deletions: deletion of nucleotides• Splice site: changes RNA splicing• Expansion of repeat units
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Nucleotide substitutionscan occur anywhere in the
genome
A
TG
C
Transversions Pyr -> PurPur -> Pyr
Transitions Pyr -> PyrPur -> Pur
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Missense mutation in coding sequence
Normal sequence
ATG CCG TTT
Met Pro Phe
Mutant Sequence
ATG CTG TTT
Met Leu Phe
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Nucleotide changes favor certain spots
• CpG dinucleotide– C frequently methylated– Spontaneous deamidation to T
• 8.5 x more likely to change than any other dinucleotide pair
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Insertions/Deletions
• Insertions (1 bp or >1 bp)
• Deletions (1 bp or >1 bp)
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≤ 3 bp change (coding)• ins or del
– 3 bp - ins or del one AA (most common mutation in CF delF508)– 2 bp ins or del - frame shift– 1 bp ins or del - frame shift
• 1 bp substitution– Silent - “wobble”– Nonsense - AA to “stop”– Missense
• Conservative - changes AA to same or similar AA• Non-conservative - changes AA by function or charge• May not change a basepair but may change the RNA splice recognition
site
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Changes in > 3 bp
• Whole gene deletions or duplications– Often due to repeated sequences and
mispairing in replications
• Portion of gene deleted or fragment inserted– Often due to aberrant splicing
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What does it look like?
THE BIG RED DOG RAN OUT.
THE BIG RAD DOG RAN OUT.
THE BIG RED.
THE BGR EDD OGR ANO….
THE BIG RED DOO GRA NOU
THE BIG DOG RAN OUT.
THE BIG BIG BIG BIG BIG RED DOG RAN OUT.
Normal
Missense
Nonsense
Frameshift (1 bp deletion)
Frameshift (1 bp insertion)
Frameshift (3bp deletion)
Triplet repeat expansion
Modifed from ASCO
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Non-coding mutations that affect gene function
• Promoter/enhancer element Trinucleotide repeats in 5 and 3’UTRs
• Splice sites
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Factors that influence how mutations alter gene function
• Increase or decrease expression of gene product
• Is one altered allele sufficient to cause disease?
• Modifiers • Proportion of cells affected• Parent of origin
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Effects of mutation on gene product
• Null allele (loss of function) - no gene product• Hypomorph - decreased amt/activity
• Gain of function - increased amt/activity• Dominant negative - antagonizes normal product• Neomorph - novel activity of product
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Predicting that a gene product won’t do the job
• Deletion, nonsense, frameshift of sequence is deleterious
• Mutation in splice site usually bad
• Missense mutations– Depends on location in protein– Is it non-conservative?
• Is the AA conserved in evolution?
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Which ones will cause disease?
• All but silent or conservative missense sequence changes are likely to significantly alter product function
• Among frameshifts, location of mutation alters likelihood of severity
• Mutations in coding sequence are identified most frequently…but this may change
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You only see the ones that hurt...
• Sequence changes or variants can be – Silent (no change in product): Polymorphism
• We have thousands of these
– Manifesting (changing RNA or protein product): Mutation
We all carry 7-10 gene mutations
AHHHH!
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Polymorphism
• A change in DNA sequence that is not disease causing
• Occurs usually in greater than 1% of population
• Usually does not change an amino acid sequence or produces a significant change (ie: valine for isoleucine)
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Autosomal Dominant
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Autosomal Dominant Inheritance
• males and females equally affected• 1 in 2 chance of affected offspring
from an affected parent• male to male transmission• structural genes, transcription
factors• only one abnormal copy of the
gene (allele) to have the phenotype
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Mechanisms yielding dominant alleles
• Haploinsufficiency: if one copy isn’t enough for function
• Dominant negative: when a mutant product dimerizes or oligomerizes
• Gain of Function: FGFR mutations causing activation of the receptor without a ligand present
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Autosomal Dominant probabilities
D
d
d
d
Dd dd
Dd dd
Daughters 50% normal50% affected
Sons 50% normal50% affected
Mother
Fat
her
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Variations in the AD “rules”
• Co-dominant expression• New mutation• Homozygosity for an AD trait
– May be a more severe phenotype
• Variable expression• Penetrance• Sex limited• Variation in age of onset
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Variations:Co-dominant expression
Definition: alleles that are both expressed when they occur in the heterozygous state.
Example: ABO blood group antigens
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ABO Blood Groups
Defined by the presence or absence of two antigens on the surface of the red cell
A and B• if you have A, you have anti-B antibodies • if you have B you have anti-A antibodies • if you have neither (O) you have both anti- A and -B• Absence of A or B = O• Three allele states: Ia Ib Inull
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ABO blood typing: co-dominant alleles
A/- B/- B/- BB
BBB/-ABA/--/-
AB BBA/-
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Variations: New Mutations
• Occur at a rate of 10-4 to 10-7 per locus per cell division
• “Hot spots” occur: CG pairs (8.5 x higher rate)
• More easily seen in a very large gene
• Paternal age effects
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Autosomal dominant: new mutation
dd dd dd dd
dddddddddd
dd ddDd
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Achondroplasia• Autosomal dominant
• 100% penetrance
• 1/26000: most common genetic dwarfism
• 80% new mutations
• Features– rhizomelic dwarfism (upper arms and thighs are
short) – lumbar lordosis (lower spine curves out)– large head– small foramen magnum – intact intellect– Mutation in FGFR3: activating mutation
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Fibroblast Growth Factor Receptors
• Receptor tyrosine kinases
• Four distinct genes: 1 through 4
• Critical in coordination of proportionate bone growth and development
• Signaling regulates cellular processes
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Achondroplasia and FGFR
• Mutations in FGFR3 cause achondroplasia
• Despite frequent new mutations almost all are caused by the same mutation (G -> A at nt 1138, causes gly 380 arg)
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Effects of homozygosity
dd dd dd dd
ddDdDddd
dd DdDD
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Homozygosity for some dominant traits is lethal
Homozygosity for achondroplasia causes very severe phenotype
http://www.echt.chm.msu.edu/courseware/blockII/Pathology/382131.jpeg
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AD and variable expression
• Pleiotropy: one gene, many effects on different systems
• Random chance
• Modifier genes
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Marfan Syndrome: variable expression
• Skeletal findings- disproportionate long bone growth
• Tall Stature• Eyes- dislocated
lenses• Heart-dilation of
aortic arch http://medgen.genetics.utah.edu/
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AD traits are often variable in expression
Dd dd dd dd
ddddDdDd
dd DdDd
dd
Normal
TallDislocated lensesDilated Ao
TallDilated Ao
Dislocated lensesDilated Ao
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Variations: reduced penetrance
• An individual may carry an altered allele and never manifest phenotypic evidence of this.
• Penetrance: an “all or nothing” phenomenon in expression of a trait in a population–phenotype, NOT genotype
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Tumor Suppressor GenesClinical Effects of Mutations
• Cancers due to mutations are early in onset• Cancers due to mutations are often bilateral• Phenotype is inherited as a dominant trait BUT at the
cellular level these are manifest as recessive: two abnormal alleles are required for manifestation
• Genotype is that of one germline abnormal allele: malignancy occurs with environmental damage of second normal allele (Knudsen two hit hypothesis)
• Penetrance reduced: no 2nd hit, no malignancy occurs
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Variation: reduced penetrance
dd Dd dd dd
ddddDddd
dd Dddd
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Familial Retinoblastoma: a recessive state in the cell
inherited as AD trait
http://www.retinoblastoma.com/Images/CT%20Scan.jpg
http://www.people.virginia.edu/~rjh9u/retblst.html
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Familial RetinoblastomaCase history:6 month old child found to have leucocoria (white pupil) On exam
there is a large mass in the eye. The other eye has a small lesion
Father gives the history that his mother had only one eye because the other was removed when she was a baby. He and his 2 sibs were healthy and have both eyes
Explanation: REDUCED PENETRANCE of this trait
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Autosomal Dominant: sex limited trait
Dd dd dd dd
ddddDddddd
dd ddDdDd
Dd
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A sex-limited AD trait
• Familial male precocious puberty • Pubertal onset in males by age 4.• Due to gain of function mutation
that keeps the leutinizing hormone (LH) receptor in an “on” state
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Autosomal Dominant: variation in age of
onsetDd dd dd dd
ddddDdDddd
dd ddDd
Dd dd
dd Dd
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Variation:Altered age of onset
• Huntington’s Chorea– Progressive dementia
– Choreiform movements
• Autosomal Dominant pattern
• Age of onset usually after 30
• Triplet repeat expansion in the Huntington gene that can expand
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What to expect for the next lecture:
• Recessive inheritance
• X-linked inheritance– Dominant– Recessive
•Population genetics for docs
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Example Question• Find the one true statement about dominant
inheritance :– A. Male are more commonly affected than
females.– B. Two copies of the gene carry mutations to have
the phenotype– C. Only gain of function mutations are dominant.– D. Haploinsufficiency mutations can only cause
dominant disorders.– E. Mutations can be passed from fathers to sons.