Genetics — Inheritance and Mutation

Gregor Mendel (1822–1884) discovered the fundamental laws of inheritance by studying pea plants. His work, ignored during his lifetime, became the foundation of modern genetics when rediscovered in 1900. Key terminology: Gene: a segment of DNA that codes for a specific trait or protein. Allele: alternative versions of a gene (e.g., round vs wrinkled peas). Locus: the specific position of a gene on a chromosome. Genotype: the genetic makeup (e.g., AA, Aa, aa). Phenotype: the observable characteristic (e.g., round or wrinkled). Homozygous: both alleles identical (AA or aa). Heterozygous: two different alleles (Aa). Dominant: an allele that is expressed even when only one copy is present (A). Recessive: an allele expressed only when two copies are present (aa). Mendel's First Law — Law of Segregation: Each organism has two alleles for each gene. These segregate (separate) during gamete formation — each gamete receives only one allele. At fertilisation, offspring receive one allele from each parent. Mendel's Second Law — Law of Independent Assortment: Genes on different chromosomes assort independently during meiosis. This produces genetic diversity. However, genes on the same chromosome (linked genes) do not assort independently — they tend to be inherited together.

Punnett squares predict the probability of offspring genotypes and phenotypes. Monohybrid cross (one gene): Cross of two heterozygous parents: Aa × Aa A a A AA (25%) Aa (25%) a Aa (25%) aa (25%) Genotype ratio: 1 AA : 2 Aa : 1 aa Phenotype ratio: 3 dominant : 1 recessive (if A is dominant) Dihybrid cross (two genes): AaBb × AaBb produces 9:3:3:1 phenotype ratio (classic Mendelian dihybrid ratio). Incomplete dominance: Neither allele is completely dominant. Heterozygote has intermediate phenotype. Example: red × white flower → pink heterozygote. Genotype and phenotype ratios are both 1:2:1. Codominance: Both alleles are expressed simultaneously. Example: ABO blood groups — type AB expresses both A and B antigens. Multiple alleles: ABO blood groups have three alleles: Iᴬ, Iᴮ, i. Six possible genotypes, four phenotypes (A, B, AB, O). This is still Mendelian — each person has only two alleles, but three exist in the population. Sex-linked inheritance: Some genes are on the X chromosome (X-linked). Males (XY) have only one copy — they are hemizygous. X-linked recessive conditions (haemophilia A, red-green colour blindness, Duchenne muscular dystrophy) affect males more frequently. Females need two affected X chromosomes to show the phenotype but can be carriers (Xᴬ X).

Chromosomal abnormalities arise during meiosis or early cell division and involve changes in chromosome number or structure. Non-disjunction: Failure of chromosomes to separate properly during meiosis. Produces gametes with an extra chromosome (n+1) or missing chromosome (n−1). When fertilised, offspring have trisomy (2n+1) or monosomy (2n−1). Common trisomies: Trisomy 21 (Down syndrome): extra chromosome 21. Incidence ~1/700 live births, increases with maternal age. Features: intellectual disability, characteristic facial features, increased risk of cardiac defects (40%) and leukaemia. Trisomy 18 (Edwards syndrome): extra chromosome 18. Severe — most affected fetuses die before birth. Trisomy 13 (Patau syndrome): extra chromosome 13. Severe. Sex chromosome abnormalities: Turner syndrome (45,X or 45,XO): monosomy X in females. Short stature, primary amenorrhoea, infertility, lymphoedema, coarctation of the aorta. Klinefelter syndrome (47,XXY): extra X chromosome in males. Tall stature, small testes, infertility, reduced testosterone, gynaecomastia. Structural abnormalities: Deletion: loss of a chromosome segment. Cri du chat syndrome (5p deletion). Translocation: segment moves to another chromosome. Robertsonian translocation of chromosomes 14 and 21 is an inherited cause of Down syndrome (without trisomy). Inversion: segment reversed. Prenatal diagnosis: Amniocentesis (15–20 weeks): amniotic fluid sampled, fetal cells karyotyped. Chorionic villus sampling (CVS, 10–13 weeks): placental cells sampled. Earlier but slightly higher miscarriage risk. Cell-free fetal DNA (cfDNA) screening: fetal DNA in maternal blood analysed for chromosomal anomalies from 10 weeks.

A mutation is any change in the DNA sequence. Mutations can be inherited (germline) or acquired (somatic). Point mutations (single nucleotide changes): Silent mutation: changes a codon but codes for the same amino acid (due to codon degeneracy). No effect on protein. Missense mutation: changes a codon to code for a different amino acid. May alter protein function. Example: sickle cell disease — glutamic acid → valine at position 6 of β-globin (single nucleotide change, A→T in codon 6). Nonsense mutation: changes a codon to a stop codon. Truncated, usually non-functional protein. Frameshift mutations: Insertion or deletion of one or two nucleotides shifts the reading frame. All downstream codons are altered — usually catastrophic for protein function. Three-nucleotide insertions/deletions don't cause frameshift (one amino acid added or deleted). Causes of mutation: Spontaneous: errors in DNA replication (~1 per 10⁸–10¹⁰ nucleotides, corrected by proofreading and mismatch repair). Mutagens: UV light (pyrimidine dimers), ionising radiation, alkylating agents, intercalating agents, aflatoxin. Transposable elements: "jumping genes" that can insert into coding sequences. Repair mechanisms: Base excision repair: removes damaged single bases. Nucleotide excision repair: removes short damaged DNA segments. Deficient in xeroderma pigmentosum — extreme UV sensitivity and skin cancer. Mismatch repair: corrects replication errors. Deficient in Lynch syndrome — predisposes to colorectal and endometrial cancer. Double-strand break repair: homologous recombination (accurate) or non-homologous end joining (error-prone). BRCA1/2 mutations impair homologous recombination — increased breast and ovarian cancer risk.

Classification of genetic disorders: Single-gene (Mendelian) disorders: Autosomal dominant: one mutant allele sufficient. Affected parent has 50% chance of passing to child. Examples: Huntington's disease, Marfan syndrome, achondroplasia, familial hypercholesterolaemia. Autosomal recessive: two mutant alleles required. Both parents usually carriers (unaffected). 25% risk to each child. Examples: cystic fibrosis (CFTR gene), sickle cell disease, PKU, Tay-Sachs disease. X-linked recessive: affected males (hemizygous), carrier females. No male-to-male transmission. Examples: haemophilia A (Factor VIII), haemophilia B (Factor IX), Duchenne muscular dystrophy (dystrophin). X-linked dominant: rare. Affects heterozygous females and hemizygous males. Examples: hypophosphataemia (X-linked dominant rickets). Polygenic and multifactorial disorders: Multiple genes + environmental factors. Most common conditions: Type 2 diabetes, hypertension, coronary artery disease, schizophrenia. Higher heritability than random chance, but not simple Mendelian ratios. Gene therapy: Introduction of genetic material into cells to treat or prevent disease. Ex vivo: cells removed, genetically modified in lab, reinfused. Used for CAR-T cell cancer therapy, some forms of SCID. In vivo: vector delivers gene directly into patient's tissues. Viral vectors (AAV, lentivirus) or non-viral (lipid nanoparticles — used for mRNA COVID vaccines). CRISPR-Cas9: revolutionary genome editing technology. Guide RNA directs Cas9 nuclease to a specific DNA sequence for precise cutting and editing. Clinical trials for sickle cell disease, β-thalassaemia, and transthyretin amyloidosis are showing dramatic results.