Block 4 Lecture Questions Summary Packet 2024 PDF

In lecture Questions Summary Packet FALL 2024  Exam Breakdown 56 questions ◦ Gene Regulation = 7 ◦ Protein Modifications and Aggregation = 4 ◦ Complex Inheritance and Pedigree Analysis = 13 ◦ Neurogenetics and Structural Abnormalities = 8 ◦ Inborn Errors of Metabolism/Common M...

In lecture Questions Summary Packet FALL 2024  Exam Breakdown 56 questions ◦ Gene Regulation = 7 ◦ Protein Modifications and Aggregation = 4 ◦ Complex Inheritance and Pedigree Analysis = 13 ◦ Neurogenetics and Structural Abnormalities = 8 ◦ Inborn Errors of Metabolism/Common Metabolic Disorder = 5 ◦ Molecular Biology of Human Disease = 10 ◦ Cancer Biology = 8 ◦ Cancer Genetics = 7 Common areas of difficulty: ◦ Applying a specific example to a generic situation ◦ Discussing the generalization or background that a specific example in meant to represent These 2 go together. We must see both the trees and the forest to achieve a deeper understanding of the implications and importance of pathogenic variants in Genetics and human disease.  Additional Inheritance and Human Pedigrees Questions An individual inherits a pathogenic variant of a gene: ◦ If the pathogenicity is inherited in an autosomal dominant manner, what are the possible genotypes of the parents? (LO3, LO5, LO6) ◦ AA or Aa for at least 1 ◦ If the pathogenicity is inherited in an autosomal recessive manner, what are the possible genotypes of the parents? (LO3, LO5, LO6) ◦ aa or Aa for both ◦ Affected parents MUST be aa. Unaffected parents MUST be Aa. ◦ Draw the pedigree adding in the following features: the individual is male, neither parent is affected, there are 3 siblings as follows: male with, male without, female without. The maternal grandfather was affected but the maternal grandmother was not (no additional relatives on maternal side). Neither paternal grandparent was affected and one additional child was also not affected. ◦ Condition is most likely recessive. There does appear to be a discrepancy between males and females so it is most likely x - linked though there is insufficient information to confirm. Details on mom’s siblings as well as on any offspring from the two affected sons would be necessary to clarify. What would you expect for manifestation of a genetic disorder if disease phenotype is influenced by environment and no environmental triggers are present? (LO5, LO8) ◦ No phenotype without trigger OR very mild or low presentation ◦ 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.  Gene Regulation Questions Which operon example is turned on when needed? (LO4, LO5) ◦ Lac operon Which operon example also has significant translational regulation? (LO4, LO5) ◦ Trp operon Translational regulation in eukaryotes can be thought of as a method that affects the level of translation and/or _________? (LO6) ◦ Location; affects timing and location What is the role of mRNA higher order structures in regulation? (LO6) ◦ Folding or 3D conformations affect access to both transcriptional and translational machinery 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? (LO4, LO5, LO7) ◦ Can be on due to presence of lactose but will be suppressed as utilization of glucose eliminates cAMP MORE LO7: Presence of GLUCOSE shuts OFF operon because GLUCOSE is a preferred fuel What is the expected consequence in terms of gene expression for the following changes: When lots of glucose metabolism = low cAMP constitutive binding of repressor to operator? and lac operon is OFF (even in absence of ◦ Operon OFF repressor) When glucose metabolism is absent = high cAMP constitutive binding of cAMP to operon? and lac operon can be ON (unless repressor is ◦ Operon ON; cAMP available to promote operon present) 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? ◦ Shortened transcripts (premature termination) or lower level of transcription BOTH have the potential to cause lower function of product Proteins and Protein Aggregation Questions 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? (LO1 and LO3) ◦ Both tertiary and quaternary; loss of molecular interactions 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? (LO1, LO4, and LO5) ◦ 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 The genetic sequence of a protein whose active site is made available via conformational changes induced via phosphorylation is altered turning all serine sites to threonine. What is the potential consequence of this change? (LO6) ◦ As serine/threonine kinases can often simply phosphorylate both residues, this molecule may still retain function provided all other factors are equal ◦ If this was a complete loss in the ability to be phosphorylated, then this could result in a loss of function Neurogenetics Questions A pathogenic variant in the RYR1 gene is observed. ◦ What condition is this associated with? (LO3/LO6) ◦ congenital myopathies; specifically central core myopathies ◦ If this variant is a biallelic change that causes a nonsense mutation, which inheritance pattern is expected? (LO6) ◦ Autosomal recessive ◦ Severe forms of this mutation are linked with which clinical features in addition to the myopathy? (LO4/LO5) ◦ Facial dysmorphisms and severe respiratory involvement  Inborn Errors of Metabolism Questions What is the relationship between metabolic disorders and clinical presentation based on tissues? (LO3 and LO4) ◦ Tissue specificity based on pathway expression; tissues that do not utilize the pathway are not affected A disorder that affects catabolic breakdown of amino acids is most likely to result in what? (LO3, LO5, LO6) ◦ Toxic build-up of the amino acid and/or disruption of downstream pathways Milder PKU could also be thought of as what? (LO5, LO6) ◦ non-PKU hyperphenylalanemia Disorder Gene(s) Onset and Noteworthy or Expected Presentation Fill in the following chart: (LO5, LO6) Fructosemia ALDOB Cross-over with other pathways; correlates with hepatosplenomegaly Galatosemia GALT, GALK1, GALE GALT = most severe; disorder generates galacitol (toxic) PKU PAH Loss of enzyme function can be variable; impacts during pregnancy MSUD BCKDHA, BCKDHB, and DBT Multi-subunit complex needed for breakdown of branched chain amino acids; Branched-chain-α-keto acid dehydrogenase Check-in Questions A family is struggling with infertility and seek additional information from your clinic. Analysis of the male sperm identifies azoospermia. This indicates a loss of function mutation in DAZ associated with the AZFc region on chromosome Y. Evaluation of the male’s father did not indicate any issues with spermatogenesis. What could explain the mutation in the male? ◦ de novo chromosomal rearrangement or mutation in gametogenesis OR mutation during embryogenesis OR confined gonadal mosaicism in parent Increased signaling through which of the following pathways has been associated with a wide range of cardiovascular complications or diseases? A. MAP Kinase signaling B. TGF-B signaling C. Interleukin Signaling D. microRNAs Check-in Question Which of the following hallmarks best explains a cell that no longer responds to death domain signaling induced by either intrinsic or extrinsic mechanisms? A. Self-sufficiency in growth signaling B. Limitless Replicative potential C. Insensitivity to anti-growth signals D. Evading apoptosis E. Sustained Angiogenesis  Check-in Questions Evaluation of cervical cells indicates dysplasia without any accompanying hyperplasia. There is no evidence of infection wit h any form of HPV and the dysplasia is highly localized to one region of the cervix. A scientist uses the cells in an experimental therapy that uses gene editing t hat readily reverses the dysplastic phenotype. Based on this information, in which stage of carcinogenesis were the cells most likely discovered? A. Initiation B. Progression C. Invasion D. Anaplastic growth E. None of these A cancer has been identified as being stage IV with metastatic lesions in multiple tissues. Which of the following best desc ribes the expected appearance of the vasculature at or near a metastatic lesion? A. Capillary bed intact with limited permeability B. Capillary bed intact with complete basement membranes C. Capillary bed altered with limited permeability D. Capillary bed altered with incomplete basement membranes E. Capillary bed altered with small intercellular clefts Check-in Question A somatic mutation in Ras protein is identified in a tumor and is determined to be one of the initiating events for the cancer. Which of the following is most likely true about this mutation? A. The mutation is most likely a loss of function mutation B. The mutation is also a germline mutation C. The mutation is the result of a gene fusion D. The mutation is associated with a sporadic form of the cancer E. None of these are true Big Takeaway: What is more probable familial or sporadic? Some Helpful Tables… THE FOLLOWIN G SLIDES ARE E XCELLENT ST UDY AIDS FOR MAKING KEY CONNECTIONS.  Operons and Gene Activity CONDITION Lac operon activity Trp operon activity High levels of trp Depends; not enough information Formation of aporepressor and reduced transcription Lower free trp but high levels of trp- Depends; not enough information Unlikely to form aporepressor so may tRNA still have transcription but will undergo attenuation and block translation via trp-tRNAs Low glucose, high trp, low lactose Low levels due to low lactose Formation of aporepressor and reduced transcription High glucose; high lactose; high trp Lower than maximum lac activity due Formation of aporepressor and to loss of cAMP reduced transcription  Neuro and Structural… Disorder Associated Genes Details Alzheimer’s disease APP, PSEN1, PSEN2, APOE All of the genes are correlated with autosomal dominant inheritance and disease severity APOE-ε4 (pathogenic variant) is correlated with increasing severity and risk in absence of the others Wolfram Syndrome WFS1 DIDMOAD presentation with autosomal recessive inheritance Huntington’s disease HTT expansion 27-35 repeats = next generation at risk but no risk to parent (CAG repeats) >35 repeats = at risk for disease presentation with increasing probability and severity with increasing number of repeats Spina bifida and MTHFR and many others Closure of the neural tube during development is HIGHLY Myelomeningocele correlated with folic acid metabolism and multiple genes Syndactyly HOXD13 Loss in apoptosis; failure to properly develop structure Congenital myopathies See other more detailed charts! Be able to differentiate the 4 we discussed based on genes and clinical presentation!!  Congenital Myopathies Inheritance Patterns Condition Inheritance Pattern Most Common Most Common change and additional information Gene Implicated Central core Myopathy Autosomal Dominant RYR1 Missense Central core myopathy Autosomal Recessive RYR1 Biallelic mutations; variable missense and nonsense Nemaline Myopathy Autosomal Dominant ACTA1 Missense (often heterozygous) Nemaline Myopathy Autosomal recessive NEB Splice site mutations, frameshifts (+ or -