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MolBio (Fach) / Lecture 6 (Lektion)

Human Genome variation

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  • Locus location of a gene on a chromosome
  • Allele different forms of a gene/DNA sequence
  • Homozygote two allels at one locus are the same
  • Heterozygote two different allels at one locus
  • Hemizygote unpaired genes in an otherwise diploid cell (e.g. X-linked genes in males) 
  • Wild-Type most common allele usually present in more then half of the individuals 
  • Variant allele that differs from the wild type due to DNA-changes
  • Sequence variant, allelic variant, Alteration, change = mutation = single nucleotide polymorphism (SNP)
  • Nature of genetic variation human genome project chromosomal aberration (structural & numerical) alteration of DNA sequence 
  • Chromosomal Aberration (changes,scale,Damage) changes: number/structure of chromosome scale: can include many alterations damage: large scale
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  • DNA-Alterations (changes,scale,damage) Changes: occur in DNA-Base-sequence scale: single gene alteration or alteration of non-coding sequence damage: smal
  • Origin of genetic Variation: spontaneous Errors in DNA-replication (insertion/deletion may lead to DNA slippage)  Errors in DNA reperation Errors in recombination (Meta-, Anaphase) Errors in cell division 
  • Origin of genetic Variation: induced physical: ionized radiation chemical: oxidative stress, deaminating agents  biological: viruses, transposones
  • Mutation-rate average human mutation rage: 1,1 - 1,7 * 10^-8
  • Types of allelic variants and their consequences: Base substitution Missense: -single-nucleotide nonsynonymous replacement of an amino acid in coding region Silent: -single-nucleotide synonymous replacement in coding region Nonsense -single-nucleotide replacemet with a stop-codon in coding region (UAA,UAG,UGA)
  • Human pathology: missense Substitution: Sickle cell anaemia Symptoms: anaemia, tissue infarctions, multiple infections Molecular mechanism: single missense mutation (glutamic acid -> valine) in 6. position in beta-globin chain
  • Base-Substitution: Affecting RNA (transcribtion,processing,translation) splice site mutation  - recognition error Intron <> Exon
  • Types of allelic variants and their consequences: Deletion loss of base pair(s)  can lead to frameshift mutation when missing bases is not 3 or a multiple of 3
  • Types of allelic variants and their consequences: Insertion Insertion of base pair(s) can lead to frameshift mutation when extra bases is not 3 or a multiple of 3  Insertion of mobile elements: -LINE and Alu repeats can cause frameshift mutations Dinamic mutation: -amplification of a simple nucleotide repeat sequence
  • Consequences of allelic variants in functional level Gain-of-function Loss-of-function Dominant negative -abnormal protein inhibits function of normal protein
  • Interpretation of DNA sequence alteration Pathogenic likely pathogenic benign likely benign uncertain significance (VUS) ?
  • Human Pathology: Phenylketonuria (PKU) Example for Loss-of-function: missense substitution error of metabolism deficience of phenylalanine hydroxlase activity can result in hyperphenyalaninemia (can cause impaired cognitive development) missense-substitution: Arg->Trp
  • Chromosomal Aberration: Numerical Aberration: aneuploidy 2n+1 / 2n-1 missegregation of a chromosome (during cell division) one per 25-50 cell cycles
  • Chromosomal Aberration: numerical Aberration: Polyploidy Euploidy: complete set of chromosomes Polyploidy: 3n, 4n  meiotic/mitotic cell division failure
  • Chromosomal aberratio: structural Aberration (in General) can be balanced or unbalanced  can occur when homologous chromosomes line up improperly chromosome breakage
  • Structural aberrations: Deletion Chromosome break - loss of information deletion at chromosomes tip: terminal deletion two breaks, material in between gets lost: interstitial deletion occurs when deletion at both tips of a chromosome happen: Ring chromosome
  • Structural Aberration: Translocation interchange of genetic information between non-bivalents divided in: reciprocal & robertsonian translocation resulting chromosomes: derivative chromosomes
  • Structural Aberration: Inversion Double break + re-insertion but 180 degree inverted  if this includes centromere = pericentric inversion in this doen´t include centrome = paracentric inversion is balanced
  • Structural Aberration: Duplication gain of genetic material unequal crossing over can be responsible  less serious consequences 
  • Human pathology: numerical aberrations: Down-Syndrome mental retardation trisomy 21 gene dosage of critical region of chromosome 21 -NFATc -DYRK1A -DSCR1
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  • CNV (gene copy number variants) structural variation in human genome, which leads to different ammount of genes makes it possible to distinguish between individuals

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