Genes and Genetic Diseases

DNA structure and the genetic code

  • DNA (Deoxyribonucleic acid) is the molecule that directs the synthesis of all proteins in the body.
  • Composition:
    • Pentose sugar: deoxyribose
    • Phosphate group
    • Four nitrogenous bases: cytosine (C), thymine (T), adenine (A), guanine (G)
    • Bases: Pyrimidines = {C, T}; Purines = {A, G}
  • DNA structure:
    • Generally described as a double helix with two antiparallel strands and complementary base pairing (A with T; C with G).
  • DNA vs RNA (differences highlighted further below) and the universality of the genetic code, except in mitochondria.

DNA vs RNA

  • DNA uses deoxyribose; RNA uses ribose.
  • Bases: DNA = A, T, C, G; RNA = A, U, C, G (uracil replaces thymine).
  • Pairing: A pairs with T in DNA; A pairs with U in RNA; C pairs with G in both.
  • Structure: DNA typically double-stranded; RNA is typically single-stranded.
  • Overall implication: DNA stores genetic information; RNA transmits and helps convert that information into proteins.

The genetic code: codons and amino acids

  • Proteins are built from amino acids (20 standard types).
  • Coding for amino acids uses triplets of bases (codons).
  • Each codon specifies a particular amino acid or a stop signal; codons are universal across organisms (with mitochondria as a noted exception).
  • Start codon: AUG (codes for Methionine in many contexts; also signals initiation of translation).
  • Stop codons: UAA, UAG, UGA (signal termination of translation).
  • Examples of codon assignments (illustrative subset):
    • UUU
      ightarrow ext{Phenylalanine}
    • UUC
      ightarrow ext{Phenylalanine}
    • UCU
      ightarrow ext{Serine}
    • UGU
      ightarrow ext{Cysteine}
    • AUG
      ightarrow ext{Methionine (Start)}
    • GGC
      ightarrow ext{Glycine}
  • Note: A codon table summarizes all 64 codons mapping to 20 amino acids plus stop signals.

DNA: mutations and their types

  • Any inherited alteration in genetic material falls under DNA mutation.
  • Base-pair mutation: a single nucleotide substitution leading to an altered amino acid sequence (example: Sickle cell disease caused by a point mutation in the beta-globin gene).
  • Frameshift mutation: insertion or deletion of one or more DNA base pairs that changes the reading frame (not a full triplet insertion/deletion).
  • Spontaneous mutation: occurs without exposure to external mutagens.
  • Mutagens: agents that increase mutation frequency, e.g.,
    • Radiation
    • Chemicals (e.g., nitrogen mustard, vinyl chloride, alkylating agents, formaldehyde, sodium nitrite)
  • Example: Sickle cell disease as a classical base-pair mutation example affecting hemoglobin.

DNA replication and transcription

  • DNA Synthesis (Replication):
    • Involves untwisting and unzipping of the DNA strands and breaking hydrogen bonds.
    • Each single strand serves as a template for complementary base pairing.
    • Enzyme: DNA polymerase carries out replication.
  • DNA Synthesis: Transcription
    • RNA is synthesized from a DNA template.
    • RNA polymerase binds to a promoter site and initiates formation of messenger RNA (mRNA).
    • RNA polymerase detaches; mRNA moves from the nucleus to the cytoplasm.
    • Transcription continues until a termination sequence is reached.
  • RNA processing (Gene splicing):
    • After transcription, introns are removed and exons are spliced together.
    • The functional mRNA (with exons only) migrates to the cytoplasm for translation.
  • Translation:
    • RNA directs synthesis of a polypeptide via interaction with transfer RNA (tRNA).
    • The site of protein synthesis is the ribosome.
    • tRNA carries amino acids and contains an anticodon that pairs with the codon on the mRNA.
    • The ribosome moves along the mRNA to translate the amino acid sequence.
  • Visual overview (conceptual):
    • Transcription produces pre-mRNA in the nucleus; processing yields mature mRNA with exons only; translation occurs in the cytoplasm at the ribosome to build a polypeptide chain.

Chromosomes and chromosomal aberrations: structure and number

  • Human cells are categorized as:
    • Somatic cells: contain 46 chromosomes (diploid, 2n), formed by mitosis and cytokinesis.
    • Gametes: contain 23 chromosomes (haploid, n), formed by meiosis.
  • Chromosome classification:
    • Autosomes: first 22 pairs; homologous (virtually identical) between sexes.
    • Sex chromosomes: the 23rd pair; females have XX, males have XY.
  • Centromere and chromatids:
    • Centromere is the constricted region important for movement of replicated chromosomes.
    • Centromere types: Metacentric (centromere near middle); Submetacentric; Acrocentric (near end).
    • Chromatid: one of two DNA strands into which a replicated chromosome divides; each contains a DNA double helix.

Euploidy, polyploidy, and aneuploidy

  • Euploid: cells with a multiple of the normal chromosome number; can be haploid or diploid.
  • Polyploid: euploid cells with more than the diploid number.
    • Triploidy (3 copies of each chromosome, 69): not life-compatible; usually aborted or stillborn.
    • Tetraploidy (4 copies, 92): not compatible with life.
  • Aneuploidy: cells that do not contain a multiple of 23 chromosomes; commonly due to nondisjunction.
    • Trisomy: three copies of a chromosome in a diploid cell.
    • Monosomy: one copy of a chromosome.
  • Nondisjunction: failure of homologous chromosomes or sister chromatids to separate during meiosis or mitosis.

Common aneuploidies: autosomes and sex chromosomes

  • Autosomal aneuploidy: examples include Down syndrome (trisomy 21).
    • Down syndrome incidence: frac{1}{800} live births (approximately 1:800).
    • Risk increases with maternal age (e.g., >35 years).
  • Sex chromosome aneuploidy:
    • Trisomy X (XXX): frequent sex chromosome aneuploidy; many have no overt abnormalities; some mild features.
    • Turner syndrome (45,XO): female with a single X; features include underdeveloped ovaries, short stature, webbed neck, shield-like chest, underdeveloped breasts, wide-spaced nipples.
    • Klinefelter syndrome (47,XXY): male with at least two X chromosomes and one Y; features include smaller testes, partial breast development, sparse body hair, tall stature, reduced muscle tone.
  • Fragile sites: areas prone to gaps and breaks; most are not disease-related except for Fragile X syndrome.
    • Fragile X syndrome: X-linked; females carriers; about 1/3 of affected females show mild expression; features: intellectual disability, broad forehead, elongated face, large ears.

Structural chromosomal abnormalities

  • Deletion: loss of a chromosome segment due to breakage; e.g., Cri du Chat syndrome (terminal deletion of the short arm of chromosome 5); features: low birth weight, mental retardation, microcephaly, heart defects.
  • Duplication: presence of a repeated gene or gene sequence; may be less severe than deletion but can cause mental retardation or other abnormalities.
  • Inversion: a chromosome segment is inverted after two breaks and reinsertion occurs in reverse order (e.g., ABCDEFG → ABEDCFG).
  • Translocation: interchange of material between nonhomologous chromosomes.
    • Reciprocal translocation: segments exchanged between two different chromosomes.
    • Robertsonian translocation: fusion of the long arms of two nonhomologous chromosomes at the centromere, forming a single chromosome.

Fragile sites and Fragile X syndrome details

  • Fragile sites are regions prone to gaps/breaks; most are not disease-related except the X chromosome long arm involvement in Fragile X.
  • Fragile X syndrome: important X-linked condition with variable expressivity; females may be mildly affected or asymptomatic carriers.
  • Clinical features of Fragile X: intellectual disability, broad forehead, elongated face, large ears.

Genetics: key definitions

  • Locus: position of a gene on a chromosome.
  • Allele: a different form of a gene at a given locus.
  • Homozygous: two identical alleles at a locus (e.g., blood type OO).
  • Heterozygous: two different alleles at a locus (e.g., blood type AB).
  • Genotype: genetic composition at a locus (what one has genetically).
  • Phenotype: outward appearance, result of genotype and environment (e.g., blood type A could be AA or AO).
  • Dominant allele: observable effects are exhibited by the phenotype.
  • Recessive allele: effects are hidden in heterozygotes; expressed in homozygotes.
  • Carrier: carries the disease allele but is phenotypically normal (e.g., Ss for Sickle cell trait).

Mendelian genetics and inheritance patterns

  • Mode of inheritance: pattern by which a genetic disease is passed down.
  • Principles (from Mendel):
    • Principle of segregation: homologous genes separate during reproduction; each gamete carries one copy of a gene.
    • Principle of independent assortment: transmission of one gene does not affect transmission of another.
  • Pedigree: diagrammatic summary of family relationships and disease status; starts with a proband (first diagnosed individual).

Inheritance patterns and clinical probability

  • Autosomal dominant disorders:
    • Abnormal allele is dominant; normal allele recessive; genes on autosomes.
    • Males and females equally affected; no generation skipped; heterozygous affected individuals transmit the trait to about half of their children.
    • Recurrence risk when one parent is affected and the other is not: frac{1}{2} for each pregnancy.
  • Recurrence risk (autosomal dominant): for each child, risk is frac{1}{2} if one parent is affected.
  • Penetrance: percentage of individuals with a specific genotype who express the phenotype.
    • Incomplete penetrance: some individuals with the genotype do not express the disease but may transmit it.
  • Expressivity: extent of phenotypic variation among individuals with the same genotype.
    • Example: Neurofibromatosis (Chromosome 17) shows variability from skin spots to malignant tumors.
  • Autosomal recessive disorders:
    • Abnormal allele recessive; must be homozygous for disease expression.
    • Males and females are affected in equal proportions.
    • Consanguinity increases risk.
    • Recurrence risk when both parents are carriers: typically, 1/4 normal homozygotes, 1/2 carriers, 1/4 affected children (for each pregnancy).
  • Sex-linked disorders (X-linked):
    • Most are located on the X chromosome.
    • Males more often affected; females often carriers or mildly affected due to second X chromosome.
    • Affected males cannot transmit to sons but can to all daughters; daughters may be carriers.
    • Recurrence risk patterns depend on carrier status of mothers.

Recap of key numerical and probabilistic concepts

  • Chromosome counts: somatic cells 46; gametes 23.
  • Down syndrome incidence: frac{1}{800} live births; risk increases with maternal age (> 35 years).
  • Mendelian inheritance probabilities:
    • Autosomal dominant: each child has a frac{1}{2} risk when one parent is affected.
    • Autosomal recessive: offspring probabilities from carrier parents are frac{1}{4} affected, frac{1}{2} carriers, frac{1}{4} unaffected non-carriers.
  • Penetrance and expressivity are qualitative concepts describing the variability of phenotype given genotype.

Connections and real-world relevance

  • DNA structure underpins how genetic information is stored and passed on during reproduction (mitosis, meiosis).
  • Mutations drive genetic diversity but also cause inherited diseases when they disrupt essential proteins.
  • Understanding chromosomal aberrations helps explain congenital disorders and developmental issues.
  • Genetic testing and family history (pedigrees) guide risk assessment, prenatal counseling, and targeted therapies.

Ethico-social and practical implications

  • Genetic screening raises questions about privacy, consent, and potential discrimination.
  • Counseling for recurrence risk aids informed family planning decisions.
  • Understanding gene expression variability (penetrance/expressivity) informs prognosis and management.

References

  • Huether, S. E., & McCance, K. L. (2008). Understanding pathophysiology. 4th ed. St. Louis, Mo.: Mosby/Elsevier.