The molecular basis of inheritance describes how genetic information is stored, replicated, expressed, and regulated at the molecular level. Understanding this topic requires tracing the historical sequence of experiments that identified DNA as the genetic material, followed by the structural, mechanistic, and regulatory details of DNA function.

Proof That DNA is the Genetic Material

The story begins with Frederick Griffith's 1928 transformation experiment using Streptococcus pneumoniae. He discovered that mixing heat-killed virulent S-strain (with polysaccharide capsule) with live non-virulent R-strain (without capsule) killed mice, even though neither component alone was lethal. A mysterious "transforming principle" from the dead S-strain had permanently converted R-strain bacteria into the virulent form. The transformed phenotype was heritable across generations.

In 1944, Oswald Avery, Colin MacLeod, and Maclyn McCarty biochemically identified this transforming principle. By systematically treating the principle with DNase, RNase, or protease, they found that only DNase destroyed the transforming activity. This biochemical elimination approach conclusively identified DNA — not protein or RNA — as the genetic material.

The most dramatic confirmation came from Alfred Hershey and Martha Chase in 1952. Using bacteriophage T2, they labelled DNA with radioactive ^32P (phosphorus is a backbone component of DNA) and protein with ^35S (sulfur is found in amino acids cysteine and methionine). After allowing phage to infect bacteria, blending to separate phage coats from bacteria, and centrifuging, they found ^32P (DNA) in the bacterial pellet and ^35S (protein) in the supernatant. This physically demonstrated that DNA — not protein — entered the bacteria to direct new phage production.

Structure of DNA

The double-helical structure proposed by James Watson and Francis Crick in 1953 (using X-ray crystallographic data from Rosalind Franklin and Maurice Wilkins) elegantly explained these chemical findings. DNA is a right-handed double helix consisting of two antiparallel polynucleotide strands connected by hydrogen bonds between complementary nitrogenous bases: adenine pairs with thymine via two hydrogen bonds (A=T), and guanine pairs with cytosine via three hydrogen bonds (G≡C). This base pairing follows Chargaff's rules (A=T, G=C), which state that in any double-stranded DNA molecule, the molar amount of adenine equals thymine and guanine equals cytosine. The greater number of hydrogen bonds in G-C pairs makes GC-rich DNA more thermally stable (higher melting temperature). The sugar-phosphate backbone runs antiparallel (one strand 5'→3', the complementary strand 3'→5'), and the helix has major and minor grooves where regulatory proteins interact with the bases.

DNA Packaging

In eukaryotes, the enormous length of DNA (approximately 2 metres in humans) must be compacted into a nucleus measuring about 10 micrometres. This is achieved by hierarchical packaging. The fundamental unit of chromatin is the nucleosome, consisting of approximately 200 base pairs of DNA wound 1.65 turns around a histone octamer (two copies each of H2A, H2B, H3, and H4). Histone H1, the linker histone, binds at the DNA entry and exit points but is not part of the core octamer. Nucleosomes are then coiled into the 30 nm fibre (solenoid), which forms larger loop domains attached to a protein scaffold, and ultimately the highly condensed metaphase chromosome.

DNA Replication

Replication is semiconservative, meaning each daughter DNA molecule retains one original parental strand and gains one newly synthesized complementary strand. This was proven by Meselson and Stahl (1958) using bacteria grown in heavy ^15N medium, transferred to ^14N, and analyzed by CsCl density gradient centrifugation. After one generation, all DNA was hybrid density (one ^15N + one ^14N strand); after two generations, the ratio was 50% hybrid and 50% light — consistent only with semiconservative replication.

At the replication fork, helicase unwinds the double helix; SSBs stabilize single-stranded templates; topoisomerase relieves supercoiling ahead of the fork; primase synthesizes short RNA primers; DNA polymerase III extends new strands 5'→3' (reading template 3'→5'). The leading strand is synthesized continuously toward the fork, while the lagging strand is synthesized discontinuously as Okazaki fragments (~1000 nt in prokaryotes) in the opposite direction relative to fork movement. DNA polymerase I removes RNA primers and fills gaps; DNA ligase seals remaining nicks.

Transcription and Translation

The central dogma (Crick, 1958) states that information flows from DNA to RNA (transcription) to protein (translation). RNA polymerase, which unlike DNA polymerase does not need a primer, binds the promoter and synthesizes mRNA by reading the template strand 3'→5' and producing RNA 5'→3'. In eukaryotes, the primary transcript undergoes three processing steps: addition of a 5' methylguanosine cap, addition of a 3' poly-A tail, and splicing of introns (non-coding sequences), leaving only the exons in the mature mRNA.

The genetic code consists of 64 triplet codons: 61 sense codons (encoding 20 amino acids) and 3 stop codons (UAA, UAG, UGA). AUG is the universal start codon encoding methionine. The code is degenerate (multiple codons for one amino acid), non-ambiguous (one codon specifies only one amino acid), non-overlapping, comma-less, and nearly universal. Translation occurs on ribosomes with three functional sites: the A-site (aminoacyl-tRNA entry), P-site (peptide bond formation), and E-site (tRNA exit). Peptidyl transferase activity resides in the 23S rRNA of the large subunit, making the ribosome a ribozyme.

Gene Regulation — The Lac Operon

The Lac operon of E. coli exemplifies negative inducible gene regulation. The regulatory gene lacI constitutively produces a repressor protein that normally binds the operator, blocking RNA polymerase from transcribing the structural genes lacZ, lacY, and lacA. When lactose is present, it is converted to allolactose (by basal-level beta-galactosidase), which binds the repressor and causes a conformational change preventing it from binding the operator. RNA polymerase is then free to transcribe beta-galactosidase, permease, and transacetylase.

Genomics and Applications

The Human Genome Project revealed approximately 20,000–25,000 protein-coding genes within 3.2 billion base pairs, with less than 2% of the genome actually coding for proteins. DNA fingerprinting exploits the variability of Variable Number Tandem Repeats (VNTRs), detected by Southern blotting, to create unique genetic profiles used in forensics, paternity testing, and identification.