The Molecular Basis of Inheritance

DNA Structure: DNA (deoxyribonucleic acid) is characterized by an elegant double helical structure proposed by James Watson and Francis Crick in April 1953.
Significance: DNA contains all your genes, which are your genetic information.

Definition: Each gene is a hereditary information unit consisting of a specific DNA sequence.
- Unduplicated chromosome: consists of one DNA molecule and proteins.
- Duplicated chromosome: consists of two DNA molecules and proteins.
Process Breakdown:
- DNA replication begins at multiple origins, forming replication bubbles with forks at each end.
- Genetic information is transmitted from parent cell to daughter cells through mitosis and from generation to generation through meiosis.

DNA Is the Genetic Material
- Historical Background: The identification of DNA as the hereditary molecule involved extensive scientific inquiry.
- Initial Challenge: Proteins were primarily believed to be the genetic material due to their complexity.
- Transformation in Bacteria:
  - Frederick Griffith’s experiment showed that a nonpathogenic strain of Streptococcus pneumoniae could become pathogenic when mixed with heat-killed pathogenic strains, termed transformation.
  - Definition: Transformation is defined as a change in genotype and phenotype due to assimilation of external DNA by a cell.
  - Conclusion from Griffith’s work: The heritable substance was identified as DNA.
Hershey-Chase Experiment
- Objective: To identify whether DNA or protein is the genetic material in T2 bacteriophage.
- Methodology:
  - Virus components were separated using radioactive isotopes (sulfur for protein, phosphorus for DNA).
  - Results indicated that DNA entered bacterial cells, while proteins remained outside, demonstrating DNA is genetic material.
Chargaff's Rules
- Established by Erwin Chargaff, these rules formulated regarding the base composition of DNA:
  - DNA base composition varies across species.
  - For any given species, the amount of adenine (A) roughly equals thymine (T), and the amount of guanine (G) roughly equals cytosine (C).
  - Example Composition: Sea urchin DNA shows A = 32.8% and T = 32.1%, G = 17.7% and C = 17.3%.

Nucleotide Composition: Each DNA nucleotide consists of:
1. A nitrogenous base (adenine, thymine, guanine, or cytosine).
2. A pentose sugar (deoxyribose).
3. A phosphate group.
Formation of DNA: Nucleotides bond via phosphodiester linkages, forming a sugar-phosphate backbone. The orientation is critical: Each strand has a distinct 5′ end and a 3′ end.

Discovery Process: Watson, inspired by Rosalind Franklin’s X-ray diffraction data, conceptualized the double helix structure.
Key Elements:
- The double helix of DNA consists of two antiparallel strands.
- Base pairing: A pairs with T, G pairs with C, suggesting methods of replication.

Semiconservative Replication:
- Each parental strand serves as a template for a new strand, leading to two identical DNA molecules, each containing one original and one newly synthesized strand.
- Distinction among models of replication:
  - Semiconservative: Each strand is a template; produces one old and one new strand.
  - Conservative: Two parental strands reassociate after replication.
  - Dispersive: Each strand contains a mix of old and new DNA.
Experimental Validation: The semiconservative model was confirmed by the Meselson-Stahl experiment using nitrogen isotopes to distinguish between old and new DNA strands, confirming semiconservative replication as the accurate mechanism.

Enzymes Involved: The mechanism of DNA replication relies on various enzymes, including:
- Helicases: Unwind the double helix at the replication fork, separating parental strands.
- DNA Polymerases: Synthesize new DNA strands by adding nucleotides to the 3′ end.
- Primases: Synthesize RNA primers for initiation of strand synthesis.
- Ligases: Join Okazaki fragments on the lagging strand to create a continuous DNA strand.
Leading vs Lagging Strand:
- Leading strand synthesized continuously towards the replication fork.
- Lagging strand synthesized discontinuously in short segments (Okazaki fragments) away from the replication fork.

Proofreading: DNA polymerases proofread newly synthesized DNA, correcting mismatched nucleotides to maintain fidelity.
Mismatch Repair: Enzymes detect and correct errors after replication, enhancing accuracy.
Types of DNA Damage and Repair: Various types of DNA damage, including those caused by environmental factors, are rectified using different repair systems, such as nucleotide excision repair.

Role of Telomeres: Protect the ends of linear DNA molecules from erosion during replication. Contain repetitive sequences and do not code for proteins.
Functionality: Telomerase enzyme extends telomeres in germ cells, maintaining chromosomal integrity across generations.

Organization: Chromatin consists of DNA wound around histone proteins, forming nucleosomes, which condense into higher-order structures during cell division.
Euchromatin vs Positional Heterochromatin:
- Euchromatin is loosely packed and accessible for transcription.
- Heterochromatin is densely packed and typically not transcriptionally active.

Understanding the molecular basis of inheritance requires an appreciation for DNA's structure, replication mechanisms, and the various processes that ensure genetic integrity. The interaction of DNA with histones and the organization of chromatin also play critical roles in gene expression and cellular function.