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ABC for the AEA

ABC for the AEA. Basic biological concepts for genetic epidemiology. Martin Kennedy Department of Pathology Christchurch School of Medicine. Topics. DNA, chromosomes & genes Transcription and translation Sex, meiosis, and all that Mendelian inheritance Molecular biology methods

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ABC for the AEA

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  1. ABC for the AEA Basic biological concepts for genetic epidemiology Martin Kennedy Department of Pathology Christchurch School of Medicine

  2. Topics DNA, chromosomes & genes Transcription and translation Sex, meiosis, and all that Mendelian inheritance Molecular biology methods Types of DNA variation

  3. DNA, chromosomes & genes

  4. Chromosome structure

  5. Base pairing

  6. Eukaryotic genes are split • Exons - fused to form mRNA • Introns - spliced out of mRNA • (intron = intervening sequence)

  7. Genome statistics 3 billion basepairs 5-10% coding sequences 23 pairs of chromosomes 50-60% repeats

  8. Transcription & translation

  9. promoter transcription nuclear RNA AAAAAA splicing 3’ UTR 5’ UTR messenger RNA AAAAAA AUG TAG Typical gene structure

  10. Ribonucleic acid (RNA)

  11. From gene to protein

  12. The genetic code

  13. Proteins

  14. Protein folding

  15. Summary

  16. Sex, meiosis, and all that

  17. Definitions GeneA functional unit of inheritance GenomeAll of the genetic material in the chromosomes of an organism AlleleAlternative forms of a gene or marker due to changes at the DNA level LocusThe physical location of a gene Genotype The specific alleles present for a given gene or set of genes HaplotypeA particular combination of alleles in a specific region of a chromosome

  18. Mitosis Daughter cells Meiosis Gametes Cell divisions

  19. Recombination Meiosis Gametes

  20. Mendel’s laws Good for peas, people and anything else that has sex Segregation: The reproductive cells of hybrids randomly transmit either one or the other of paired parental alleles to their offspring. The alleles are unchanged during passage through each generation. Independence: When individuals with different alleles of more than one gene are crossed, alleles of each gene are assorted into the offspring (segregated) independently of the others. This law applies only when there is no linkage between the genes.

  21. Mendelian inheritance • Mendelian conditions generally have a monogenic basis - “causative genes” • Complex disease is polygenic or multifactorial - “susceptibility genes”

  22. Mendelian inheritance Autosomal dominant

  23. Mendelian inheritance Autosomal recessive

  24. Mendelian inheritance X-linked recessive

  25. Mendelian disorders

  26. Molecular biology methods • Nucleic acid collection • Nucleic acid hybridization • Restriction enzymes • Electrophoresis • Southern blots • Polymerase chain reaction • DNA sequencing

  27. Nucleic acid collection • Blood sample • Buccal swabs • Blood spot on paper • Tissue sample

  28. Nucleic acid hybridization The 2 DNA strands can be dissociated by heat or alkali Complementary strands will reanneal during cooling or under neutral conditions Reannealing is highly specific: only complementary sequences will anneal

  29. Restriction enzymes ---GATTGAG GATCCTTATAT--- ---CTAACTCCTAG GAATATA--- ---GATTGAGGATCCTTATAT--- ---CTAACTCCTAGGAATATA--- ---GATTGAGGATCCTTATAT--- ---CTAACTCCTAGGAATATA--- EcoRI recognition site

  30. Electrophoresis

  31. Molecular biology methods (demos) Southern blot Polymerase chain reaction

  32. DNA sequencing

  33. DNA variation -Polymorphisms occur at more than 1% -Mutations occur at less than 1% • Chromosomal loss, gain or rearrangements • Deletions • Insertions • Inversions • Point mutations/polymorphisms • Trinucleotide repeats (expansions)

  34. transcription nuclear RNA AAAAAA AAAAAA splicing AUG TAG 3’ UTR 5’ UTR messenger RNA DNA variants can occur anywhere in the genome * * * * * * *

  35. DNA variants • Polymorphisms and mutations are the basis of genetic diversity • Polymorphisms provide markers with which we can track the inheritance of chromosomal regions and genes

  36. DNA markers • Restriction fragment length polymorphisms (RFLPs) • Variable number tandem repeats (VNTR) • Microsatellites or short tandem repeats (STRs) • Single nucleotide polymorphism (SNPs)

  37. 691bp 527bp 164bp Restriction fragment length polymorphisms (RFLPs) Exon 3 691bp 527bp 164bp AvaII • Maximum of two alleles • Of limited use for linkage • Commonly used in association analysis • Detected by blot or PCR

  38. Variable number tandem repeats (VNTRs) • Tandem repeats of between 14 and 100bp in length • Multiple alleles • Detected by blot or PCR • Of limited application

  39. Microsatellites or short tandem repeats (STRs) • Detected by PCR • Multiple alleles • Widely used in linkage analysis • Detected by PCR

  40. Single nucleotide polymorphisms (SNPs)

  41. Single nucleotide polymorphisms (SNPs)

  42. Equipment

  43. The genome era

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