Principles of Genetic Inheritance Flashcards
Lyonization
is called X-inactivation. The choice of which X chromosome to be inactivated is random
Mosaicism
is a condition in which cells from a patient have different genotypes (& karyotypes): – Downs Syndrome: some 46XX; some 47XX,+21 – Klinefelter Syndrome: some 46XY; some 47XXY – Turner Syndrome: some 46XX; some 45XO
Interphase:
chromosome duplication
Cell division:
one copy of each chromosome (chromatid)
and ½ of the cytoplasm/organelles are distributed
between the two daughter cells
Mitosis of somatic cells results in
two identical diploid
daughter cells
Stem cells undergo mitosis, but
divide asymmetrically,
resulting in one stem cell, and one daughter cell
Meiosis
reduces the total number of chromosomes by half, producing four gametes (haploid) – Occurs in germ-line cells
In meiosis, —————— can
produce new combinations of
genes
homologous recombination
Meiosis
consists of
one round of DNA replication – two rounds of nuclear divisions
Meiosis creates
genetic diversity in
2 ways:
Random segregation of homologs – Cross-over exchange (homologous recombination)
Euploid
Cells with a normal number of chromosomes
– Ex. Haploid gametes and diploid somatic cells
Polyploidy
presence of a complete set of extra chromosomes in a
cells
– Often seen in plants
Aneuploidy
Cells with a missing or additional individual
chromosomes
– Monosomy, trisomy
Translocation
Non-homologous
chromosomes exchange
genetic material
Reciprocal Translocation
an exchange of material
between nonhomologous
chromosomes
Robertsonian Translocation
Long arm of two
acrocentric chromosomes
combined, short arm
typically is lost
Turner Syndrome
EXAMPLE OF MOSACISIM 45, XO karyotype – Female (no Y) – Short stature – Ovarian hypofunction/premature ovarian failure – Many do not undergo puberty without hormone therapy – Most are infertile – ~30% webbed neck – Low hairline on neck – CV defects (coarctation of aorta, bicuspid aortic valve) – Normal intelligence
Klinefelter Syndrome
EXAMPLE OF MOSAICISM 47, XXY – Some with no/limited symptoms – Varying degrees of cognitive, social, behavioral, learning difficulties – Primary hypogonadism (low T) – Small and/or undescended testes – Gynecomastia – Tall stature – Infertility – Can be mosaic – Variability in X numbers can increase symptoms (48, XXXY; 49, XXXXY)
Trisomy 13
Patau Syndrome EXAMPLE OF MOSAICISM Autosomal trisomy Robertsonian translocation der(14:21)(q10;q10)+21 or be mosaic
47, XX +13;
Patau Syndrome– Severe developmental abnormalities
– Most perinatal death within 1 week (13% of
live births survive to 10 y.o.)
47, XX +18
Edwards Syndrome
– Abnormal development
– Most perinatal death within 1 year (10% of
live births survive to 10 y.0.)
Genomic Imprinting
CARRIED OUT BY DNA METHYLATION
for some human genes, one of the alleles is
transcriptionally inactive (no mRNA produced)
– Depending on the parent from whom the allele was received
Imprinting is essentially gene
silencing
– Through methylation of 5’ region
of gene
– Chromatin condensation
Genomic imprinting and role of epigenetics
Epigenetic imprints remain throughout the lifespan of the individual in somatic cells • In germ cells, epigenetic imprints are reset at each generation • During meiosis, imprints are erased and new ones are set
Prader Willie Sydrome
example of uniparental disomy Deletion of a region of chromosome 15 Phenotype depends on if deletion is on paternal or maternal chromosome – Paternal = Prader Willie Sydrome Paternal PWS genes are active and AS gene in mother is inactive • Short stature, hypotonia, small hands/feet, obesity, mild to moderate intellectual disability
Angelman Syndrome
Maternal deletion of PWS/AS gene
Paternal PWS genes are active and AS gene in mother is inactive
Paternal AS gene is inactive
Severe intellectual disability, seizures,
ataxic gait
Uniparental Disomy
Related to non-disjunction and genomic imprinting If two chromosomes are inherited from the same parent (Uniparental Disomy), they will have parent-specific imprinting – No gene product
Genotype
an individual’s genetic makeup
Phenotype
what is actually observed
Cystic Fibrosis
Individuals with distinct genotypes can
have a single phenotype
pleiotropy
individuals with the same genotype can have
multiple phenotypes Ex. PKU
Proband (propositus)
First diagnosed person in the
pedigree
Autosomal Dominant Inheritance
Only 1 allele of a gene is needed for expression
• Affected offspring has one affected parent
• Unaffected individuals do not transmit trait
• Males and females can transmit trait to both males and females –
autosomal
• Trait is expected in every generation
• Recurrent risk is 50%
ex. POSTAXIAL POLYDACTYLY
Autosomal Recessive Inheritance
2 copies of a gene is needed to influence phenotype
ex. TYROSINASE-NEGATIVE
ALBINISM
X-linked Recessive
Disease allele on X in males is termed “hemizygous”
• Females can be heterozygous or homozygous
• Unaffected males don’t transmit the trait (no carriers)
• Female carriers transmit the disease allele to 50% of
sons and 50% of daughters
• All daughters of affected males
are heterozygous carriers
EXAMPLE:
DUCHENNE MUSCULAR DYSTROPHY
X-linked Dominant
Very rare; no carriersMales with the disease allele transmit the trait:
– only to females
– 100% transmission
• Females with the disease allele transmit the trait:
– To both males and females
– 50% transmission to offspring
HYPOPHOSPHATEMIA:Low phosphorus in blood due to defective reabsorption of phosphate in kidney
Deficient absorption of calcium in intestines causes softening of bone (Rickets)
Vitamin D metabolism abnormal
Short stature
Incidence: 1/60,000
Treatment: oral phosphate & vitamin D
HYPOPHOSPHATEMIA
X-linked Dominant Disease
Low phosphorus in blood due to defective reabsorption of phosphate in kidney
Deficient absorption of calcium in intestines causes softening of bone (Rickets)
Vitamin D metabolism abnormal
Short stature
Incidence: 1/60,000
Treatment: oral phosphate & vitamin D
Reduced Penetrance
The frequency a gene manifests itselfIn some cases, 100% of individuals inheriting a genetic defect
show the clinical presentation (phenotype) of the disease (100%
penetrance)
• In other cases penetrance is less than 100%
RETINOBLASTOMA
autosomal dominant inheritance – Phenotype occurs in 90% of individuals inheriting gene defect; so 90% penetrance EXAMPLE OF REDUCED PENETRANCE
Variable Expressivity
Term used to describe the range of phenotypes that
vary between individuals with a specific genotype
NEUROFIBROMATOSIS
EXAMPLE OF VARIABLE EXPRESSIVITYDevelop tumor-like growths called neurofibromas
Patients have café-au-lait spots – pigmented areas the color of coffee with cream (spots differ in number, shape, size
and position)
Locus Heterogeneity
Single disorder, trait, or pattern of traits caused by mutations in genes at different
chromosomal loci
OSTEOGENESIS
IMPERFECTA
EXAMPLE OF LOCUS HETEROGENEITY Brittle-bone disease – Mutations in collagen genes (two loci: chromosome 7 and 17), either mutation exhibits the same phenotype
PROBABILITY
defined as the proportion of times that a specific
outcome occurs in a series of events
• As proportions, probabilities are between 0 and 1
INDEPENDENCE PRINCIPLE
MULTIPLICATION RULE: probability of a given outcome in multiple trials is the product of the
probabilities of each trial outcome
THE ADDITION RULE: probability of either one outcome or another is the sum of the two probabilities
The Hardy-Weinberg Principle
Specifies the relationship between Gene
Frequencies and Genotype Frequencies
Useful in estimating Gene Frequencies from
Disease Prevalence Data and in estimating the
incidence of heterozygous carriers of recessive
disease genes
Cystic Fibrosis
In recessive disease, only the affected homzygotes, with
genotype aa, are distinguishable
e frequency of aa should be q^2
Autosomal Dominant Inheritance
characterized by vertical
transmission of the disease phenotype, a lack of skipped
generations, and roughly equal numbers of affected males
and females. Father-to-son transmission may be observed
Autosomal Recessive Inheritance
characterized by
clustering of the disease phenotype among siblings, but the
disease is not usually seen among parents or other ancestors.
Equal numbers of affected males and females are usually
seen, and consanguinity may be present
Consanguineous mating
more likely to produce offspring
affected by rare Autosomal Recessive Disorders
Studies show that mortality rates
among the offspring of first-cousin
mating’s are up to 9% higher than
those of the general population
Each person carries one to five recessive mutations lethal to offspring if matched with
another copy of the mutation (homozygosity)
Mitochondrial DNA
Several copies of 16,569 bp, double-stranded, circular
mtDNA molecule per mitochondria
– Encodes rRNA, tRNA, and 13 polypeptides involved
in oxidative phosphorylation
– Transcription takes place in the mitochondrion,
independently of the nucleus
– Contain no introns
– Inherited exclusively through the maternal line
– Mutation rate is approx. 10x higher than nDNA
• Relative lack of DNA repair mechanisms
• Damage from free oxygen radicals released
during oxidative phosphorylation
Mitochondrial Heteroplasmy
Primordial germ line cell has divides into germ line cells and carries mutant mitchondria -> Depending on the amount of mutant mitochondira, the child will express the disease if meet threshold: about 60% diseased mitchonchondria in a cell causes symptoms. Mitchondria are divided unequally, so some germ line cells will be normal, and others can have large amount of mutant mitochondria.
Leber’s hereditary optic neuropathy (LHON)
EXAMPLE OF MITCHOCHONDRIAL DISEASE
Degeneration of retinal ganglion cells
– Acute or subacute loss of central vision
• Typically early teens or 20’s
Mitochondrial encephalomyopathy, lactic acidosis, and
stroke-like episodes (MELAS)
Affects many body systems, particularly brain and nervous
system, and muscles
– Stroke and dementia
– Lactic acidosis
Polygenic inheritance
Traits in which variations are thought to be
caused by the combined effects of multiple
genes
Multifactorial Inheritance
When environmental factors cause variation
in the trait, the term multifactorial is used
Because these traits are caused by the additive effects of many genetic and environmental factors, they tend to follow a normal, or bell -shaped distribution in populations
liability
distribution
For diseases that do not follow the bell
-curve
distribution
threshold of liability
For multifactorial diseases that are either
present or absent, it is thought that a ——–must be crossed before
the disease is expressed
• Below the threshold, the person appears normal • Above the threshold, the person is affected by
the disease
Transmitting muscular hypertrophy
Muscular hypertrophy between stomach and
duodenum – leading to vomiting and obstruction
• Five times more common in males than females
• Males need less risk genes to show disease;
females need more risk genes
• The least affected sex has a higher risk threshold
and transmits the condition more often to the
most frequently affected sex
• Children of women with pyloric stenosis are more
likely to be born with condition (especially males)
• Children of affected males with pyloric stenosis
are less likely to be born with condition
Recurrence Risk
The recurrence risk is higher if more than one family member is affected
• If the expression of the disease in the proband is more severe, the
recurrence risk is higher
• The recurrence risk is higher if the proband is of the less commonly affected
sex
• The recurrence risk for the disease usually decreases rapidly in more
remotely related relatives
Multifactorial Disease
is caused by the
simultaneous influence of multiple genetic and
environmental factors
In some cases, a trait may be influenced by the
combination of both a single gene with large
effects and a multifactorial background in
which additional genes and environmental
factors have small individual effects
