Genetics: From Mendel to Molecular Biology

Genetics is the science of heredity and variation. It moved from Mendel's peas to genome editing in roughly 150 years.

Mendelian genetics

Gregor Mendel (1822–1884) — Augustinian monk; Versuche über Pflanzenhybriden (1866) on Pisum sativum (garden pea). Re-discovered in 1900 by Hugo de Vries, Carl Correns and Erich von Tschermak.

Mendel's laws

1. Law of Dominance — in a heterozygote, one allele masks the other.
2. Law of Segregation — paired alleles separate during gamete formation; each gamete receives one allele.
3. Law of Independent Assortment — alleles of different genes assort independently (now known to apply only to genes on different chromosomes or far apart on the same chromosome).

Classical Mendelian ratios

• Monohybrid cross (heterozygous selfing): 3 : 1 phenotypic.
• Dihybrid cross: 9 : 3 : 3 : 1 phenotypic.
• Test cross: ratios reveal genotype.

Deviations / extensions

• Incomplete dominance — heterozygote shows blended phenotype (snapdragon flower colour: 1:2:1).
• Co-dominance — both alleles fully expressed (AB blood group).
• Multiple alleles — ABO has three alleles (Iᴬ, Iᴮ, i).
• Polygenic inheritance — many genes, continuous traits (skin colour, height).
• Sex linkage — colour blindness, haemophilia (X-linked recessive).
• Linkage and recombination — genes on the same chromosome (Morgan 1910, Drosophila).
• Epistasis — one gene masks another (coat colour in Labradors).

Chromosomal theory of inheritance

• Walter Sutton (1902) and Theodor Boveri (1902) — independently proposed that chromosomes carry genes.
• Thomas Hunt Morgan — Nobel 1933; Drosophila genetics, gene mapping, sex linkage.
• Barbara McClintock — Nobel 1983; transposable elements ("jumping genes") in maize.

DNA: the molecule of heredity

• Griffith (1928) — transforming principle in Streptococcus.
• Avery, MacLeod, McCarty (1944) — DNA, not protein, is the genetic material.
• Hershey–Chase (1952) — phage labelling confirmed DNA.
• Watson, Crick, Franklin, Wilkins (1953) — double helix structure; Nobel 1962 (Franklin had died in 1958).

DNA structure

• Two anti-parallel strands; double helix.
• Backbone: alternating deoxyribose and phosphate.
• Bases: adenine, guanine (purines), cytosine, thymine (pyrimidines).
• A pairs with T (2 H-bonds); G pairs with C (3 H-bonds) — Chargaff's rules.
• 10.4 base pairs per turn; major and minor grooves.

Replication, transcription, translation — the Central Dogma

Coined by Francis Crick (1958): DNA → RNA → Protein.

Process	Where	Enzymes
Replication	Nucleus (S phase)	DNA polymerase, helicase, primase, ligase
Transcription	Nucleus	RNA polymerase
Translation	Cytoplasm / ER ribosomes	Ribosome, tRNA, aminoacyl tRNA synthetase

The genetic code is universal (with minor exceptions), triplet, degenerate, non-overlapping, comma-less. 64 codons code for 20 amino acids and 3 stop codons.

Mutations

• Point mutations — base substitution (silent, missense, nonsense).
• Frameshift — insertion or deletion shifting the reading frame.
• Chromosomal aberrations — deletion, duplication, inversion, translocation.
• Aneuploidy — abnormal chromosome number (Down syndrome: trisomy 21; Klinefelter XXY; Turner XO).
• Polyploidy — common in plants, rare in animals.

Mutagens: ionising radiation, UV (pyrimidine dimers), chemical agents (EMS, nitrosamines).

Sex determination

• XY system — mammals; male XY, female XX.
• ZW system — birds; female ZW, male ZZ.
• Temperature-dependent — many reptiles.
• Haplodiploidy — bees, wasps, ants (females diploid, males haploid).

Karyotype

• Human karyotype: 46 chromosomes (2n) = 22 autosomes + XX (♀) or XY (♂).

Population genetics

• Hardy–Weinberg equilibrium (1908).
• Allele frequencies change by selection, drift, mutation, migration, non-random mating.
• Effective population size (Ne) — relevant for drift and conservation.

Genetic engineering and modern tools

• Recombinant DNA — Berg, Cohen, Boyer (1972).
• PCR — Kary Mullis (1983; Nobel 1993).
• Sanger sequencing — 1977; Nobel 1980.
• Next-generation sequencing — Illumina, PacBio, Nanopore.
• CRISPR/Cas9 — Doudna & Charpentier 2012; Nobel 2020.
• Genetic counselling, forensic DNA fingerprinting (Alec Jeffreys 1984).

Human genetic disorders

Disease	Inheritance	Defect
Sickle cell anaemia	Autosomal recessive	Haemoglobin β chain (Glu→Val)
Cystic fibrosis	Autosomal recessive	CFTR chloride channel
Huntington's disease	Autosomal dominant	CAG repeat expansion in HTT
Haemophilia A	X-linked recessive	Factor VIII
Duchenne muscular dystrophy	X-linked recessive	Dystrophin
Down syndrome	Trisomy 21	Three copies of chr 21
Phenylketonuria	Autosomal recessive	Phenylalanine hydroxylase

Genetics in Pakistan

• NIBGE (Faisalabad) and NIBD (Karachi) lead applied genetic research.
• Centre of Excellence in Molecular Biology (CEMB), Punjab University.
• Active research on consanguinity and recessive disorders — Pakistan has high consanguineous marriage rates (~60%), elevating recessive disease prevalence.