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Questions and Answers
What can cause AR disease to appear as a single case in families?
What can cause AR disease to appear as a single case in families?
What does genetic heterogeneity refer to?
What does genetic heterogeneity refer to?
What is a common issue in pedigree analysis?
What is a common issue in pedigree analysis?
What examples illustrate allelic heterogeneity?
What examples illustrate allelic heterogeneity?
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What genetic defect leads to phenylketonuria (PKU)?
What genetic defect leads to phenylketonuria (PKU)?
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What is the phenotype ratio of offspring from a heterozygote cross Rr x Rr?
What is the phenotype ratio of offspring from a heterozygote cross Rr x Rr?
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In an autosomal dominant inheritance pattern, how many copies of the allele are needed to express the trait?
In an autosomal dominant inheritance pattern, how many copies of the allele are needed to express the trait?
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What term describes the effect when a mutation in one copy of a gene results in a disease phenotype due to reduced gene product?
What term describes the effect when a mutation in one copy of a gene results in a disease phenotype due to reduced gene product?
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In pedigree analysis, how are multiple siblings typically arranged?
In pedigree analysis, how are multiple siblings typically arranged?
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Which of the following is an example of a gain of function mutation?
Which of the following is an example of a gain of function mutation?
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What is the typical allele frequency in autosomal dominant diseases?
What is the typical allele frequency in autosomal dominant diseases?
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Which phenomenon occurs when an abnormal protein produced by a mutation interferes with the normal allele's function?
Which phenomenon occurs when an abnormal protein produced by a mutation interferes with the normal allele's function?
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What is the genotype ratio observed in the offspring during a heterozygous cross Rr x Rr?
What is the genotype ratio observed in the offspring during a heterozygous cross Rr x Rr?
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What is the total number of chromosomes in a diploid human cell?
What is the total number of chromosomes in a diploid human cell?
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Which term describes different versions of a gene?
Which term describes different versions of a gene?
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What defines an individual as a homozygote?
What defines an individual as a homozygote?
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What does genetic heterogeneity refer to?
What does genetic heterogeneity refer to?
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Which genotype indicates a heterozygous condition?
Which genotype indicates a heterozygous condition?
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What characterizes autosomal recessive inheritance?
What characterizes autosomal recessive inheritance?
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Which of the following is NOT a characteristic of a phenotype?
Which of the following is NOT a characteristic of a phenotype?
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How many pairs of homologous autosomes do humans possess?
How many pairs of homologous autosomes do humans possess?
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What is eliminated from the bloodstream in familial hypercholesterolemia?
What is eliminated from the bloodstream in familial hypercholesterolemia?
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In autosomal dominant inheritance, what is the expected probability that an offspring will be affected if one parent is affected?
In autosomal dominant inheritance, what is the expected probability that an offspring will be affected if one parent is affected?
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Which condition is characterized by abnormal collagen leading to bone fragility?
Which condition is characterized by abnormal collagen leading to bone fragility?
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What does reduced penetrance refer to in genetics?
What does reduced penetrance refer to in genetics?
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What inheritance pattern is observed in cystic fibrosis?
What inheritance pattern is observed in cystic fibrosis?
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Which of the following genetic conditions displays a vertical pattern in a pedigree chart?
Which of the following genetic conditions displays a vertical pattern in a pedigree chart?
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What is the genotype of an affected individual with an autosomal recessive condition?
What is the genotype of an affected individual with an autosomal recessive condition?
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What ratio results from a cross between two carriers of an autosomal recessive trait?
What ratio results from a cross between two carriers of an autosomal recessive trait?
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Which of these diseases is an example of reduced ability to grow due to a loss of a tumor suppressor gene?
Which of these diseases is an example of reduced ability to grow due to a loss of a tumor suppressor gene?
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What describes the phenotype of individuals in a horizontal inheritance pattern?
What describes the phenotype of individuals in a horizontal inheritance pattern?
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What do you call the genetic makeup of an organism?
What do you call the genetic makeup of an organism?
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Which of the following represents the conditions of a recessive trait's manifestation?
Which of the following represents the conditions of a recessive trait's manifestation?
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What describes a situation where multiple genetic defects can lead to the same phenotype?
What describes a situation where multiple genetic defects can lead to the same phenotype?
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How many sets of chromosomes do diploid individuals have?
How many sets of chromosomes do diploid individuals have?
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Which of the following is a valid example of genetic polymorphism?
Which of the following is a valid example of genetic polymorphism?
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What principle explains that a change in one allele can sometimes lead to a disease phenotype without a complete loss of function?
What principle explains that a change in one allele can sometimes lead to a disease phenotype without a complete loss of function?
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Which genotype is classified as a homozygote?
Which genotype is classified as a homozygote?
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Which of the following best describes how genotypes influence phenotypes?
Which of the following best describes how genotypes influence phenotypes?
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Which statement best describes haploinsufficiency?
Which statement best describes haploinsufficiency?
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What is the expected phenotype ratio from a cross of two heterozygous peas?
What is the expected phenotype ratio from a cross of two heterozygous peas?
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Which inheritance pattern requires only one affected allele in the phenotype expression?
Which inheritance pattern requires only one affected allele in the phenotype expression?
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Which of the following is NOT a result of a dominant negative effect?
Which of the following is NOT a result of a dominant negative effect?
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In an ADHD inherited via X-linked dominant trait, how is inheritance typically observed in pedigrees?
In an ADHD inherited via X-linked dominant trait, how is inheritance typically observed in pedigrees?
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What commonly characterizes autosomal recessive inheritance?
What commonly characterizes autosomal recessive inheritance?
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Which characteristic is associated with a gain of function mutation?
Which characteristic is associated with a gain of function mutation?
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In pedigree analysis, how is the proband typically indicated?
In pedigree analysis, how is the proband typically indicated?
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What challenge does genetic heterogeneity pose in understanding genetic diseases?
What challenge does genetic heterogeneity pose in understanding genetic diseases?
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Which situation is likely to result in difficulty during pedigree analysis?
Which situation is likely to result in difficulty during pedigree analysis?
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What characterizes allelic heterogeneity in genetic conditions?
What characterizes allelic heterogeneity in genetic conditions?
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What is a common consequence of reduced penetrance in genetic diseases?
What is a common consequence of reduced penetrance in genetic diseases?
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What typical feature might indicate a case of autosomal recessive (AR) disease in a family?
What typical feature might indicate a case of autosomal recessive (AR) disease in a family?
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What characterizes the inheritance pattern seen in autosomal dominant disorders?
What characterizes the inheritance pattern seen in autosomal dominant disorders?
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Which of the following is an autosomal recessive condition?
Which of the following is an autosomal recessive condition?
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What describes the expected genotype ratio from a cross between two carriers of an autosomal recessive trait?
What describes the expected genotype ratio from a cross between two carriers of an autosomal recessive trait?
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Which of the following disorders is linked to a mutant protein that damages neurons?
Which of the following disorders is linked to a mutant protein that damages neurons?
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Which statement is true regarding reduced penetrance?
Which statement is true regarding reduced penetrance?
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What is the expected phenotype ratio for offspring when a carrier mates with a non-carrier for an autosomal recessive trait?
What is the expected phenotype ratio for offspring when a carrier mates with a non-carrier for an autosomal recessive trait?
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What does variable expressivity in genetics refer to?
What does variable expressivity in genetics refer to?
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In a typical autosomal dominant mating scenario represented by Aa + aa, what is the probability of the offspring being affected?
In a typical autosomal dominant mating scenario represented by Aa + aa, what is the probability of the offspring being affected?
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Which of the following conditions frequently exhibits a 'horizontal' pattern in pedigree analysis?
Which of the following conditions frequently exhibits a 'horizontal' pattern in pedigree analysis?
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What genetic factor allows for the development of colorectal tumors in familial adenomatous polyposis?
What genetic factor allows for the development of colorectal tumors in familial adenomatous polyposis?
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Which factor could lead to AR disease being perceived as a unique occurrence in families with small sizes?
Which factor could lead to AR disease being perceived as a unique occurrence in families with small sizes?
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In pedigree analysis, which aspect can complicate the identification of accurate genetic relationships?
In pedigree analysis, which aspect can complicate the identification of accurate genetic relationships?
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What is the major complication arising from genetic heterogeneity in clinical phenotypes?
What is the major complication arising from genetic heterogeneity in clinical phenotypes?
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Which of these best illustrates the concept of allelic heterogeneity?
Which of these best illustrates the concept of allelic heterogeneity?
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Which statement most accurately describes a challenge that can arise from reduced penetrance in genetic diseases?
Which statement most accurately describes a challenge that can arise from reduced penetrance in genetic diseases?
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What is the expected phenotype ratio for offspring produced from a cross between two heterozygous parents (Rr x Rr)?
What is the expected phenotype ratio for offspring produced from a cross between two heterozygous parents (Rr x Rr)?
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Which condition is most likely to occur due to a gain of function mutation?
Which condition is most likely to occur due to a gain of function mutation?
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In a pedigree analysis, which symbol typically represents an affected male?
In a pedigree analysis, which symbol typically represents an affected male?
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Which term describes the phenomenon where a mutation produces an abnormal protein that hampers the normal allele's function?
Which term describes the phenomenon where a mutation produces an abnormal protein that hampers the normal allele's function?
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How does haploinsufficiency lead to a disease phenotype?
How does haploinsufficiency lead to a disease phenotype?
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In autosomal dominant inheritance, which statement accurately represents the likelihood of homozygotes surviving to reproductive age?
In autosomal dominant inheritance, which statement accurately represents the likelihood of homozygotes surviving to reproductive age?
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Which protein is commonly affected in familial hypercholesterolemia?
Which protein is commonly affected in familial hypercholesterolemia?
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What distinguishes locus heterogeneity from allelic heterogeneity in genetic conditions?
What distinguishes locus heterogeneity from allelic heterogeneity in genetic conditions?
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Which of the following patterns is typical for diseases caused by autosomal recessive conditions?
Which of the following patterns is typical for diseases caused by autosomal recessive conditions?
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Which of the following best describes the relationship between genotypes and phenotypes?
Which of the following best describes the relationship between genotypes and phenotypes?
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In a diploid organism, how many alleles exist for a single gene in the context of genetic polymorphism?
In a diploid organism, how many alleles exist for a single gene in the context of genetic polymorphism?
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What is the significance of having multiple alleles for a gene in a population?
What is the significance of having multiple alleles for a gene in a population?
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Which of the following statements about autosomal recessive inheritance is true?
Which of the following statements about autosomal recessive inheritance is true?
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What characterizes autosomal dominant inheritance compared to autosomal recessive inheritance?
What characterizes autosomal dominant inheritance compared to autosomal recessive inheritance?
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Which scenario illustrates the concept of reduced penetrance in a genetic condition?
Which scenario illustrates the concept of reduced penetrance in a genetic condition?
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How are genetic heterogeneity and its implications important for understanding genetic disorders?
How are genetic heterogeneity and its implications important for understanding genetic disorders?
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Which statement accurately describes the inheritance pattern of Huntington's disease?
Which statement accurately describes the inheritance pattern of Huntington's disease?
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In which of the following conditions does the function of a protein become detrimental to the cell?
In which of the following conditions does the function of a protein become detrimental to the cell?
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Which of the following statements regarding reduced penetrance is true?
Which of the following statements regarding reduced penetrance is true?
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Which disease is characterized by a vertical pattern in pedigree analysis due to its autosomal dominant inheritance?
Which disease is characterized by a vertical pattern in pedigree analysis due to its autosomal dominant inheritance?
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What is the expected genetic outcome when two carriers of an autosomal recessive disorder mate?
What is the expected genetic outcome when two carriers of an autosomal recessive disorder mate?
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Which of the following factors does NOT affect the expressivity of a genetic trait?
Which of the following factors does NOT affect the expressivity of a genetic trait?
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In the context of familial adenomatous polyposis, what specific genetic event commonly leads to cancer?
In the context of familial adenomatous polyposis, what specific genetic event commonly leads to cancer?
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Which combination represents the most common mating type in autosomal dominant disorders?
Which combination represents the most common mating type in autosomal dominant disorders?
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Which of the following is an example of a condition associated with abnormal collagen resulting in bone issues?
Which of the following is an example of a condition associated with abnormal collagen resulting in bone issues?
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Which of the following patterns is typical for autosomal recessive disorders in pedigree analysis?
Which of the following patterns is typical for autosomal recessive disorders in pedigree analysis?
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Study Notes
Mendelian Genetics
- Genome: all genetic material in an organism, approximately 3 billion base pairs (bp)
- Genome is organized into chromosomes: individual DNA molecules
- Humans have 22 pairs of autosomes and 1 pair of sex chromosomes
- Diploid: 2 sets of chromosomes (n=46), Haploid: 1 set of chromosomes (n=23)
Alleles
- Most cells are diploid containing two homologous copies of each chromosome (one maternal and one paternal)
- Each gene has two copies, one on each chromosome
- Each gene copy is an allele
- Alleles can vary in DNA sequence; these variations are called genetic polymorphisms
Genotypes
- Genotype: genetic makeup
- Phenotype: physical and/or biochemical characteristics of an organism based on the genotype
- Phenotype is largely determined by genotype
- Dominant allele: determines phenotype even when paired with a recessive allele
- Recessive allele: only determines phenotype when paired with another recessive allele
Simple Mendelian Inheritance
- Traits can be dominant (eg. in peas, round shape is dominant) or recessive (eg. wrinkled shape is recessive)
- Heterozygous: two different alleles
- Homozygous: two identical alleles
Mendelian Inheritance Patterns
- Autosomal dominant (AD)
- Autosomal recessive (AR)
- Y-linked
- X-linked dominant
- X-linked recessive
- Mitochondrial
Pedigree Analysis
- Used to identify inheritance patterns in families
- Proband: individual who first brings a family to the attention of a geneticist
Autosomal Dominant Inheritance
- Expressed in both homozygotes (AA) and heterozygotes (Aa)
- Most cases of AD disease are heterozygous because homozygotes may not survive to reproduction age
- Allele frequencies in AD are typically low
How Single Gene Mutations Cause Disease in AD
- Haploinsufficiency: Reduced gene product leads to disease; normal physiology requires >50% of a gene product
- Dominant Negative Effect: Mutant protein interferes with the function of the normal allele
- Gain of Function: Mutant protein functions are enhanced
- Loss of Heterozygosity: Inherited mutation and random loss of the normal allele can lead to cancer
Examples of AD Inheritance
- Familial hypercholesterolaemia: Low LDL cholesterol removal
- Huntington's disease: Neuron damage due to mutant huntingtin protein
- Osteogenesis imperfecta: Fragile bones due to abnormal collagen
- Neurofibromatosis: Uncontrolled cell growth due to loss of neurofibromin protein
- Familial adenomatous polyposis: Development of colorectal tumours due to damage to APC protein
AD Pedigree Characteristics
- Vertical pattern: phenotype seen in every generation
- Affected individuals have an affected parent
- Both sexes have equal probability of being affected
- Approximately 50% of offspring from an affected parent are affected
Most Common AD Mating Type
- Aa + aa
Apparent Exceptions to AD Inheritance Pattern
- Mutations: Sporadic cases due to new mutations
- Variable Expressivity: Different degrees of phenotype severity in individuals with the same genotype
- Reduced Penetrance: Not every individual with the genotype exhibits the phenotype
Autosomal Recessive Inheritance
- Expressed only in homozygotes (aa)
- Heterozygotes are carriers and are usually phenotypically normal
- AR diseases are more common than AD; carriers are not at a selective disadvantage
- AR diseases can become widespread even if affected individuals don't reproduce
AR Pedigree Characteristics
- Horizontal pattern: Affected individuals are in a single sib-ship and disease doesn't occur in multiple generations
- Both sexes affected with equal probability
- When two carriers mate: 25% affected, 50% carriers, 25% normal
Examples of Autosomal Recessive Inheritance
- Cystic fibrosis
- Phenylketonuria
- Albinism
- Sickle-cell anaemia
- α and β thallassaemia
Most Common AR Mating Type
- Carrier x Carrier: Aa x Aa
Less Common AR Mating Types
- Carrier x Affected: Aa x aa
- Normal x Affected: AA x aa
General Problems in Pedigree Analysis
- Uncertain parentage
- Small family size
- Difficulty obtaining accurate information about relatives
- De novo mutations
- Reduced penetrance/variable expressivity
- Genetic heterogeneity
Genetic Heterogeneity
- Different genetic defects can produce similar clinical phenotypes:
- Allelic heterogeneity: Different mutations in the same gene
- Locus heterogeneity: Mutations in different genes, often affecting complex pathways
Allelic Heterogeneity: Example: Phenylketonuria (PKU)
- PKU involves a build-up of phenylalanine and ketones that can lead to mental retardation
- Different mutations in the PAH gene can lead to different levels of enzyme activity and various severities of PKU.
### Genetics Basics
- Genome is the complete set of genetic material, consisting of 3 billion base pairs
- Human genome organized into chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes
- Diploid cells contain 2 sets of chromosomes (n=46), haploid cells have 1 set (n=23)
- Most cells are diploid, containing two homologous copies of each chromosome, one from each parent. Gametes are haploid.
Alleles
- Each gene has two copies, one on each chromosome
- Different versions of a gene are called alleles
- Alleles can vary in their DNA sequence leading to different versions of a gene
- Populations with genes having at least two alleles are considered genetically polymorphic
Genotypes and Phenotypes
- Genotype refers to the combination of alleles an individual possesses e.g., AA, aa, Aa
- Phenotype refers to the physical characteristics determined by the genotype and its interaction with the environment
- Dominant alleles determine the phenotype when present in a heterozygote, a recessive trait only appears in homozygotes
Mendelian Inheritance
- Traits can be followed in families using pedigrees
- Inheritance patterns include: autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, Y-linked
Autosomal Dominant Inheritance
- Disease phenotype appears when one copy of the gene is affected
- Affected individuals are either homozygous or heterozygous for the dominant allele
- The dominant allele is usually rare, thus most cases of AD disease are heterozygous
- AD disease is more likely to be diagnosed in every generation, with affected individuals usually having an affected parent
Mechanisms of Dominance
- Haploinsufficiency: 50% loss in gene product function leads to disease
- Dominant Negative Effect: Abnormal protein interferes with the function of the normal allele
- Gain of Function: Mutant protein has an enhanced function
- Loss of Heterozygosity: Random loss of the normal allele in cells with an inherited mutant allele can lead to cancer
Autosomal recessive Inheritance
- Disease phenotype appears only when both copies of the gene are affected
- Heterozygotes are carriers of the recessive allele
- Carriers are not at a selective disadvantage
- AR diseases are more common than AD
- AR families often display affected individuals in a single generation (horizontal pattern)
- Parents of affected individuals are often carriers
Genetic Heterogeneity
- Different genetic defects can result in identical or similar phenotypes
- Allelic Heterogeneity: Different mutations in the same gene cause the same disease
- Locus Heterogeneity: Mutations in different genes result in the same disease, often involving complex pathways that can be interrupted at multiple points
Examples of Genetic Heterogeneity
- Phenylketonuria (PKU): Different mutations in the PAH gene (encoding phenylalanine hydroxylase) can cause varying degrees of PKU severity.
- Retinitis Pigmentosa: Mutations in different genes involved in the visual pathway can lead to this retinal degeneration.
Mendelian Genetics
- Genome: The complete genetic material of an organism, comprising 3 billion base pairs.
- Chromosomes: Individual DNA molecules that organize the genome.
- Humans have 23 pairs of chromosomes: 22 pairs of autosomes (homologous) and 1 pair of sex chromosomes (heterologous).
- Diploid: Cells with two sets of chromosomes (n=46).
- Haploid: Cells with one set of chromosomes (n=23).
- Alleles: Different versions of the same gene, located at the same locus on homologous chromosomes.
- Genetic polymorphisms: Genes with two or more alleles present in the population.
- Genotype: The genetic makeup of an individual.
- Phenotype: The observable characteristics of an individual resulting from the genotype and its interaction with the environment.
- Dominance: One allele masks the expression of another allele.
- Recessive: An allele whose effect is masked by a dominant allele.
Autosomal Dominant (AD) Inheritance
- Disease phenotype: Only one copy of the gene needs to be affected for the disease to manifest.
- AD traits expressed in: Homozygotes (AA) and heterozygotes (Aa).
- Most AD cases are heterozygous: Homozygotes may be at a selective disadvantage and die before reproductive age.
- Low allele frequencies: typically associated with AD diseases.
Mechanisms of AD Disease
-
Haploinsufficiency: Normal physiology requires more than 50% of the gene product.
- Loss of 50% normal activity of a protein leads to disease.
- Examples: LDL receptor in familial hypercholesterolaemia.
-
Dominant Negative Effect: Abnormal protein interferes with the function of the normal allele.
- Example: Collagen disorders, like osteogenesis imperfecta.
-
Gain of Function: Mutant protein function is enhanced.
- Examples: Achondroplasia and Huntington disease.
-
Loss of Heterozygosity: Inherited copy of a mutant gene and random loss of the normal allele leads to cancer.
- Examples: Retinoblastoma and Familial Adenomatous Polyposis.
Examples of AD Inheritance
- Familial Hypercholesterolaemia: Reduced ability to remove LDL cholesterol from the bloodstream leading to atherosclerosis and early MI.
- Huntington's Disease: Mutant huntingtin protein damages neurons.
- Osteogenesis Imperfecta: Abnormal collagen leads to brittle bones.
- Neurofibromatosis: Loss of neurofibromin protein allows uncontrolled cell growth (NF type 1).
- Familial Adenomatous Polyposis: Damage to APC protein leads to colorectal tumor development.
AD Pedigree Characteristics
- Vertical pattern:" phenotype appears in each generation.
- Affected individuals have at least one affected parent.
- Both sexes affected with equal probability.
- Approximately 50% of offspring from an affected parent will be affected.
Most Common AD Mating Type
- Aa + aa: A (affected allele) is typically present at low frequencies in the population.
Apparent Exceptions to AD Inheritance Pattern
- Mutation: Sporadic cases in families can arise from a new mutation.
- Variable Expressivity: The severity and nature of the phenotype can differ among individuals with the same genotype.
- Reduced Penetrance: Not all individuals with the genotype exhibit the phenotype.
Autosomal Recessive (AR) Inheritance
- Disease phenotype: Both copies of the gene must be affected for the disease to manifest.
- Heterozygotes (Aa) are carriers: Do not have the disease but can pass the affected allele to their offspring.
- AR diseases are more common than AD diseases.
AR Pedigree Characteristics
- Horizontal pattern: Affected individuals tend to be in a single sibship, not seen in multiple generations.
- Both sexes affected with equal probability.
- When two carriers mate: ¼ affected, ½ carrier, ¼ normal.
Examples of AR Inheritance
- Cystic Fibrosis: 1/1600 (USA) frequency, 1/20 is a carrier.
- Phenylketonuria: 1/12000 frequency.
- Albinism
- Sickle Cell Anemia
- α and β Thalassemia
Most Common AR Mating Type
- Carrier x Carrier (Aa x Aa): ¼ AA (normal), ½ Aa (carrier), ¼ aa (affected).
Less Common AR Mating Types
- Carrier x Affected (Aa x aa): ½ Aa (carrier), ½ aa (affected).
- Normal x Affected (AA x aa): All Aa (carrier).
Problems in Pedigree Analysis
- Uncertain Parentage
- Small Family Size
- Accurate Information about Relatives
- De novo Mutation
- Reduced Penetrance/Variable Expressivity
- Genetic Heterogeneity
Genetic Heterogeneity
- Different genetic defects can produce the same or similar phenotypes.
- Allelic Heterogeneity: Different mutations in the same gene lead to the same phenotype.
- Locus Heterogeneity: Mutations in different genes lead to the same phenotype. Often involves complex pathways where disruption at different points can lead to the same outcome.
Allelic Heterogeneity Example: Phenylketonuria (PKU)
- Phenylalanine hydroxylase (PAH) converts phenylalanine to tyrosine: A defect in this pathway leads to a buildup of phenylalanine and phenylketones, which can cause mental retardation.
- Multiple mutations in PAH exist: Some lead to milder forms of PKU with varying degrees of severity.
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Description
Explore the fundamental concepts of Mendelian genetics, including genome organization, alleles, genotypes, and simple inheritance patterns. This quiz covers the essential principles that govern how traits are inherited from one generation to the next.
