Summary: Eigen Hmd Samenvatting Week 4 Tot Week 8

Read the summary and the most important questions on eigen HMD samenvatting week 4 tot week 8

• 1 molecular pathology - effects of genetic variation on gene function

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• What is a variant and a polymorphism?

  Variant = a DNA sequence that does not correspond with the reference genome.
  polymorphism = a common (~50% population frequency genetic variant) a benign variant

• What means LoF and GoF?

  • Loss-of-function = variant reduce or abrogate gene function
    
  • more likly to happen
  • many wyas to lose activity
  • acquiring functions requires one specific event
  • gain-of-function = variants enhace or create novel gene function

• What sort of mutations in dominant disorders? (3)

  1. Gain of function
     
  2. haploinsufficieny
  3. dominant negative
     

• What sort of mutations in recessive disorders?

  1. Loss of function
     
  2. hypomorph

• 1.1 SNVs and indels causing LoF

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• What happens if a SNVs (single nucleotide variant) introduce a stopgain?

  You can gain stopcodons. A variant that is changes to a stopcodon gives you los of a part of the protein. So loss of funtion.
  how much impact it has depends on the lenght of the protein missing after the premature stopcodon

• What happens when a SNVs initiate a startloss?

  • You loss the AUG
    
  • If you have the SNV that gives you a startloss than yoy will have a loss of function. In this case you have an other AUG, so you only mis a small part of the protein. In this case you need more moleculair information to kown if it is a loss of function of the protein. 
    

• What does nonsense mediated decay?

  • It degrades mRNA with a premature stopcodon, because the exon junction complexes (ECJ) are still present. 
  • In case of a permature stopcondon the ECJ stays on the mRNA and the mRNA is degrated, by nonsense mediated decay
    
  • if the permature stopcodon occures in the last exon there is no ECJ, so no nonsense mediated decay. 
  • pre last exon it is also not always detected
  • it needs to be 50NT upstrem of last exon-exon junction

• 1.2 structural variation

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• What are the 3 sort of copy number gains and the context?

  1. Tandem gene duplicate
     
  1. it is hypermorph
  2. disruptive insertion
  1. loss of function, the insert part can have a premature stopcodon or frame shift but can also be neomorph
  3. gene fusion
  1. gain of function (hypermorph)
  2. identifying is hard with short reads NGS, because you need to find the overlap
  1. nanopore is better --> long read

• 1.3 repeat expansions

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• what occures with repeat expansions?

  • Slippage can occure, can cause repeat expension
  • repeats can fold on to them selfs and give replication difficulty
  • repeats near promoter regions

• 1.5 missense variants

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• Molecular impact of missense variants?

  • Often neutral variation, because only one nucelotide is mutated
  • can be conservated when functionele