Genetic Basis Of Human Disease: Polygenic Diseases and Imprinted Disorders

Question 1

Victor McKusick

Answer 1

Established a catalogue of inherited clinical disorders in 1966

Question 2

Single Nucleotide Polymorphisms (SNPs)

Answer 2

• Sequence differences we all exhibit
• An individual human genome exhibits ~10^7 SNPs with any other genome
  
  • ~1 nucleotide difference every ~1200bp
• Distributed randomly across genome
• 
  
  • Polymorphic for T/C
  • ~500,000 SNPs distributed throughout human genome provide detailed map of DNA sequence variation across genome
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Question 3

Using SNPs to ID DNA sequences associated with common diseases:

Steps

Answer 3

Genome Wide Association Studies (GWAS)

1. Genome-wide analysis allows all SNP sequence variation to be catalogued and compared from one person to the next
2. SNPs from pts are compared with healthy genomes (case vs control comparison)
3. SNPs identified that are found more frequently in cases than controls
4. High scoring SNPs associated with disease and may play a potentially causative role in disease process

• Score high on Manhattan plot - strongly associated with disease

Question 4

Genomic Imprinting In Mammals

Answer 4

• Structural modifications to specific regions of particular chromosomes that prevent transcription of genes within such regions
  
  • incl methylation of DNA sequences

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• Reciprocal genomic imprinting

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Question 5

Genomic Imprinting

Maternal and Paternal Imprinting

Answer 5

• Maternal/ paternal imprints are stable but not permanent epigenetic changes
• Maintained in somatic cells
• Erased in embryonic precursers of germ cells during development of offspring
• Re-established during spermatogenesis/ oogenesis depending on sex of offspring
• =>Imprints are selectively removed from germline and re-established depending on sex of offspring

Question 6

Genomic Imprinting

Mutation

Answer 6

• Since only one of 2 alleles of an imprinted gene is transcribed in somatic cells, heterozygosity for a mutation that inactivates the product encoded by the transcribed copy may cause disease

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Question 7

Disorders Of Genomic Imprinting

Prader-Willi Syndrome

Answer 7

• Signs:
  
  • Low muscle tone
  • Short stature
  • Cognitive disability
  • Chronic hunger
  • Morbid obesity
• Mutated paternal copy of SNORD116
  
  • No functional gene product will be synthesised as silent maternal allele
• Maternal imprint
• Affect both boys and girls: the genomic imprints and origins of syndromic mutations are parent of origin specific

Question 8

Disorders Of Genomic Imprinting

Angelman Syndrome

Answer 8

• Signs:
  
  • Cognitive disability
  • Sleep disturbance
  • Seizures
  • Jerky movements
  • Frequent ‘smiling’
• No functional gene product of UBE3A is synthesised due to maternal mutation and silent paternal allele
• Paternal imprint
• Affect both boys and girls: the genomic imprints and origins of syndromic mutations are parent of origin specific