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Questions and Answers
Humans have 23 pairs of homologous chromosomes.
Humans have 23 pairs of homologous chromosomes.
False
A diploid organism has two sets of chromosomes.
A diploid organism has two sets of chromosomes.
True
Autosomal dominant inheritance requires only one copy of the mutated gene to express the phenotype.
Autosomal dominant inheritance requires only one copy of the mutated gene to express the phenotype.
True
Gametes are diploid cells.
Gametes are diploid cells.
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A genotype is determined solely by environmental factors.
A genotype is determined solely by environmental factors.
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Allelic heterogeneity refers to different mutations at the same locus causing the same phenotype.
Allelic heterogeneity refers to different mutations at the same locus causing the same phenotype.
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PKU is an example used to illustrate genetic heterogeneity.
PKU is an example used to illustrate genetic heterogeneity.
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Homozygotes have two identical alleles for a given gene.
Homozygotes have two identical alleles for a given gene.
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The allele R represents a wrinkled phenotype in peas.
The allele R represents a wrinkled phenotype in peas.
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In a heterozygote cross Rr x Rr, the genotype ratio of offspring is 1:2:1.
In a heterozygote cross Rr x Rr, the genotype ratio of offspring is 1:2:1.
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An autosomal dominant trait requires only one copy of the affected gene to express the phenotype.
An autosomal dominant trait requires only one copy of the affected gene to express the phenotype.
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Homozygotes for autosomal dominant traits are more common than heterozygotes.
Homozygotes for autosomal dominant traits are more common than heterozygotes.
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Haploinsufficiency causes disease when the body has less than 50% of the normal gene product.
Haploinsufficiency causes disease when the body has less than 50% of the normal gene product.
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Dominant negative effects occur when the normal protein function is enhanced.
Dominant negative effects occur when the normal protein function is enhanced.
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X-linked recessive traits can be identified through pedigree analysis.
X-linked recessive traits can be identified through pedigree analysis.
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Gain of function mutations enhances the function of the normal protein.
Gain of function mutations enhances the function of the normal protein.
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AR disease can appear as a single case when families are small.
AR disease can appear as a single case when families are small.
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Genetic heterogeneity means different genetic defects lead to the same clinical phenotype.
Genetic heterogeneity means different genetic defects lead to the same clinical phenotype.
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Allelic heterogeneity involves different genes causing a disease.
Allelic heterogeneity involves different genes causing a disease.
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Phenylketonuria (PKU) can result from various mutant versions of the PAH enzyme.
Phenylketonuria (PKU) can result from various mutant versions of the PAH enzyme.
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Reduced penetrance can complicate pedigree analysis.
Reduced penetrance can complicate pedigree analysis.
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Autosomal dominant inheritance is characterized by a 'horizontal' pattern in pedigrees.
Autosomal dominant inheritance is characterized by a 'horizontal' pattern in pedigrees.
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Carrier individuals in autosomal recessive diseases exhibit the disease phenotype.
Carrier individuals in autosomal recessive diseases exhibit the disease phenotype.
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Both sexes have an equal probability of being affected by autosomal dominant conditions.
Both sexes have an equal probability of being affected by autosomal dominant conditions.
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The penetrance of a genetic condition indicates the severity of the phenotype.
The penetrance of a genetic condition indicates the severity of the phenotype.
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Sickle-cell anemia is an example of an autosomal dominant disease.
Sickle-cell anemia is an example of an autosomal dominant disease.
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Reduced ability to remove LDL cholesterol from the bloodstream is associated with Huntington's disease.
Reduced ability to remove LDL cholesterol from the bloodstream is associated with Huntington's disease.
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Affected individuals with autosomal recessive disorders often occur in multiple generations of a family.
Affected individuals with autosomal recessive disorders often occur in multiple generations of a family.
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Neurofibromatosis type 1 involves uncontrolled cell growth due to loss of the neurofibromin protein.
Neurofibromatosis type 1 involves uncontrolled cell growth due to loss of the neurofibromin protein.
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Huntington's disease is associated with the accumulation of mutant huntingtin protein, which damages neurons.
Huntington's disease is associated with the accumulation of mutant huntingtin protein, which damages neurons.
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Individuals with two copies of a recessive gene are called heterozygotes.
Individuals with two copies of a recessive gene are called heterozygotes.
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A diploid organism has a single set of chromosomes.
A diploid organism has a single set of chromosomes.
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Homozygotes have two different alleles for a given gene.
Homozygotes have two different alleles for a given gene.
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The haploid number of chromosomes in humans is 23.
The haploid number of chromosomes in humans is 23.
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Autosomal recessive inheritance can sometimes appear as a single case in families.
Autosomal recessive inheritance can sometimes appear as a single case in families.
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In a genotype of Aa, the A allele is considered dominant and the a allele is recessive.
In a genotype of Aa, the A allele is considered dominant and the a allele is recessive.
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Genetic polymorphism occurs when there is only one allele present in a population.
Genetic polymorphism occurs when there is only one allele present in a population.
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Phenotype is solely determined by environmental factors.
Phenotype is solely determined by environmental factors.
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Gain of function mutations diminish the activity of the normal protein.
Gain of function mutations diminish the activity of the normal protein.
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Small family size can complicate pedigree analysis due to uncertain parentage.
Small family size can complicate pedigree analysis due to uncertain parentage.
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Locus heterogeneity refers to different mutations producing various phenotypes within the same gene.
Locus heterogeneity refers to different mutations producing various phenotypes within the same gene.
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The demonstration of a partial defect in obligate heterozygotes can indicate a genetic disease.
The demonstration of a partial defect in obligate heterozygotes can indicate a genetic disease.
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De novo mutations have a minimal impact on pedigrees since they occur only in existing families.
De novo mutations have a minimal impact on pedigrees since they occur only in existing families.
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Individuals affected by PKU can have varying degrees of severity due to different mutant versions of the PAH enzyme.
Individuals affected by PKU can have varying degrees of severity due to different mutant versions of the PAH enzyme.
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The phenotype of offspring in a heterozygote cross Rr x Rr follows a ratio of 1:2:1.
The phenotype of offspring in a heterozygote cross Rr x Rr follows a ratio of 1:2:1.
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Autosomal dominant traits are expressed in both homozygotes and heterozygotes.
Autosomal dominant traits are expressed in both homozygotes and heterozygotes.
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Homozygotes for autosomal recessive traits are typically more prevalent than heterozygotes.
Homozygotes for autosomal recessive traits are typically more prevalent than heterozygotes.
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Gain of function mutations typically result in the loss of normal protein activity.
Gain of function mutations typically result in the loss of normal protein activity.
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A mutation leading to haploinsufficiency results in a normal level of gene product when only one copy of the gene is affected.
A mutation leading to haploinsufficiency results in a normal level of gene product when only one copy of the gene is affected.
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Dominant negative effects occur when the product of the mutated gene enhances the function of the normal allele.
Dominant negative effects occur when the product of the mutated gene enhances the function of the normal allele.
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Familial hypercholesterolemia is an example of a dominant negative effect caused by mutations in the LDL receptor.
Familial hypercholesterolemia is an example of a dominant negative effect caused by mutations in the LDL receptor.
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The allele R represents a round phenotype in peas.
The allele R represents a round phenotype in peas.
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Familial hypercholesterolaemia is a condition that leads to reduced ability to remove LDL cholesterol from the bloodstream and can cause atherosclerosis.
Familial hypercholesterolaemia is a condition that leads to reduced ability to remove LDL cholesterol from the bloodstream and can cause atherosclerosis.
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Autosomal dominant inheritance can skip generations, resulting in a 'horizontal' pattern in pedigrees.
Autosomal dominant inheritance can skip generations, resulting in a 'horizontal' pattern in pedigrees.
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In an autosomal recessive pedigree, affected individuals are typically found in multiple generations.
In an autosomal recessive pedigree, affected individuals are typically found in multiple generations.
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Huntington's disease is caused by a toxic accumulation of mutant huntingtin protein that damages neurons.
Huntington's disease is caused by a toxic accumulation of mutant huntingtin protein that damages neurons.
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Osteogenesis imperfecta is associated with excessive collagen production leading to bone fragility.
Osteogenesis imperfecta is associated with excessive collagen production leading to bone fragility.
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Cystic fibrosis is an example of an autosomal dominant disease commonly affecting individuals.
Cystic fibrosis is an example of an autosomal dominant disease commonly affecting individuals.
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Allelic heterogeneity implies that different mutations within the same gene can lead to the same clinical phenotype.
Allelic heterogeneity implies that different mutations within the same gene can lead to the same clinical phenotype.
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In a carrier x affected mating type (Aa x aa), the expected percentage of carriers among the offspring is 50%.
In a carrier x affected mating type (Aa x aa), the expected percentage of carriers among the offspring is 50%.
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Variable expressivity means that individuals with the same genotype may exhibit the phenotype to varying degrees.
Variable expressivity means that individuals with the same genotype may exhibit the phenotype to varying degrees.
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An individual with homozygous recessive alleles for a gene, denoted as AA, will show the recessive phenotype.
An individual with homozygous recessive alleles for a gene, denoted as AA, will show the recessive phenotype.
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Alleles are identical copies of a gene found on homologous chromosomes.
Alleles are identical copies of a gene found on homologous chromosomes.
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A phenotype describes the genetic makeup of an organism.
A phenotype describes the genetic makeup of an organism.
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Homozygotes for a gene can have either two dominant alleles or two recessive alleles.
Homozygotes for a gene can have either two dominant alleles or two recessive alleles.
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In genetic polymorphism, all individuals have only one allele for a particular gene.
In genetic polymorphism, all individuals have only one allele for a particular gene.
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In a heterozygote, the presence of a dominant allele is masked by the recessive allele.
In a heterozygote, the presence of a dominant allele is masked by the recessive allele.
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Autosomal recessive conditions can appear as isolated cases in small families.
Autosomal recessive conditions can appear as isolated cases in small families.
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An individual with two different alleles for a gene is referred to as a homozygote.
An individual with two different alleles for a gene is referred to as a homozygote.
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Autosomal dominant inheritance patterns can show a 'vertical' transmission in pedigrees.
Autosomal dominant inheritance patterns can show a 'vertical' transmission in pedigrees.
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De novo mutations are always inherited from affected parents.
De novo mutations are always inherited from affected parents.
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Locus heterogeneity is characterized by different mutations in different genes leading to the same clinical phenotype.
Locus heterogeneity is characterized by different mutations in different genes leading to the same clinical phenotype.
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Phenylalanine hydroxylase (PAH) is responsible for converting phenylalanine to aspartate.
Phenylalanine hydroxylase (PAH) is responsible for converting phenylalanine to aspartate.
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Accurate information about relatives is essential for effective pedigree analysis.
Accurate information about relatives is essential for effective pedigree analysis.
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Genetic heterogeneity can simplify the understanding of genetic diseases.
Genetic heterogeneity can simplify the understanding of genetic diseases.
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The phenotype of offspring from a heterozygote cross Rr x Rr is expressed in a ratio of 3:1 for the dominant traits.
The phenotype of offspring from a heterozygote cross Rr x Rr is expressed in a ratio of 3:1 for the dominant traits.
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An individual must inherit both copies of a mutated gene to express an autosomal dominant trait.
An individual must inherit both copies of a mutated gene to express an autosomal dominant trait.
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Haploinsufficiency refers to the loss of function when more than 50% of the gene product is required for normal physiology.
Haploinsufficiency refers to the loss of function when more than 50% of the gene product is required for normal physiology.
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Autosomal recessive disorders often affect multiple generations in a pedigree due to their mode of inheritance.
Autosomal recessive disorders often affect multiple generations in a pedigree due to their mode of inheritance.
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Dominant negative effects occur when the abnormal protein enhances the function of the normal protein.
Dominant negative effects occur when the abnormal protein enhances the function of the normal protein.
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Gain of function mutations lead to an increased activity of the normal protein.
Gain of function mutations lead to an increased activity of the normal protein.
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Pedigree analysis can help identify all types of gene mutations, including Y-linked mutations.
Pedigree analysis can help identify all types of gene mutations, including Y-linked mutations.
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The genotype ratio from a heterozygote cross Rr x Rr is 1:2:1.
The genotype ratio from a heterozygote cross Rr x Rr is 1:2:1.
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Huntington's disease is caused by a gain of function mutation in the huntingtin protein.
Huntington's disease is caused by a gain of function mutation in the huntingtin protein.
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In autosomal dominant inheritance, both parents contribute equally to the phenotype of affected offspring.
In autosomal dominant inheritance, both parents contribute equally to the phenotype of affected offspring.
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Cystic fibrosis is an example of an autosomal recessive disorder.
Cystic fibrosis is an example of an autosomal recessive disorder.
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Reduced penetrance means that all individuals with a given genotype will display the associated phenotype.
Reduced penetrance means that all individuals with a given genotype will display the associated phenotype.
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In a carrier x affected cross for an autosomal recessive trait, 50% of the offspring will be affected.
In a carrier x affected cross for an autosomal recessive trait, 50% of the offspring will be affected.
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Variable expressivity refers to the different traits exhibited by individuals with the same genotype.
Variable expressivity refers to the different traits exhibited by individuals with the same genotype.
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Osteogenesis imperfecta is a result of an abnormality in proteins involved in neurotransmission.
Osteogenesis imperfecta is a result of an abnormality in proteins involved in neurotransmission.
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Familial adenomatous polyposis is associated with a mutation affecting the APC protein.
Familial adenomatous polyposis is associated with a mutation affecting the APC protein.
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Autosomal recessive diseases are more likely to appear in every generation of a family.
Autosomal recessive diseases are more likely to appear in every generation of a family.
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Neurofibromatosis type 1 is caused by a recessive mutation.
Neurofibromatosis type 1 is caused by a recessive mutation.
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Autosomal recessive disorders typically skip generations in a pedigree analysis.
Autosomal recessive disorders typically skip generations in a pedigree analysis.
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In humans, the genome consists of 46 chromosomes organized into 23 pairs.
In humans, the genome consists of 46 chromosomes organized into 23 pairs.
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Allelic heterogeneity is the phenomenon where different genes cause the same phenotype.
Allelic heterogeneity is the phenomenon where different genes cause the same phenotype.
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A mutation that leads to gain of function typically enhances the activity of the normal protein.
A mutation that leads to gain of function typically enhances the activity of the normal protein.
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Phenotypes are determined solely by genotypes and do not interact with environmental factors.
Phenotypes are determined solely by genotypes and do not interact with environmental factors.
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Homozygous individuals have two identical alleles for a given gene.
Homozygous individuals have two identical alleles for a given gene.
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In a genotype of aa, the a allele is dominant and will express the phenotype.
In a genotype of aa, the a allele is dominant and will express the phenotype.
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Genetic polymorphism indicates that there are multiple alleles of a gene that exist in a population.
Genetic polymorphism indicates that there are multiple alleles of a gene that exist in a population.
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Genetic heterogeneity can cause identical clinical phenotypes through different genetic defects.
Genetic heterogeneity can cause identical clinical phenotypes through different genetic defects.
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A dominant negative effect occurs when an abnormal protein enhances the function of the normal allele.
A dominant negative effect occurs when an abnormal protein enhances the function of the normal allele.
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Allelic heterogeneity involves variations across different genes leading to identical clinical manifestations.
Allelic heterogeneity involves variations across different genes leading to identical clinical manifestations.
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Haploinsufficiency occurs when the normal physiological function requires less than 50% of the gene product.
Haploinsufficiency occurs when the normal physiological function requires less than 50% of the gene product.
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A partial defect in obligate heterozygotes can be used to indicate the presence of autosomal recessive disorders.
A partial defect in obligate heterozygotes can be used to indicate the presence of autosomal recessive disorders.
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All instances of autosomal dominant conditions will have a pedigree with a 'vertical' pattern of inheritance.
All instances of autosomal dominant conditions will have a pedigree with a 'vertical' pattern of inheritance.
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De novo mutations are genetic changes that arise in an individual and do not originate from either parent.
De novo mutations are genetic changes that arise in an individual and do not originate from either parent.
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Multiple affected siblings within large families suggest a dominant inheritance pattern.
Multiple affected siblings within large families suggest a dominant inheritance pattern.
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The phenotype ratio of offspring from a heterozygote cross Rr x Rr is 1:1.
The phenotype ratio of offspring from a heterozygote cross Rr x Rr is 1:1.
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Mutations in structural proteins can lead to a dominant negative effect as seen in collagen disorders.
Mutations in structural proteins can lead to a dominant negative effect as seen in collagen disorders.
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The genotype ratio for a heterozygote cross Rr x Rr is 2:1.
The genotype ratio for a heterozygote cross Rr x Rr is 2:1.
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In pedigree analysis, the convention dictates that siblings are arranged in order of age from oldest to youngest from left to right.
In pedigree analysis, the convention dictates that siblings are arranged in order of age from oldest to youngest from left to right.
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An example of a gain of function mutation is familial hypercholesterolaemia, which affects the LDL receptor.
An example of a gain of function mutation is familial hypercholesterolaemia, which affects the LDL receptor.
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Autosomal recessive diseases generally show a 'vertical' inheritance pattern in families.
Autosomal recessive diseases generally show a 'vertical' inheritance pattern in families.
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Loss of neurofibromin protein in Neurofibromatosis type 1 leads to uncontrolled cell growth.
Loss of neurofibromin protein in Neurofibromatosis type 1 leads to uncontrolled cell growth.
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Individuals who are heterozygotes can express an autosomal recessive phenotype.
Individuals who are heterozygotes can express an autosomal recessive phenotype.
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The penetrance of a genetic condition indicates the proportion of individuals with a genotype that displays the associated phenotype.
The penetrance of a genetic condition indicates the proportion of individuals with a genotype that displays the associated phenotype.
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Cystic fibrosis is an example of an autosomal dominant disorder.
Cystic fibrosis is an example of an autosomal dominant disorder.
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Familial adenomatous polyposis is characterized by damage to the APC protein that leads to a buildup of benign polyps in the colon.
Familial adenomatous polyposis is characterized by damage to the APC protein that leads to a buildup of benign polyps in the colon.
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Reduced ability to remove LDL cholesterol from the bloodstream is a hallmark of Familial hypercholesterolemia.
Reduced ability to remove LDL cholesterol from the bloodstream is a hallmark of Familial hypercholesterolemia.
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In a typical autosomal dominant trait, 25% of the offspring from an affected individual will show the phenotype.
In a typical autosomal dominant trait, 25% of the offspring from an affected individual will show the phenotype.
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Sickle-cell anemia is classified as an autosomal dominant disease.
Sickle-cell anemia is classified as an autosomal dominant disease.
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Huntington's disease shows variable expressivity, meaning symptoms can differ in severity among affected individuals.
Huntington's disease shows variable expressivity, meaning symptoms can differ in severity among affected individuals.
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Study Notes
Mendelian Genetics
- Genome: comprises all genetic material, totaling 3 billion base pairs (bp). It's organized into chromosomes, which are individual DNA molecules.
- Chromosomes: Humans have 22 pairs of homologous autosomes and one pair of heterologous sex chromosomes.
- Diploid: Cells contain two sets of chromosomes (n=46) - one set from the mother and one set from the father.
- Haploid: Gametes (sperm and egg cells) possess only one set of chromosomes (n=23).
- Alleles: Each gene has two copies, one on each chromosome. These copies are called alleles, and can vary in their DNA sequence.
- Genotype: This term describes the genetic makeup of an individual - i.e., the combination of alleles they possess.
- Phenotype: This term describes the observable physical and/or biochemical characteristics of an individual, determined by the genotype and how it interacts with the environment.
- Dominant Allele: An allele that expresses its phenotype even in the presence of a recessive allele.
- Recessive Allele: An allele that only expresses its phenotype when two copies of the recessive allele are present.
Simple Mendelian Inheritance
- Recessive Traits: Examining a recessive trait in peas as an example, the phenotype can be either round or wrinkled.
- Alleles: Two alleles exist: "R" for round (dominant) and "r" for wrinkled (recessive).
Mendelian Inheritance Patterns
- Autosomal Dominant: A disease phenotype occurs when only one copy of the gene is affected.
- Autosomal Recessive: A disease phenotype occurs only when both copies of the affected gene are mutated.
- Y-Linked: Passed from father to son, mutations in genes on the Y chromosome.
- X-Linked Dominant: Inheritance pattern where a dominant gene is located on the X chromosome.
- X-Linked Recessive: Inheritance pattern where a recessive gene is located on the X chromosome.
- Mitochondrial Inheritance: The inheritance of genetic material located in the mitochondria, passed from mother to child.
Autosomal Dominant Inheritance
- Heterozygotes: Most individuals affected by an autosomal dominant disorder are heterozygotes (Aa) because homozygotes (AA) often face a selective disadvantage and die before reaching reproductive age.
- Haploinsufficiency: A single copy of the normal gene is insufficient to produce the required amount of gene product, leading to disease.
- Dominant Negative Effect: The abnormal protein produced by the mutant allele interferes with the function of the normal allele's product.
- Gain of Function: The mutant protein's function is enhanced, which can lead to disease.
- Loss of Heterozygosity: Often linked with dominant inherited cancers, where the loss of the normal copy of the gene, coupled with the inherited mutant copy, results in cancer.
Autosomal Recessive Inheritance
- Heterozygotes: Individuals carrying one copy of the mutated allele are considered carriers.
- Affected Individuals: Only individuals homozygous for the recessive allele exhibit symptoms.
Genetic Heterogeneity
- Genetic Heterogeneity: Different genetic defects can lead to the same or similar phenotypes.
- Allelic Heterogeneity: Different mutations within the same gene produce the same phenotype, but with varying degrees of severity.
- Locus Heterogeneity: Mutations in different genes, often involved in complex pathways, can lead to the same phenotype.
Mendelian Genetics
- Genome encompasses all genetic material, totalling 3 billion base pairs.
- Chromosomes are individual DNA molecules that organize the genome.
- Humans have 22 pairs of autosomes and 1 pair of sex chromosomes.
- Diploid cells have 2 sets of chromosomes (n=46), while haploid cells have 1 set (n=23).
- Alleles are different versions of a gene, occurring due to slight variations in DNA sequence.
- Genotype refers to an individual's genetic makeup, while phenotype describes their observable characteristics.
- A dominant allele expresses its trait even if the other allele is recessive.
- Recessive alleles only express their traits when paired with another recessive allele.
- Genetic polymorphism refers to genes with two or more alleles in a population.
- Haploinsufficiency describes situations where a 50% loss of normal gene product leads to disease, for example, LDL receptor deficiency.
- Dominant negative effect occurs when an abnormal protein produced by a mutant allele interferes with the normal allele's product, such as in collagen disorder.
- Gain of function refers mutations enhancing the function of a protein, like in Achondroplasia or Huntington disease.
- Loss of heterozygosity in tumor suppressor genes can lead to cancer, as an inherited mutation combined with the random loss of the normal allele renders cells cancerous.
- Vertical pattern of inheritance occurs in Autosomal Dominant (AD) disorders, where the phenotype appears in every generation.
- Affected individuals with AD disorders have a 50% chance of passing on the trait.
- Variable expressivity refers to the varying severity or nature of the phenotype even within families.
- Reduced penetrance describes situations where individuals carrying a specific genotype might not exhibit the corresponding phenotype.
- Horizontal pattern is characteristic of Autosomal Recessive (AR) inheritance, meaning affected individuals are typically within a single generation.
- AR disorders tend to appear as a single case in small families but can present as multiple affected siblings in larger families.
- Genetic heterogeneity is a complex phenomenon where different genetic defects can cause similar phenotypes.
Allelic vs. Locus heterogeneity
- Allelic heterogeneity: Different mutations within the same gene result in similar phenotypes.
- Locus heterogeneity: Mutations in different genes can lead to the same phenotype, indicating that the genes involved are part of a complex pathway.
- Example of allelic heterogeneity: Phenylketonuria (PKU) arises from various mutations in the PAH gene, all affecting phenylalanine metabolism.
- Example of locus heterogeneity: Retinitis pigmentosa, caused by mutations in different genes involved in photoreceptor function.
Learning Objectives
- Identify inheritance models in genetic disease from pedigrees.
- Describe autosomal dominant inheritance and explain exceptions in pedigrees.
- Explain how a mutation at a single gene can cause a disease phenotype.
- Describe autosomal recessive inheritance.
- Explain genetic heterogeneity, distinguishing between allelic and locus heterogeneity.
- Illustrate genetic heterogeneity with examples of PKU and retinitis pigmentosa.
Basics
- The genome is all genetic material, containing 3 billion base pairs (bp).
- The genome is organized into individual DNA molecules called chromosomes.
- Humans have 22 pairs of homologous autosomes and 1 pair of heterologous sex chromosomes.
- Diploid cells have 2 sets of chromosomes (n=46).
- Haploid cells have 1 set of chromosomes (n=23).
Alleles
- Most cells are diploid, containing two homologous copies of each chromosome (one maternal and one paternal).
- Gametes are haploid.
- Two copies of each gene exist, one per chromosome.
- Each gene copy is called an allele.
- Alleles can vary slightly in their DNA sequence and result in different alleles of a gene, for example, A and a.
- Genes with two or more alleles in a population are called genetic polymorphisms.
Genotypes
- Different alleles combine to produce different genotypes:
- AA or aa: Homozygote
- Aa: Heterozygote
- Genotype refers to the genetic make-up of an individual.
- Phenotype refers to the visible or measurable physical and/or biochemical characteristics of an organism.
- Phenotype is largely determined by genotype.
- If A determines phenotype, it is dominant, and a is recessive.
Simple Mendelian Inheritance
- Example: Recessive trait in peas.
- Phenotype: Round or wrinkled.
- Alleles: R (round, dominant) and r (wrinkled, recessive).
- Heterozygote cross (Rr x Rr):
- Gametes: R and r.
- Independent assortment leads to 4 possible arrangements of parental alleles in the offspring.
- Genotype of offspring: 1:2:1
- Phenotype of offspring: 3:1
Mendelian inheritance Patterns
- Autosomal Dominant
- Autosomal Recessive
- Y-linked
- X-linked Dominant
- X-linked Recessive
- Mitochondrial
- Identified in families by pedigree analysis.
Standard Symbols in Pedigree Analysis
- Proband: The individual whose phenotype first brought the family to medical attention.
Autosomal Dominant Inheritance
- A mutation in one copy of the gene can cause disease.
- AD traits are expressed in homozygotes (AA) and heterozygotes (Aa).
- Most cases of AD disease are likely heterozygous, as homozygotes may be at a selective disadvantage and die before reproductive age.
- Allele frequencies in AD disease are usually low.
How a mutation in a single copy of the gene can cause a disease phenotype:
- Haploinsufficiency: Normal physiology requires more than 50% gene product. Structures like proteins, transcription factors, receptors, and enzymes, require a certain level of activity to function correctly. Loss of 50% normal activity leads to disease. Example: LDL receptor (familial hypercholesterolaemia).
- Dominant Negative Effect: Abnormal protein interferes with the function of normal allele products. Example: Collagen disorders like osteogenesis imperfecta.
- Gain of Function: Enhanced function of the mutant protein. Example: Achondroplasia, Huntington disease.
- Loss of Heterozygosity: Dominantly inherited cancers occur when an individual inherits a mutant copy of a tumor suppressor gene and randomly loses the normal allele. This can render a cell cancerous. Example: Retinoblastoma, Familial Adenomatous Polyposis.
Examples of Autosomal Dominant Inheritance
- Familial hypercholesterolaemia: Reduced ability to remove LDL cholesterol from the bloodstream, leading to atherosclerosis and myocardial infarction at a young age.
- Huntington’s disease: Mutant huntingtin protein damages neurons.
- Osteogenesis imperfecta: Abnormal collagen leads to bone fragility.
- Neurofibromatosis: Loss of neurofibromin protein allows uncontrolled cell growth (NF type 1).
- Familial adenomatous polyposis: Damage to APC protein allows development of colorectal tumors.
Autosomal Dominant Pedigree
- Characterized by a ‘vertical’ pattern: Phenotype is seen in every generation.
- Every affected individual has an affected parent.
- Both sexes have equal probability of being affected.
- Approximately 50% of the offspring of an affected parent will be affected.
Most Common Autosomal Dominant Mating Type
- Aa + aa: The frequency of A in the population is usually low.
Apparent Exceptions to Autosomal Dominant Inheritance Pattern
- Mutation: Sporadic cases may arise within families due to mutation.
- Variable Expressivity: Expressivity refers to the nature and severity of the phenotype. Individuals with the same genotype may have different degrees of severity.
- Reduced Penetrance: Penetrance refers to the proportion of individuals with a given genotype who show the associated phenotype.
Autosomal Recessive Inheritance
- Only seen in homozygotes: aa.
- Heterozygotes (Aa) are carriers and are not at a selective disadvantage.
- AR diseases are more common than AD.
Autosomal Recessive Pedigree
- Characterized by a 'horizontal' pattern. Affected individuals tend to be in a single sib-ship and disease does not occur in multiple generations.
- Both sexes are affected with equal probability.
- When two carriers mate:
- ¼ affected
- ½ carrier
- ¼ normal
Examples of Autosomal Recessive Inheritance
- Cystic fibrosis: 1/1600 (USA) (1/20 is a carrier)
- Phenylketonuria: 1/12000
- Albinism
- Sickle-cell anaemia
- α and β thallassaemia
Most Common Autosomal Recessive Mating Type
- Carrier x Carrier: Aa x Aa
Less Common Autosomal Recessive Mating Types
- Carrier x Affected: Aa x aa
- Normal x Affected: AA x aa
General Problems in Pedigree Analysis
- Uncertain parentage
- Small human family size
- Accurate information about relatives
- De novo mutation
- Reduced penetrance / variable expressivity
- Genetic heterogeneity
Disease Complexity: Genetic Heterogeneity
-
Genetic heterogeneity: Different genetic defects produce identical or similar clinical phenotypes.
- Allelic heterogeneity: Different mutations in the same gene.
- Locus heterogeneity: Mutations in different genes. Often involves complex pathways that can be interrupted at many points with the same result.
Allelic Heterogeneity: Example - Phenylketonuria (PKU)
- Phenylalanine hydroxylase (PAH) converts Phe to Tyr. A defect in this enzyme leads to a build-up of phenylalanine and phenylketones, potentially causing mental retardation.
- Many different mutant versions of PAH are known, leading to PKU of varying degrees of severity.
Introduction to Inheritance Models in Genetic Diseases
- Pedigrees are a tool to identify inheritance models in genetic diseases.
Autosomal Dominant Inheritance
- AD traits: Expressed in both homozygotes (AA) and heterozygotes (Aa).
- Heterozygotes: Most AD disease cases are heterozygous.
- Selective Advantage: Homozygotes experience a selective disadvantage compared to heterozygotes, often dying before reproductive age.
- Allele Frequency: Allele frequencies in AD diseases are typically low.
How a Single Copy Mutation Causes Disease Phenotype
-
Haploinsufficiency: Normal physiology requires more than 50% of a gene product:
- Structural proteins
- Transcription factors
- Receptors
- Enzymes
-
Loss of 50% normal protein activity can result in disease.
-
Example: Familial hypercholesterolaemia: LDL receptor deficiency.
-
Dominant Negative Effect: An abnormal protein interferes with the function of the normal allele.
- Example: Collagen disorders, like osteogenesis imperfecta (brittle bone disease)
-
Gain of Function: The mutant protein’s functionality is enhanced:
- Example: Achondroplasia, Huntington disease (mutant protein forms aggregates, toxic to the cell)
- Note: Huntington disease demonstrates a novel function which is detrimental to the cell.
-
Loss of Heterozygosity
- Dominantly Inherited Cancers: Involves tumor suppressor genes
- Mechanism: An inherited copy of the mutant gene, coupled with the random loss of the normal allele, even in a few cells, can lead to cancer.
- Examples: Retinoblastoma, Familial Adenomatous Polyposis
Examples of Autosomal Dominant Inheritance
- Familial Hypercholesterolaemia: Reduced ability to remove LDL cholesterol from the bloodstream, leading to atherosclerosis and myocardial infarction at a young age.
- Huntington Disease A mutant huntingtin protein damages neurons.
- Osteogenesis Imperfecta: Abnormal collagen results in bone fragility.
- Neurofibromatosis: Loss of neurofibromin protein allows uncontrolled cell growth (NF Type 1).
- Familial Adenomatous Polyposis: Damage to APC protein leads to the development of colorectal tumors.
Autosomal Dominant Pedigree
-
Key Features:
- Vertical Pattern: Phenotype appears in every generation.
- Affected Parents: Every affected individual will have an affected parent.
- Equal Sex Probability: Both sexes have an equal chance of being affected.
- Offspring Probability: Approximately 50% of an affected parent’s offspring will be affected.
Autosomal Dominant Mating Types
- Most Common: Aa + aa
- Rare: AA + Aa
Apparent Exceptions to AD Inheritance Pattern
-
Mutation: Sporadic cases can arise within families due to a new mutation.
-
Variable Expressivity: The nature and severity of the phenotype vary, but individuals with the genotype will express the phenotype to some degree.
-
Reduced Penetrance: The proportion of individuals with a given genotype who express the phenotype is lower than expected.
Autosomal Recessive Inheritance
- Affected Individuals: Only homozygotes (aa) express the phenotype.
- Carriers: Heterozygotes (Aa) are carriers without any symptoms.
- Carrier Frequency: Affected individuals may not reproduce leading to widespread carrier frequency in the population, despite not expressing the disease
- AR Diseases: More common than AD diseases.
AR Pedigree
-
Key Features:
- Horizontal Pattern: Affected individuals are primarily within a single sib-ship, with the disease not recurring in multiple generations.
- Equal Sex Probability: Both sexes have equal probability of being affected.
- Carrier x Carrier Mating: When two carriers mate, the offspring have a ¼ chance of being affected, a ½ chance of being a carrier, and a ¼ chance of being normal.
Examples of Autosomal Recesive Inheritance
- Cystic Fibrosis: One in 1600 individuals in the USA are affected (carrier frequency of 1/20)
- Phenylketonuria: One in 12,000 individuals are affected.
- Albinism
- Sickle-cell anemia:
- α and β thallassaemia:
Autosomal Recessive Mating Types
-
Most Common: Aa x Aa
- ¼ AA - normal
- ½ Aa - carrier
- ¼ aa - affected
-
Less Common:
- Carrier x Affected: Aa x aa
- Normal x Affected: AA x aa
General Problems with Pedigree Analysis
- Uncertain Parentage Information about family relationships might be unclear.
- Small Family Size: Small families make it difficult to observe clear inheritance patterns.
- Accurate Information: Incomplete or inaccurate information regarding family members can hinder pedigree analysis.
- De Novo Mutation: A new mutation may arise spontaneously, affecting the analysis.
- Reduced Penetrance/Variable Expressivity: Individuals with the genotype may not show the phenotype, or they may express it differently.
- Genetic Heterogeneity : Different genetic defects can cause the same or similar phenotypes, making interpreting pedigrees more complex.
Disease Complexity: Genetic Heterogeneity
-
Genetic Heterogeneity: Different genetic defects lead to identical or similar clinical phenotypes.
-
Allelic Heterogeneity: Different mutations in the same gene.
-
Locus Heterogeneity: Mutations in different genes, often within complex pathways, can be disrupted at many points, leading to the same outcome.
Allelic Heterogeneity Example: Phenylketonuria (PKU)
- Affected Gene / Pathway: Phenylalanine hydroxylase (PAH) converts phenylalanine (Phe) to tyrosine (Tyr) in the phenylalanine degradation pathway. A defect in PAH causes a buildup of phenylalanine and phenylketones.
- Symptoms: Can lead to mental retardation.
- Mutations: Multiple mutant versions of PAH exist, leading to varying degrees of PKU severity.
- Enzyme Activity: PAH mutant versions have varying levels of enzyme activity, influencing disease severity.
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Test your knowledge of Mendelian genetics, including key concepts such as genome structure, chromosome pairs, and the differences between diploid and haploid cells. Explore terms like genotype and phenotype, and understand the roles of dominant and recessive alleles. This quiz is perfect for students studying genetics.
