Week 3 Flashcards
Does phenotypic expression directly associate with genotype
Phenotypic expression is not always a direct reflection of the genotype
Variables known to modify gene expression
What are the extensions of Mendelian genetics
- Penetrance & expressivity
- Suppression & position effects
- Temperature effects
- Nutritional effects
- Onset of genetic expression
- Genetic anticipation
- Genomic (parental) imprinting
Explain the difference between penetrance and expressivity
• Penetrance – the percentage of individuals that show at least some degree of expression of the mutant genotype in a population
– Partial penetrance
• Expressivity – the range of expression of the mutant
phenotype
• The molecular explanation of expressivity and incomplete penetrance may not always be understood
• In most cases, the range of phenotypes is thought to be due to influences of the environment and/or other genes (genetic background)
Provide an example of what expressivity in humans
• In some instances, a dominant allele is not expressed in a heterozygote individual
– Autosomal dominant trait
– Affected individuals have additional fingers and/or
toes
– A single copy of the polydactyly allele is usually sufficient to cause this condition
– In some cases, however, individuals carry the dominant allele but do not exhibit the trait
What are the suppression and position effects
Suppression
• Expression of other genes throughout the genome may have effect on the phenotype produced by the gene in question
Position effect
• Physical location of a gene in relation to other genetic material may influence its expression
Provide and explain an example of the position effect
• Position Effect
a) Female heterozygote for white eye genotype showing normal dominant phenotype
b) Chromosomal rearrangement leading to variegated effect (also female heterozygote for white eye)
What are temperature effects
- Chemical activity depends on kinetic energy of the reacting substances which in turn depends on the surrounding temperature
- Temperaturecan influence phenotypes
Write a paragraph explaining the nutritional effects on cytogenetics
• Mutation may prevent an individual from metabolizing some substance commonly found in normal diets
– Phenylketonuria
• Cannot metabolize phenylalanine
• Too much phenylalanine in the body causes problems with the brain and other organs.
• Damage from a build up of phenylalanine can begin within the first month of life and, if undetected and/or untreated, PKU results in severe mental retardation, hyperactivity, and seizures.
– Galactosemia
• accumulation of galactose in blood
• rare genetic metabolic disorder that affects an individual’s ability to metabolize the sugar galactose properly.
• organs that may be affected - brain, eyes, liver and kidneys.
• Infants with galactosemia usually have diarrhoea and vomiting within a few days of
drinking milk or formula containing lactose
– Lactose intolerance
• Lactose intolerance is a digestive disorder caused by the inability to digest lactose, the main carbohydrate in dairy products. It can cause various symptoms, including bloating, diarrhoea and abdominal cramps. People with lactose intolerance don’t make enough of the enzyme lactase, which is needed to digest lactose.
Explain what an onset of genetic expression is
- Human prenatal,infant,preadult and adult stages require different genetic information
- Critical expression of normal genes varies throughout the life cycle – gene products may play more essential roles at certain times
- The internal physiological environment of an organism changes with age
- Tay-Sachs disease
- Duchene Muscular Dystrophy (DMD)
- Huntington Disease
- Lesch-Nyhan Syndrome
Explain the mechanism of Huntington’s disease
• Progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition).
– Symptoms: Adult-onset, behavioural changes, neurodegeneration, and premature death.
– The most common form of this disorder, usually appears in a person’s thirties or forties.
• Caused by the expansion of CAG repeats – each of which codes for the insertion of the amino acid glutamine in the protein product.
– Known as polyglutamine/polyQ disorder
- Region containing the gene is within band 4p16.3
- The HTT gene encodes a large protein. In normal alleles, a region near the 5′ end of the gene contains the 6 – 35 CAG repeats, encoding a stretch of glutamines in the protein product
- Disease causing mutant alleles contain an expanded number of CAG repeats (>36) that increase the number of glutamine residues in the mutant protein
• The extended polyQ region of the mutant HTT protein (mHTT) causes misfolding and the formation of aggregates held together by hydrogen bonds.
• PolyQ regions of these aggregates bind to and inactivate regulatory molecules
– disrupting cellular functions leading to neurodegenration.
• The HD mutation is a gain-of-function mutation – Increasing quantity of gene product
What is the onset of genetic expression
- Human prenatal,infant,preadult and adult stages require different genetic information
- Critical expression of normal genes varies throughout the life cycle – gene products may play more essential roles at certain times
- The internal physiological environment of an organism changes with age
- Tay-Sachs disease
- Duchene Muscular Dystrophy (DMD)
- Huntington Disease
- Lesch-Nyhan Syndrome
What is huxngtingtons disease
• Progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition).
– Symptoms: Adult-onset, behavioural changes, neurodegeneration, and premature death.
– The most common form of this disorder, usually appears in a person’s thirties or forties.
• Caused by the expansion of CAG repeats – each of which codes for the insertion of the amino acid glutamine in the protein product.
– Known as polyglutamine/polyQ disorder
• Region containing the gene is within band 4p16.3
• The HTT gene encodes a large protein. In normal alleles, a region near the 5′ end of the gene contains the 6 – 35 CAG repeats, encoding a stretch of glutamines in the protein product
• Disease causing mutant alleles contain an expanded number of CAG repeats (>36) that increase the number of glutamine residues in the mutant protein
• The extended polyQ region of the mutant HTT protein (mHTT) causes misfolding and the formation of aggregates held together by hydrogen bonds.
• PolyQ regions of these aggregates bind to and inactivate regulatory molecules
– disrupting cellular functions leading to neurodegenration.
• The HD mutation is a gain-of-function mutation – Increasing quantity of gene product
What is leach-nyhan syndrome
• X-linked recessive disease (mutation in hypoxanthine-guanine phosphoribosyl transferase gene)
• Abnormal nucleic acid metabolism
• Purines (A&G) synthesized from
basic chemical components
• Mammals evolved the ability to extract them from degraded DNA in the form of the purine Hypoxanthine
• Hypoxanthine converted to A and G containing nucleotides by HPTR
• Mutation in HPTR
– Accumulation of uric acid in blood and tissues, mental retardation, palsy, self- mutilation of lips & fingers
What is genetic anticipation and provide an example
Some heritable disorders exhibit a progressively earlier age of onset and increased severity of the disorder in each successive generation
• Myotonic dystrophy (DM)
• A short (3 nucleotide) DNA sequence of the DM gene is
repeated a variable number of times and is unstable.
• Normal individuals 5-35 copies, minimally affected individuals ~ 150 copies, severely affected ~1500 repeats
• Size of repeated segment increases in successive generations
• RNA is transcribed from mutant genes alters the expression of
other genes
• Association between size of specific region and disease severity (also in Huntington disease, and fragile X syndrome)
What is genomic imprinting
• The phenotypic effects of some mammalian genes depend on whether they were inherited from the mother or the father. Some chromosome regions and their genes somehow retain a memory (“imprint”) of their parental origin that influences whether expressed or not.
• Imprinting step thought to occur before or during gamete formation
• Leading to differentially marked genes in sperm-forming vs. egg- forming tissues
• Major difference is the amount of DNA methylation
• UPD has no phenotypic effect for some chromosomes, for others
it produces abnormal phenotypes
• About 150 genes imprinted in mice and about 100
DNA carried by sperm and eggs are highly methylated.
• Shortly after fertilization most of the germline
methylation marks are erased.
• Providing embryonic cells with a clean pre-epigenetic state – to allow them to undergo new epigenetic modifications to form the 200 + cell types found in the human body.
• About the same time the embryo is implanting in the wall of the uterus – cells take on tissue specific epigenetic identities – methylation and patterns and histone modifications change rapidly to reflect those seen in differentiated cells.
• some genomic regions escape these rounds of demethylation and remethylation.
