L15: Patterns of Inheritance Flashcards
What two components contribute to human disease?
Environmental and genetic factors
What is the spectrum of genetic diseases?
Genetic diseases range from those caused by a single gene mutation (e.g., Duchenne muscular dystrophy) to those influenced by both genetic and environmental factors (e.g., spina bifida), and those primarily caused by environmental factors with minimal genetic influence (e.g., scurvy, tuberculosis)
Name some diseases caused by genetic factors
- Duchenne muscular dystrophy
- Haemophilia
Name some diseases caused by environmental factors
- Tuberculosis
- scurvy
Name some human diseases caused by both environmental and genetic factors
- Spina bifida
-diabetes
-ischaemic heart disease
What characterises genetic factors in causing human disease?
- Rare
- genetics simple
- unifactorial
- high recurrence rate
What characterises environmental factors causing human disease?
- Common
- Genetics complex
- Multifactorial
- Low recurrence rate
What can mutations in genes cause?
Loss or gain of gene function
What ways can mutations affect genes?
- Involve a single gene (Mendelian inheritance)
- Involve a chromosomal segment (or whole chromosome) which affects thousands of genes
- Involve several genes acting with environmental influences (multifactorial inheritance)
What is multifactorial inheritance?
- Involves multiple genes and environmental factors
- Examples include spina bifida, where both genetic susceptibility and environmental influences (like maternal health) contribute to the condition.
- Variants in genes causing alteration in function
What are mitochondrial disorders?
Generally affect organ systems with high energy requiments
What are chromosomal disorders?
- Caused by mutations or abnormalities in large segments of chromosomes, which may involve hundreds or thousands of genes (imbalance causes alteration in gene dosage)
- Excess or deficiency of genes or structural changes in chromosomes
- Typically result in syndromes with multiple symptoms affecting various systems in the body
What are somatic disorders?
Cause cancer,inactivation of both alleles (two’hits’ ) of a gene involved in growth
Where are genes controlling structure and function of mitochondria found?
Both mitochondrial and nuclear DNA
What are single-gene disorders?
Single-gene disorders are caused by mutations in one gene, often resulting in the loss of gene function. They can follow patterns of inheritance such as autosomal dominant, autosomal recessive, and X-linked
What is a genotype?
A pair of alleles at a locus
What is a phenotype?
The observable characteristics of an individual resulting from the interaction of its genotype with the environment
What is autosomal dominance?
- What we call a dominant allele (mutation) will determine a phenotype when only one copy is present in the genome of the individual
- Not from the sex chromosomes (not the X or Y chromosomes)
Give some examples of autosomal dominant disorders
- Achondroplasia - dwarfism (mutation of FGFR3 gene)
- Marfan Syndrome - connective tissue disorder-patients very tall (mutation of FBN1 gene)
- Neurofibromatosis
What are the features of autosomal dominant inheritance?
- Affected individuals in every generation
- Male and female equally likely to be affected
- Inherited from one OR other affected parent, BUT can be a new mutation e.g. neurofibromatosis, achondroplasia - known as a de novo mutation
What type of mutant phenotypes are in autosomal dominant families?
Usually only the wild type and heterozygous mutant phenotypes encountered
Can homozygous mutant phenotypes occur in autosomal dominant disorders?
- Very rare and not seen
- Usually very severe phenotypes which are often lethal
What is autosomal recessive inheritance?
- Both copies of the gene must be mutated for the disease to manifest
- Carriers (with one mutated allele) typically do not show symptoms
What is the best example of a autosomal recessive disease?
Cystic fibrosis
What are the features of cystic fibrosis?
- Affects the lungs, pancreas, sweat glands, and sometimes other organs
- 4% of caucasians are carriers of CF mutation
What effect does cystic fibrosis have on the body?
- Encodes a transmembrane protein (CFTR) that transports chloride ions
- Mutations disrupt this chloride conductance
How is cystic fibrosis inherited?
- Follows autosomal recessive inheritance. Both parents must be carriers for the disease to manifest in their child
- The chance of having an affected child is 1 in 4 if both parents are carriers
What are examples of recessive disorders?
- Hemochromatosis: A disorder affecting iron metabolism, leading to organ damage.
- Sickle cell disease: Caused by mutations in the beta-globin gene, leading to severe anemia.
- PKU (Phenylketonuria): A metabolic disorder that can cause brain damage if not managed early with a special diet.
What is the carrier frequency of sickle cell disease in African populations? What is the molecular cause?
- Approximately 1 in 12 in African populations, leading to an incidence of 1 in 600 for the disease in those populations
- A mutation in the beta-globin gene, which leads to abnormal hemoglobin production, resulting in sickled red blood cells that can block blood flow and cause severe anemia
Why do recessive genetic disorders often have carriers? How they be identified?
- Carriers typically do not show symptoms, because the normal allele compensates for the mutated one, but they can pass the mutation onto their offspring
- Genetic testing can identify them
- They have one normal and one mutated allele for a given gene
What is the Punnett square and how does it relate to inheritance?
- Used to predict the inheritance of genetic traits
- For recessive disorders, there is a 1 in 4 chance that two carrier parents will have a child with the disorder
How does genetic counseling relate to autosomal dominant and recessive diseases?
- Genetic counseling helps families understand inheritance patterns, risks, and the likelihood of passing on genetic disorders
- This is particularly important for autosomal dominant diseases where new mutations can complicate inheritance predictions
What are some of the challenges in genetic counseling for dominant diseases?
- Genetic counseling for dominant diseases can be complex due to the possibility of new mutations (de novo mutations), meaning parents can be unaffected but still pass on the mutation to their children
- Adds an element of uncertainty when predicting inheritance patterns
What is the genetic basis for why some diseases are dominant and others recessive?
- Recessive mutations typically occur because the loss of function of one allele can be compensated by the other normal allele. Homozygous recessive mutations cause disease because there is no functional allele to compensate.
- Dominant mutations often cause disease because the mutation in one allele is sufficient to disrupt function, even if the other allele is normal.
What are de novo mutations?
- De novo mutations are new mutations that occur in an individual, not inherited from either parent
- They can cause dominant diseases even if neither parent shows symptoms
What does penetrance mean in genetics?
- Penetrance refers to the proportion of individuals with a particular genetic mutation who actually express the associated phenotype
- In some genetic conditions, such as spina bifida, the condition may be genetically influenced but not fully penetrant, meaning not all individuals with the mutation will show the disease
What is the importance of residual gene product in a heterozygous state with one normal and one mutant allele?
If the residual gene product is insufficient to maintain normal function, the mutation may cause a dominant genetic disorder
What does “dominant” mean in terms of genetic inheritance?
A dominant disorder occurs when a single copy of a mutant allele is enough to cause the disorder, even if one normal allele is present
What is haploinsufficiency?
Haploinsufficiency refers to a situation where one copy of a gene is not enough to provide sufficient gene product for normal function, leading to a disorder
What is an example of a disorder caused by haploinsufficiency?
Hypercholesterolemia, where one defective receptor gene leads to insufficient regulation of cholesterol
What is gene dosage and how can it affect phenotype?
- Gene dosage refers to the number of copies of a gene
- A loss or increase in gene dosage can lead to disorders depending on whether the gene needs one or two functional copies to maintain normal function
- An increase in gene dosage, like in trisomy 21, can lead to disorders such as Down’s syndrome
What is meant by altered expression of messenger RNA?
- Refers to the loss/disruption of regulation in gene transcription, resulting in abnormal or inappropriate levels of mRNA
- E.g. the persistence of fetal hemoglobin in some genetic disorders
What can lead to increased protein activity in genetic disorders?
Mutations can increase the stability of proteins, leading to prolonged activity, which may contribute to diseases like cancer
What is an example of a mutation causing increased protein activity?
Mutations in oncogenes, like the RAF gene, can lead to increased protein activity and contribute to cancer by disrupting normal cell signaling
What are dominant negative effects?
Dominant negative effects occur when a mutated protein interferes with the normal function of the wild-type protein, often seen in multimeric protein disorders
- E.g. multi-protein complex of p53
What is a gain of function mutation?
Results in a protein having new or abnormal activity, contributing to conditions like cancer from gene fusions
What is an example of a mutation causing constitutive activation of a protein?
- Bladder cancer
- A mutation in the RAF gene prevents its deactivation, leading to uncontrolled signaling and tumor formation
What is the characteristic of X-linked inheritance?
X-linked inheritance leads to higher incidence in males, and affected fathers pass the mutation to all daughters, but never to sons
What is an example of an X-linked disorder?
Haemophilia, which is an X-linked recessive disorder, primarily affects males
What does gene duplication mean in terms of genetic disorders?
Gene duplication is when a portion of the DNA is copied more than once, leading to an increase in gene product, which can result in conditions like neurological disorders
What is the significance of genetic mutations in tumor development?
Mutations in certain genes, such as those involved in cell cycle regulation, can lead to unchecked cell growth, contributing to tumor formation
What are multifactorial inherited disorders caused by?
A combination of small variations in genes and environmental factors
Give examples of multifactorial diseases
Spinal Vista, heart disease, type 2 diabetes, obesity, mental illness, Alzheimer’s, alcoholism
What type of disorders are caused by mitochondrial diseases?
Diseases affecting organs with high energy demands, often involving neuromuscular issues
How is mitochondrial DNA inherited?
Mitochondrial DNA is inherited maternally (from the mother)
What is the mutation rate in mitochondrial DNA compared to nuclear DNA?
The mutation rate in mitochondrial DNA is about ten times higher than in nuclear DNA
What is heteroplasmy in mitochondrial DNA?
Heteroplasmy refers to a mixture of normal and mutated mitochondrial DNA in a cell, leading to varied expression of mitochondrial diseases
What is the mitochondrial bottleneck?
A process during egg cell development where the number of mitochondria is reduced before being propagated, influencing the spread of mitochondrial mutations in offspring
What is the significance of the percentage of mutated mitochondria?
The severity of mitochondrial diseases depends on how many mitochondria carry the mutation; a higher percentage leads to more severe symptoms
What is the clinical variability in mitochondrial diseases due to?
The degree of heteroplasmy, which influences the expression and severity of mitochondrial diseases
What is the function of mitochondrial donation?
It is a technique in IVF that replaces defective mitochondrial DNA in the egg with healthy mitochondrial DNA to prevent the transmission of mitochondrial diseases
Why is mitochondrial DNA prone to mutation?
It has a high proportion of coding DNA, and its structure is more susceptible to mutations compared to nuclear DNA
What can affect the clinical presentation of mitochondrial disorders?
- The number of mutated mitochondria, the tissues affected, and the specific mutation involved
- Severity of the disease is proportional to the number of mutated mitochondria present in tissues
- More mutations lead to more severe manifestations
What is the primary source of ATP in cells?
Oxidative phosphorylation, a process that takes place in the mitochondria
What is the impact of mitochondrial genome mutations on the body?
Mutations in mitochondrial DNA can lead to severe or progressive disorders, especially in organs with high energy requirements
What does reduced penetrance mean in mitochondrial disorders?
It refers to the fact that not all individuals with the mutation will show the disease, and severity can vary even among affected individuals
What is the difference between homoplasmy and heteroplasmy in mitochondrial DNA?
- Homoplasmy occurs when all mitochondria have the same DNA
- Heteroplasmy refers to a mixture of normal and mutated mitochondrial DNA within the same cell
How does mitochondrial recombination differ from nuclear DNA recombination?
Mitochondrial DNA does not undergo recombination, meaning there is no crossing over of genes like in nuclear DNA
What is the typical structure of mitochondrial DNA?
Mitochondrial DNA is a small, circular molecule containing about 15,000 base pairs
How do mitochondrial mutations spread through a population?
A new mutation can spread within the mitochondrial population if it arises early in development, especially through the mitochondrial bottleneck process
What is a common neuromuscular disease caused by mitochondrial mutations?
Leber’s hereditary optic atrophy, a condition resulting from mutations in the mitochondrial genome
What factors can contribute to variable expression in mitochondrial diseases?
Heteroplasmy levels, the specific tissue affected, and the specific mutation in the mitochondrial DNA
What is the relationship between mitochondrial diseases and the nervous system?
Mitochondrial diseases often present as neuromuscular disorders due to the high energy demands of nervous system tissues
What role do nuclear genes play in mitochondrial function?
Nuclear genes can influence mitochondrial function by encoding proteins that modify or affect the mitochondrial phenotype
What happens if a mutation in the mitochondrial genome reaches the threshold of expression?
If the number of mutated mitochondria exceeds a certain threshold, the disease phenotype will become apparent, affecting the individual
What is the advantage of mitochondrial donation in preventing mitochondrial diseases?
By replacing the defective mitochondrial DNA with healthy DNA from a donor, mitochondrial diseases can be avoided in the offspring
