Genomics: Organization of the Human Genome

Genome Organization

• The amount of DNA per haploid genome of a species is represented by the C-value.
• In somatic cells, the C-value is 2C in G1 phase and 4C in G2 phase.
• The human C-value is 3.2 gpb, which is equivalent to 3.2 x 10^9 bp.

Gene Content

• The human genome contains approximately 23,000 genes.
• On average, one protein is composed of about 500 amino acids.
• If each gene encoded only one protein, the total number of base pairs required would be approximately 34,500,000 bp.

Gene Families

• Gene families arise from gene duplication and evolutionary divergence.
• Members of a gene family have a close resemblance, similar functions, but may have different roles.
• Examples of gene families include:
  • Actins (5-30 genes)
  • Variable region of the Ig (500 genes)
  • Hemoglobin genes (e.g. HBB, HBD, HBG1, HBG2, HBA1, HBA2, HBM, HBQ1)

Types of Mutations

• Positive mutations: selection
• Neutral mutations: genetic variability between individuals
• Negative mutations: damage

Effects of Mutations on Cells

• Somatic mutations: affect the individual
• Germinal mutations: affect offspring
• Genetic mosaic: mixture of genetically different cells in an individual or offspring

Consequences of Mutations

Gene Structure

• Substitutions: errors in replication or repair
• Deletions: loss of base pairs

Ultraviolet Light

• Produces thymine dimers
• Thymine dimers: two thymine molecules bonded together
• Photoreactivation: repair of thymine dimers using visible light

Replication Errors

• Phase change mutations: repeated sequences
• Slip of the two propellers: errors in replication

Mutations Affecting DNA Structure

• Inversions: reversal of DNA segments
• Translocations: exchange of DNA segments between non-homologous chromosomes
• Insertions: addition of DNA segments

Agents Damaging DNA Structure

• Ionizing radiation

Consequences of Mutations

Gene Segments

• Changes in gene segments: can affect gene function

Intron Point Deletions

• Presence of intron sequence in mRNA: addition of corresponding stretch in polypeptide
• Splicing-site mutations: affect splicing, leading to incorrect removal of introns

Mutations in Control Elements

• Modulators of gene expression: affect transcription rate
• Promoter mutations: affect gene expression
• Examples: Lactase Persistence, Hemophilia B, Myotonic Dystrophy

Mutagenesis

• Natural gene mutation rates: 10-5– 10-7
• Elevated mutation rates in certain genes: Achondroplasia, Duchenne Muscular Dystrophy, X-fragile syndrome
• Genetic sequence: normal variants (polymorphisms), disease-causing mutations