Download Non-Mendelian Inheritance and Exceptions to Mendel`s Rules

Non-Mendelian Inheritance
and Exceptions to Mendel’s
Rules
Jane Kimani, Graduate Student
Genetics PhD Program
Objectives
• Describe maternal inheritance and mitochondrial
diseases
• Describe imprinting and disorders associated
with imprinting
• Discuss concepts that alter Mendel’s laws of
inheritance
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Outline
• Maternal inheritance and mitochondrial
diseases
• Genomic imprinting
• Variation in Mendelian Laws
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Linkage
Genetic heterogeneity
Incomplete dominance and codominance
Epistasis
Phenocopies
Variability in phenotypic manifestation of mutant
genes: Penetrance, expressivity and pleiotropy,
sex-specific expression and variable age of onset.
Key Words
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Maternal inheritance
Mitochondrial disease
Heteroplasmy vs homoplasmy
Imprinting
Uniparental disomy
Linkage
Incomplete dominance
Codominance
Epistasis
Phenocopy
Penetrance
Expressivity
Sex-limited trait
Sex-influenced trait
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Mitochondrial Genome
• Mitochondrial DNA
– Consists of a single circular
molecule of ~16.5 Kb
– Multiple copies of the
mtDNA molecule per
mitochondrion
– Genes:
• 24 RNA
• 13 proteins
http://www.historyoftheuniverse.com/mitochon.html
Mitochondrial DNA Inheritance
• Maternal inheritance
– Mitochondrial DNA is always passed from the mother
to her offspring, through the ovum.
Pedigree showing mitochondrial inheritance
http://www.mostgene.org/gd/gdvol10b.htm
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Mitochondrial Diseases
• Mutations in
mitochondrial DNA
impair:
– Energy production
– Generation of reactive oxygen
species
– Initiation of apoptosis
• Symptoms:mostly affects
tissues with high demand for
metabolic energy
http://www.mindbodyfocused.com/body/mitochondrial-disease.php
Features of Mitochondrial Diseases
• Homoplasmy
– Refers to cells that contain a population of
mitochondria that are the same (ALL are normal, or
ALL contain a mutation)
• Heteroplasmy
– Refers to cells that contain a mixture of mitochondria,
some normal and some containing a mutation in the
mtDNA molecule.
– Heteroplasmy affects the penetrance and
expressivity of mitochondrial diseases.
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Leber Hereditary Optic Neuropathy
(LHON)
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Most common disease caused by mtDNA mutations
Prevalence ~10 per 100 000 population
Mutations can occur in several mt genes
Features: Visual failure due to degeneration of the
retinal ganglion cells and their axons
Imprinting
• Imprinting is differential expression of an allele
based on the parent of origin.
• Depending on the imprint, the cell uses either
the maternal or the paternal copy of the gene.
• An imprinted gene is marked as either coming
from the father or the mother during
gametogenesis.
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Differences Between Parental
Genomes
http://unr.edu/homepage/rdrewell/images.html
Imprinting Mechanism
• Imprinting is an epigenetic modification. Epigeneticheritable changes in gene expression that are not
produced by changes in the DNA sequence.
• Methylation of cytosine at position C5 in CpG
dinucleotides.
– Represses transcription of genes by inhibiting binding
of transcription factors
• Post-translational modification of
histones
– Regulates chromatin structure
http://www.sci.osaka-u.ac.jp/introduction/eng/images/b_17.gif
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Uniparental Disomy (UPD)
• Inheritance of both copies of a gene (or a chromosome)
from the same parent
• Paternal UPD: inheritance of two copies of a
gene/chromosome from the father and no copies from
the mother.
• Maternal UPD: inheritance of two copies of a
gene/chromosome from the mother and no copies from
the father.
• Critical for imprinted genes because the individual is
missing genes that are expressed from the other
parental chromosome.
Imprinting Disorders
• Deletions of chromosomal region 15q11-q13 result in
two different diseases:
Annual Review of Genomics and Human Genetics 5:479
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Variation in Mendelian Laws
Linkage
• Linkage: Genes that are located close together on a
chromosome are inherited together.
• Crossing over: The reciprocal exchange of
chromosomal segments between homologous
chromosomes during meiosis.
– Disrupts linkage
– Depends on the distance between two genes
1. Linkage of genes on a chromosome
2. Crossing over unlinks genes
http://anthro.palomar.edu/biobasis/bio_3.htm
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Recombination and Genetic Distance
• Crossing over of homologous chromosomes during
meiosis I results in recombination.
• Recombination fraction (θ): The proportion of meioses in
which any two genetic loci are separated by
recombination.
– θ=0: No recombination
θ=0.5:Recombination
• Linkage map: a diagram showing the order and relative
position of genes on a chromosome.
Linkage mapping
• Linkage mapping: Identification of the location
of disease genes by tracking how often a DNA
marker and the disease phenotype are
inherited together.
• Linkage disequilibrium: Occurrence of alleles
on a chromosome at a frequency that is
significantly different from that predicted by
individual allele frequencies.
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Genetic Heterogeneity
• Allelic Heterogeneity
– Different mutations (alleles) of the same gene result in a
similar phenotype.
– Eg. Over 1000 mutations in the CFTR gene are reported to
cause cystic fibrosis. About 70% of these are caused by
the dF508 mutation, but different allelic combinations
produce different phenotypes (multiple alleles), a factor
that also alters Mendelian phenotypic ratios.
• Locus Heterogeneity
– Mutations in different genes result in a similar phenotype.
– Eg. Retinitis pigmentosa, a hereditary disease of the retina
occurs in several autosomal dominant, autosomal
recessive and X-linked forms. There are >200 different
entries in OMIM.
Incomplete
Dominance
• The phenotype of the
heterozygote is
intermediate between
that of the two
homozygotes due to
partial expression
from each allele
Codominance
• A relationship
between alleles of a
single gene such that
both of them are
equally expressed
and contribute to the
phenotype of the
heterozygote
http://www.gwu.edu/~darwin/BiSc150/One/genetics.htm
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Epistasis
• Epistasis is a phenomenon whereby alleles at one
genetic locus can alter the phenotypic effects of
alleles at a different locus.
• This distorts Mendelian segregation ratios since the
effects of a single gene are not expressed
independently.
Phenocopy
• A phenocopy is an environmentally induced
phenotype, that mimics an inherited phenotype
caused by a specific genotype
• Example: Alkaptonuria - an autosomal recessive disease,
characterized by dark tissue pigmentation. Features can be
phenocopied by using a skin bleach containing hydroquinone.
Variability in Phenotypic Manifestation
of Mutant Genes
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Penetrance
Expressivity
Pleiotropy
Sex-specific expression
Variable age of onset
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Penetrance
• Refers to the proportion of individuals with a disease
genotype that also exhibit the corresponding phenotype
• An all-or-none: an individual either has or does not have
the disease phenotype
• Incomplete (reduced)
penetrance: Some
people who have the
disease genotype DO NOT
manifest the corresponding
phenotype
• Complete penetrance:
ALL of the people who
have the disease genotype
also manifest the
corresponding phenotype
http://www.uic.edu/classes/bms/bms655/lesson4.html
Expressivity
• Refers to the extent to which
a trait or phenotype is
expressed
Bilateral cleft lip and palate
and lower lip pits
• Variable expressivity: A
phenotype shows variable
expressivity when the severity
of the symptoms varies in
people with the same genotype
http://www.emedicine.com/ped/topic2753.htm
Lower lip pits
• Example: Van der Woude
syndrome
http://www.uihealthcare.com/topics/medicaldepartm
ents/pediatrics/vanderwoudesyndrome/index.html
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Pleiotropy
• A single gene produces multiple and often diverse
phenotypic effects
• A gene codes for a protein, which may have various
interactions with other proteins depending on the cell
type and/or cellular process, resulting in multiple
functions.
Variable Age of Onset
• Some conditions show a late age of onset, so even if
an individual carries a mutant gene, there is no
phenotypic expression until later in life.
• Examples: Parkinson disease, Alzheimer disease
Sex-specific Expression
• Sex-Limited Trait: Refers to a characteristic that develops
or is present in one of the sexes and not the other.
• Sex-influenced trait: Refers to a characteristic that may be
present in both sexes, but the expression of the phenotype
differs from one sex to the other.
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