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65 Cards in this Set
- Front
- Back
Define: Gene |
Functional unit of DNA that makes some product needed by cells (protein or RNA) |
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Define: Locus |
The unique chromosomal location of a gene |
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Define: Allele |
A variant form of a gene, carried at a locus on a single chromosome |
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Define: Genotype |
The combination of alleles that a person possesses at a single locus or number of loci |
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Define: Phenotype |
Observable characteristics of a person, organ, or cell |
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Define: Homozygous |
Both alleles are the same at an individual locus |
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Define: Heterozygous |
Alleles at a locus are different |
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Define: Hemizygous |
Having only one copy of a gene or DNA sequence |
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Define: Monogenic |
A character in which a single locus is the primary determinant; A particular genotype at a single locus is necessary and sufficient for a particular phenotype under normal circumstances |
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Define: Dominant Disorder/Trait |
Observed in a heterozygote |
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Define: Recessive Disorder/Trait |
Not manifested in a heterozygote |
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Define: Individual Single-Gene Disorders |
Individual Single-Gene Disorders are rare |
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Explain: Principle of Uniformity |
A cross between two parents differing in one trait produces progeny that appear identical to one parent |
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Explain: Principle of Segregation |
Two copies of a gene separate from each other during gamete formation and transmission from parent to offspring |
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Explain: Principle of Independent Assortment |
Alleles of different genes segregate into gametes independently of each other |
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Define: Pedigree |
Graphical representation of a family tree using standard symbols |
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Explain: Pedigree |
- Generations are labelled with Roman numerals (I,II,III) that increase from top to bottom of pedigree - Youngest generation is at the very top - Individuals within a generation are labelled with Arabic numerals (1,2,3) that increase from left to right |
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Define: Kindred |
Extended family with many generations |
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Define: Consanguineous |
Couples who are closely related due to descent from a recent common ancestor |
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What do these symbols represent? |
Male Female Sex Unstated Unaffected Affected Obligate carrier (who will not manifest disease) Carrier who may go on to manifest disease Deceased |
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What do these symbols represent? |
Mating Consanguineous mating Siblings Twins Identical wins Four children, Sex unstated Spontaneous abortion Termination of affected pregnancy |
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What are the five basic Mendelian Inheritance Patterns / Monogenic Inheritance patterns? |
- Autosomal dominant - Autosomal recessive - X-linked dominant - X-linked recessive -Y-linked |
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What is a unique pattern of Monogenic Inheritance? |
Mitochondrial DNA |
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Explain: Autosomal Dominant Inheritance |
- Affected individuals are almost always heterozygous - Homozygotes from rare matings between two individuals are often more severely affected or this may be lethal |
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What are the key features of an Autosomal Dominant pedigree? |
- Affected individuals usually have an affected parent - There are usually affected individuals in every generation - Unaffected individuals do not transmit the disease - Both sexes are affected and equally likely to transmit the disease |
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How does the most common Autosomal Dominant matings look like? |
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How does a rare Autosomal Dominant matings look like? |
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How does an Autosomal Dominant pedigree look like? |
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What are examples of Autosomal Dominant diseases? |
- Achondroplasia - Familial Hypercholesterolemia - Waardenburg Syndrome Type I |
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Explain: Achondroplasia |
- Most common cause of disproportionate small stature (Dwarfism) - Caused by mutations in FGFR3 that cause ligand-independent activation of FGFR3 - 98% of mutations are guanine --> adenine at position 1138 - 80% of patients have a de novo mutation - Homozygous lethal |
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Explain: Familial Hypercholesterolemia |
- Caused by mutation in LDLR - Results in severely elevated low-density lipoprotein (LDL) cholesterol levels and increased risk of coronary disease - Homozygotes experience severe coronary heart disease at early age |
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Explain: Waardenburg Syndrome Type I |
- Hearing loss, dystopia canthorum, and pigment disturbances of the iris, hair, and skin - Cause by mutation of PAX3 - Transcription factor - Active in neural crest cells in developing embryo - Required for proper development of nerve tissue, craniofacial bones, and melanocytes - Homozygotes have more severe phenotype with abnormalities of the arms |
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How does a Waardenburg Syndrome Type I pedigree look like? |
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Explain: Autosomal Recessive Inheritance |
- An affected person carries two mutant alleles at the disease locus, one inherited from each parent - Affected individuals are usually born to unaffected parents - Parents are asymptomatic heterozygous carriers - Affects both sexes equally |
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How does an Autosomal Recessive Matings look like? |
Two carriers (Aa) have a 25% chance of having an affected child |
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Explain: Consanguinity in Autosomal Recessive Inheritance |
- For disorders with unknown inheritance, parental consanguinity is a strong indication of autosomal recessive inheritance - First-cousin marriages and matings most common - Consanguinity produces affected individuals with identical mutant alleles due to common ancestry - If a recessive disorder is quite frequent, carriers will be common in the population - Two common unrelated parents may carry different mutant alleles - Affected individual is often a compound heterozygote, rather than true homozygote |
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How do Autosomal Recessive pedigrees look like? |
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What are examples of Autosomal Recessive diseases? |
- Cystic Fibrosis - Sickle Cell Disease |
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Explain: Cystic Fibrosis |
- Caused by mutation in CFTR which encodes a chloride channel - Incidence ranges from 1 in 313 to 1 in 90,000 in different populations (avg. 1 in 3,200 in US) - Dysfunction impacts many organs that secrete mucus - Respiratory tract, pancreas, genitalia, intestine, sweat glands - In lungs, dehydrated and viscous secretions obstructs airflow and promotes infection |
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Explain: Sickle Cell Disease |
- Highest frequency in African Americans (1 out of 700) - Caused by a mutation in the B subunit of hemoglobin - Glutamic acid --> Valine at amino acid 6 - Mutation causes deoxygenated hemoglobin to form a gelatinous network of stiff polymers that distorts the RBCs - Leads to infarctions and frequent destruction of RBCs - Removal of RBCs exceeds production and leads to hemolytic anemia |
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What is an example of disease-related phenotype of carriers of an Autosomal Recessive disorder? |
Sickle cell heterozygotes may exhibit sickle cell trait - Mild anemia under normal conditions - Extremes of physical exertion, dehydration, and/or altitude can induce disease-like symptoms and even death - ex. Sickle cell trait associated with sudden death in competitive athletes |
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Explain: X-linked Inheritance |
- X chromosome contains many hundreds of important genes - Sex is an important consideration in inheritance patterns due to difference in chromosome composition - Females: XX - Males: XY |
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How does a X-linked Inheritance matings look like? |
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Explain: X-linked Recessive Inheritance |
- Affected individuals are mostly males, usually born to unaffected parents - Mother of an affected male is often a carrier and may have affected male relatives - No transmission from father to son - An affected male will transmit the disease allele to all daughters, who will be carriers but not affected - May appear to "skip generations" due to transmission through a series of carrier females |
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How does an X-linked Recessive pedigree look like? |
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How does an X-linked Recessive pedigree with complications due to inbreeding look like? |
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Explain: X-linked Dominant Inheritance |
- Affected individuals can be of either sex, but there are significantly more affected females than males - No father to son transmission - Usually at least one parent is affected - An affected father will have affected sons but 100% of daughters will be affected - An affected mother will transmit the mutation equally to sons and daughters - 50% chance of an affected child |
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How does an X-linked Dominant pedigree look like? |
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Explain: X-Inactivation |
- In early embryo, number of X chromosomes in each cell is determined - If number is two (or more), all except one of the X chromosomes is inactivated - Causes Barr body - X inactivation occurs randomly beginning around the 8-cell stage - Some cells inactivate paternal X, some the maternal X - Once inactivated, same X chromosome remains inactive in all daughter cells |
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Define: Barr body |
Inactivated X chromosome is induced to form a highly condensed chromosome which is mostly transcriptionally inactive |
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Compare males and females in terms of X chromosome |
- Males are constitutionally hemizygous for X chromosome - Females are functionally hemizygous for X chromosome |
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Define: Mosaics |
Females who are heterozygous for X-linked genes |
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Why are females mosaics? |
- Contain a mixture of genetically distinct somatic cells - Some cells will express the normal allele, while other cells will express the mutant allele - Pattern of X-inactivation is an important consideration for the female phenotype in X-linked disorders |
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What are the impacts of X-Inactivation? |
- Females heterozygous for an X-linked Recessive Disorder may be manifesting heterozygotes - Females heterozygous for an X-linked Dominant Disorder tend to have milder and more variable phenotypes than affected males |
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Explain why females heterozygous for an X-linked Recessive Disorder may be manifesting heterozygotes |
- "Bad Luck" of being affected by the disease, despite being heterozygous for a recessive trait - Occurs when most cells in a tissue critically important in disease development have inactivated the X with the normal allele |
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Explain why females heterozygous for an X-linked Dominant Disorder tend to have milder and more variable phenotypes than affected males |
- The mutant allele is located on an inactivated X in at least a proportion of their cells - Some X-linked dominant disorders are lethal in male, but the milder phenotype in females allows them to survive and even reproduce |
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How does an X-linked Dominant and Male Lethality pedigree look like? |
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What happens to Mosaic females if the phenotype depends on a circulating product? |
- Mosaic females are usually clinically unaffected - Averaging effect of normal and abnormal cells - Ex. Hemophilia A (X-linked recessive) |
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Explain: Hemophilia A |
- Phenotype depends on a circulating product - Mosaic females are usually clinically unaffected - X-linked Recessive - Caused by mutation in Factor 8 gene, which is a required component of blood clotting cascade - Results in severe and prolonged bleeding |
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What happens to Mosaic females if the phenotype is localized to a certain type of cell |
- Mosaic females may exhibit patches of normal and abnormal tissue - Ex. Hypohidrotic Ectodermal Dysplasia (X-linked recessive) |
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Explain: Hypohidrotic Ectodermal Dysplasia |
- Phenotype is localized to a certain type of cell - Mosaic females may exhibit patches of normal and abnormal tissue - X-linked Recessive - Caused by mutations in extodysplasin A, which is required for interaction in early embryo - Results in absence of sweat glands, sparse hair, and missing/abnormal teeth |
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What happens to Mosaic, heterozygous females? |
- Mosaic, heterozygous females may exhibit Skewed X-Inactivation - May occur due to chance alone (unbalanced random inactivation) - May also occur due to a proliferative or survival advantage in cells that inactivate one X chromosome |
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What happens to Mosaic females with X chromosome carrying the mutation? |
- Mosaic females with X chromosome carrying the mutation, may be preferentially inactivated in critical cells or tissues - Ex. Bruton agammaglobulinemia (X-linked recessive) |
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Explain: Bruton agammaglobulinemia |
- Mosaic females with X chromosome carrying the mutation, may be preferentially inactivated in critical cells or tissues - X-linked Recessive - Caused by a mutation in Bruton's tyrosine kinase (Btk) gene that leads to a severe block in B cell development - Males lack mature B cells and require a lifelong infusion of human antibodies - Females have B cells, all of which have mutant X inactivated |
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Why would a normal X chromosome may be preferentially inactivated in Mosaic females? |
In some cases for Mosaic females, the normal X may be preferentially inactivated due to an X-autosome translocation on the mutant chromosome |