Autosomal Inheritance and Pedigree Analysis
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Questions and Answers

If the pathogenicity is inherited in an autosomal dominant manner, what are the possible genotypes of the parents?

  • Only AA
  • AA or aa
  • Aa or aa
  • AA or Aa (correct)

    • If the pathogenicity is inherited in an autosomal recessive manner, what are the possible genotypes of the parents?

  • Only aa
  • AA or aa
  • AA or Aa
  • aa or Aa (correct)

    • If the pathogenicity is inherited in an autosomal recessive manner, what is the genotype of the offspring if both parents are affected?

  • AA
  • Aa
  • aa (correct)
  • Any of the above

    • What would you expect for manifestation of a genetic disorder if disease phenotype is influenced by environment and no environmental triggers are present?

    <p>No phenotype without trigger OR very mild or low presentation</p> Signup and view all the answers

    What would you expect for manifestation of a genetic disorder if the environmental trigger merely increases severity?

    <p>If the environmental trigger merely increases severity (i.e. XP tumor presentation) then I would expect a later timeline for onset of the phenotype or less severe phenotypes compared to those who experienced the environmental exposures.</p> Signup and view all the answers

    What is the role of mRNA higher order structures in regulation?

    <p>Folding or 3D conformations affect access to both transcriptional and translational machinery</p> Signup and view all the answers

    High levels of glucose are available in the environment along with high levels of lactose. What is the most likely consequence for the Lac operon in terms of relative activity?

    <p>The Lac operon can be on due to presence of lactose but will be suppressed as utilization of glucose eliminates cAMP. (B)</p> Signup and view all the answers

    What is the expected consequence in terms of gene expression for the constitutive binding of repressor to operator?

    <p>The operon will be turned off because the repressor is bound to the operator. (C)</p> Signup and view all the answers

    What is the expected consequence in terms of gene expression for the constitutive binding of cAMP to operon?

    <p>The operon will be turned on because cAMP is bound to the operon. (A)</p> Signup and view all the answers

    A change in sequence prevents mRNA folding. If folding was necessary to enable full transcription of the mRNA, what is the consequence in terms of functional product?

    <p>Shortened transcripts (premature termination) or lower level of transcription, both have the potential to cause lower function of product (D)</p> Signup and view all the answers

    Presence of GLUCOSE shuts OFF operon because GLUCOSE is a preferred fuel of glucose metabolism.

    <p>True (A)</p> Signup and view all the answers

    When lots of glucose metabolism = low cAMP and lac operon is OFF (even in absence of repressor).

    <p>True (A)</p> Signup and view all the answers

    When glucose metabolism is absent = high cAMP and lac operon can be ON (unless repressor is present).

    <p>True (A)</p> Signup and view all the answers

    A protein that does not spontaneously fold and is no longer capable of interacting with folding machinery would not be capable of what level(s) of protein structure?

    <p>Both Tertiary and Quaternary; loss of molecular interactions (E)</p> Signup and view all the answers

    A structurally abnormal protein that is capable of inducing altered structure of normal protein variants would be classified as what and would most likely cause what?

    <p>Prion or prion-like; if capable of causing that change in folding when placed in a new cell or system, then it would be infectious as well. (B)</p> Signup and view all the answers

    A pathogenic variant in the RYR1 gene is observed. What condition is this associated with?

    <p>congenital myopathies; specifically central core myopathies</p> Signup and view all the answers

    A pathogenic variant in the RYR1 gene is observed. If this variant is a biallelic change that causes a nonsense mutation, which inheritance pattern is expected?

    <p>Autosomal recessive</p> Signup and view all the answers

    A pathogenic variant in the RYR1 gene is observed. Severe forms of this mutation are linked with which clinical features in addition to the myopathy?

    <p>Facial dysmorphisms and severe respiratory involvement</p> Signup and view all the answers

    What is the relationship between metabolic disorders and clinical presentation based on tissues?

    <p>Tissue specificity based on pathway expression; tissues that do not utilize the pathway are not affected. (A)</p> Signup and view all the answers

    A disorder that affects catabolic breakdown of amino acids is most likely to result in what?

    <p>Toxic build-up of the amino acid and/or disruption of downstream pathways</p> Signup and view all the answers

    Milder PKU could also be thought of as what?

    <p>non-PKU hyperphenylalaninemia</p> Signup and view all the answers

    Match the following metabolic disorders with the genes implicated:

    <p>Fructosemia = ALDOB Galactosemia = GALT, GALK1, GALE PKU = PAH MSUD = BCKDHA, BCKDHB, and DBT</p> Signup and view all the answers

    Which operon example is turned on when needed?

    <p>Lac operon (B)</p> Signup and view all the answers

    Which operon example also has significant translational regulation?

    <p>Trp operon (A)</p> Signup and view all the answers

    Translational regulation in eukaryotes can be thought of as a method that affects the level of translation and/or what else?

    <p>Location; affects timing and location</p> Signup and view all the answers

    Match the following conditions with the genes implicated:

    <p>Fructosemia = ALDOB Galactosemia = Type I = GALT, Type II = GALK1, Type III = GALE PKU = PAH MSUD = BCKDHA, BCKDHB, DBT</p> Signup and view all the answers

    What is the most common change associated with central core myopathy?

    <p>Missense mutation (C)</p> Signup and view all the answers

    What is the most common change associated with nemaline myopathy?

    <p>Missense mutation (C)</p> Signup and view all the answers

    What is the most common change associated with centronuclear myopathy?

    <p>Missense mutation (A)</p> Signup and view all the answers

    What is the most common change associated with myotubular myopathy?

    <p>Missense mutation (E)</p> Signup and view all the answers

    What is the most common change associated with myosin storage myopathy?

    <p>Missense mutation (E)</p> Signup and view all the answers

    Match the following genetic disorders with their associated genes:

    <p>Alzheimer's Disease = APP, PSEN1, PSEN2, APOE Wolfram Syndrome = WFS1 Huntington's disease = HTT expansion (CAG repeats) Spina bifida and Myelomeningocele = MTHFR and many others Syndactyly = HOXD13 Congenital Myopathies = Various genes including RYR1, ACTA1, NEB, DNM2, MTM1, MYH7</p> Signup and view all the answers

    Flashcards

    Autosomal Dominant Inheritance

    A single copy of a mutated gene from one parent can cause the disorder.

    Autosomal Recessive Inheritance

    Two mutated copies of a gene, one from each parent, are needed for the disorder to develop.

    Parents' genotype (Autosomal Dominant)

    At least one parent must have the mutated gene (Aa or AA).

    Parents' genotype (Autosomal Recessive)

    Both parents must carry the mutated gene (Aa), and affected parents must be homozygous recessive (aa).

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    Lac Operon

    A group of genes that are regulated together, and is turned ON when lactose is available.

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    Trp Operon

    A group of genes that are regulated together, that also has translational regulation.

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    Translational Regulation (Eukaryotes)

    Regulation that affects the level and/or location of protein synthesis.

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    mRNA Higher Order Structures

    mRNA's 3D shape can affect access to protein synthesis machinery, thus affecting gene expression.

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    Lac Operon Activity (High Glucose, High Lactose)

    Operon may be ON due to lactose, but glucose utilization will suppress activity (reduced cAMP).

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    Constitutive Repressor Binding

    Constantly bound repressor, prevents operon expression.

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    Constitutive cAMP Binding

    Always bound cAMP, promotes operon expression

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    mRNA Folding Impairment

    Preventing mRNA folding results in shortened transcripts (premature termination), thus reducing the functional product, or less transcription.

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    Protein Misfolding

    Proteins that don't fold correctly cannot form tertiary and quaternary structures, thus cannot interact.

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    Prion-like Protein

    A misfolded protein capable of inducing misfolding in normal proteins.

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    RYR1 Gene Mutation

    Associated with congenital myopathies, particularly central core myopathies.

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    Biallelic Nonsense Mutation

    Two mutated copies of the gene, that cause premature stop codons, leading to truncated proteins.

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    Metabolic Disorders & Tissue Specificity

    Metabolic disorders affect tissues based on pathway expression, thus tissues not involved are unaffected.

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    Amino Acid Catabolism Disruption

    Disruptions in amino acid breakdown lead to toxic buildup of the amino acid and/or impairment of downstream processes.

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    Mild PKU

    Non-PKU hyperphenylalaninemia; milder form of phenylketonuria.

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    Study Notes

    Autosomal Inheritance

    • If a pathogenic variant is autosomal dominant, possible parental genotypes are AA or Aa (at least one)
    • If a pathogenic variant is autosomal recessive, possible parental genotypes are aa or Aa. Affected parents MUST be aa.

    Pedigree Analysis

    • Pedigree should include the individual as male, and neither parent is affected.
    • Three siblings: male with trait, male without trait, female without trait.
    • Maternal grandfather had the trait, but maternal grandmother did not.
    • Neither paternal grandparent was affected.
    • One additional child also did not have the trait.
    • Condition is likely recessive.
    • Discrepancy between male and female manifestation suggests X-linked inheritance, though more data is needed.

    Environmental Influence on Disease Manifestation

    • Disease phenotype can be influenced by environment, with or without environmental triggers.
    • No phenotype present without the trigger, or very mild presentation.
    • Trigger increases severity (e.g., XP tumor presentation), leading to delayed onset or less severe phenotypes compared to those exposed.

    Operon Regulation

    • Lac Operon: Turned on when needed.
    • Trp Operon: Has significant translational regulation.

    mRNA Regulation in Eukaryotes

    • Regulation affects the level of translation or location.
    • mRNA higher-order structures (folding or 3D conformation) impact access of both transcriptional and translational machinery.

    Operon Regulation - Consequences of Changes

    • Constitutive binding of repressor to operator: Operon OFF.
    • Constitutive binding of cAMP to operon: Operon ON (cAMP can promote operon).
    • Changes in mRNA sequence that prevent folding can result in shortened transcripts or lower transcription levels, reducing functional product.

    Protein Misfolding and Prion-like Proteins

    • Proteins that fail to spontaneously fold and interact with folding machinery lose tertiary and quaternary structure.
    • Structurally abnormal proteins that alter the structure of other normal proteins are classified as prions and can act as infectious agents.

    Protein Phosphorylation and Genetic Variants

    • Changing serine sites to threonine in a protein's sequence affects kinase activity.
    • It might preserve function if other factors remain constant.
    • If it disables phosphorylation, it can lead to a loss of function.

    RYR1 Gene Variant

    • Pathogenic variant in RYR1 gene is associated with congenital myopathies (specifically central core myopathies).
    • Biallelic nonsense mutations in the RYR1 gene indicate autosomal recessive inheritance.
    • Severe mutations are linked to facial dysmorphisms and severe respiratory involvement.

    Metabolic Disorders and Clinical Presentation

    • Clinical presentation of metabolic disorders reflects tissue-specific pathway expression with corresponding tissue impact levels.
    • Disorders affecting amino acid catabolism lead to toxic buildup of amino acids, potentially disrupting downstream pathways.
    • Milder PKU is also classified as non-PKU hyperphenylalaninemia.

    Gene Expression and Lac/Trp Operon Activity

    • Lac Operon: Operon activity depends on high lactose/low glucose leading to cAMP stimulation and decreased repressor binding.
    • Trp Operon: High tryptophan leads to aporepressor formation, blocking transcription/reducing transcription.

    Diseases Associated with Genes

    • Alzheimer's Disease: Genes like APP, PSEN1, PSEN2, and APOE are correlated with autosomal dominant inheritance, with APOE-ɛ4 variant increasing disease severity.
    • Wolfram Syndrome: Autosomal recessive inheritance; presentation is DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness).
    • Huntington's Disease: HTT expansion (CAG repeats) correlates with severity, where more repeats mean higher probability and severity.
    • Spina Bifida and Myelomeningocele/Syndactyly: Neural tube closure during development relates to Folic acid metabolism and multiple genes, highlighting the importance of development and/or loss in apoptosis for structure.
    • Congenital Myopathies: Associated with varied inheritance patterns (Autosomal dominant/recessive/X-linked) and diverse gene mutations (RYR1, ACTA1, etc).

    Other Diseases and Associated Genes (Page 8/9)

    • Asthma and COPD: COX-2 gene is linked to inflammation and mutations.
    • Male Infertility: AZF regions and DAZ genes relate to gametogenesis issues.
    • Metabolic Syndrome: Genes (LDLR, TGF-β, IL-6, SELE) are associated with insulin signaling and combined disease risk.
    • Marfan Syndrome: FBN-1 gene (and potential TGF-β implications) impact cardiovascular risk.

    Cancer Hallmarks

    • Hallmark of Cancer: Diverse aspects of cancer development and evolution are described.
    • Specific Hallmark Examples: Evading apoptosis, self-sufficiency in growth signaling, insensitivity to anti-growth signaling, sustained angiogenesis, limitless replicative potential, tissue invasion and metastases, deregulation of cellular energetics, genomic instability, avoiding immune destruction, tumor-promoting inflammation, cellular regression/de-differentiation are key aspects of cancerous development described to understand and control cancer.

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    Description

    This quiz explores the concepts of autosomal inheritance, including dominant and recessive traits, through pedigree analysis. Test your understanding of how genetic conditions can be inherited and the role of environmental factors in disease manifestation.

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