DNA Repair & How Mutations Occur (Finished)

• Human genome is diploid - one copy from father, one copy from mother
• Most of the human genome is non-coding materials (<3 of the genome can code)
• Exons are coding regions, introns are not
• Promoters regulate expression
• Humans have 23 pairs of chromosomes

  • 22 autosomes + 2 sex chromosomes
• On average, any two people's genomes are ~0.4% different

  • ~99.6% identical
• Genomic differences are the reason why no two people are identical
• Genomic variation: differences between individuals in a population caused by the human genomes
• Interactions between genotype, environment, and development impact the phenotype
• 3 types of genomic variation:

  • Chromosomal differences: large variations
  • Structural variations
  • Genetic variations at nucleotide level: <50 nucleotides; smallest changes, but the most common
• Genetic variations don't change, phenotypic variation can change throughout life
• Polymorphism: multiple variants of a gene relatively common in a population

  • Minor allele > 1%
• Mutation: variant relatively uncommon in a population

  • Minor alleles < 0.01%
• Genomic variations can lead to disease pathogenesis which can lead to:

  • Increased risk of developing a conditions (ex.: breast cancer, Alzheimer's)
  • Acquiring a disease state (ex.: sickle cell disease)
  • Modify response to therapy
  • Lead to drug-induced disease states (ex.: Stevens-Johnsons Syndrome)
• Wild-type sequences is also known as reference genome
• Types of chromosomal differences:

  • Deletion: loss of genetic material
  • Duplication: gain of genetic material
  • Inversion: flipping to cause relocation of genetic material
  • Translocation: chunk of material from another chromosome is added to cause relocation of genetic material
• Chromosomal differences are visible at the cytogenetic level
• Chromosomal aneuploidy: abnormal number of chromosomes within a cell

  • Ex.: Down Syndrome (trisomy 21), Klinefelter Syndrome (XXY)
• Chromosomal rearrangement: changes in structure of native chromosome

  • Ex.: Philadelphia chromosome
• Philadelphia chromosome: reciprocal translation between chromosomes 9 & 22

  • Over-regulation of Bcr-Abl kinase because of fusion -> promotes cell division and differentiation -> onset chronic myelogenous leukemia (CML)
• Chronic myelogenous leukemia (CML) is the first cancer to be linked to genetic abnormality
• Small-scale variants make up the most genetic variations and can be detected by conventional molecular biology or sequencing techniques
• Single nucleotide polymorphism (SNP) is caused by base substitution (1 base change)
• Small insertions/deletions (Indels):

  • Caused by insertions or deletions of a single or multiple bases (1-50 bp)
  • Can cause frameshift variant
• Nonsense mutation: changes 1 base to a stop codon to cause premature 3' end -> forms truncated protein
• Missense mutations: 1 base pair substitution that changes the amino acid sequence of the protein
• Frameshift mutation: 1 base pair change in the 5' end (start codon) of the gene
• Regulatory-region mutation: can decrease the synthesis of mRNA, therefore reducing protein production
• Sense (silent/synonymous) variation: altered codon is present but doesn't change A.A. -> no phenotypic effects
• Symbol for substitution is >
• Insertion is abbreviated as ins
• Deletion is abbreviated as del
• Sickle Cell Disease (SCD): autosomal recessive trait

  • SNP in beta subunit of hemoglobin that causes sickle shaped RBC
  • More common in people of African descent
• Symptoms of SCD:

  • Hypoxia
  • Fatigue
  • Pain from obstruction of small vessel
  • Recurrent infections
  • Enlarge spleen
• Down syndrome is an example of chromosomal aneuploidy