AR

Genetic Diseases - Basis for Genetic Disease and Inheritance

Basis for Genetic Disease

  • Mutations are permanent changes in the sequence of nucleotides (C, T, A, or G) that form the genetic material. These are the basis of genetic diseases. (Reference: Fig. 2-1 in the transcript)

Overview

  • Mutations provide the foundational basis for genetic diseases.
  • They are permanent changes in DNA sequence.

Types of Mutations

  • Single gene mutations
    • Base pair substitution (point mutation): one base pair is replaced by a different base.
    • Frameshift mutations:
    • Deletion of one base pair
    • Insertion of one base pair
  • Normal base-pairing concept (for context): G pairs with C; A pairs with T (in DNA).
  • Chromosomal mutations: changes at the chromosome level, affecting structure or number of chromosomes.

Gene Sequences

  • Definitions
    • Alleles: different DNA sequences (versions) of the same gene.
    • Locus: the specific site on a chromosome where a given allele is located.
  • Sources: information derived from educational resources (e.g., BBC static archive cited in the slides).

Gene Sequences: Genotype Terminology

  • Chromosomes occur in paired sets in somatic (body) cells.
  • Homozygote: an individual with matching alleles at the same locus on both chromosomes.
  • Heterozygote: an individual with different alleles at the same locus on the paired chromosomes.

Nomenclature for Dominant and Recessive Alleles

  • Dominant vs. Recessive Alleles
    • Dominant alleles need only one copy to be expressed in a heterozygote.
    • Recessive alleles require two copies to be expressed.
  • Convention for gene notation
    • Uppercase letter denotes the dominant allele.
    • Lowercase letter denotes the recessive allele.
    • Example: A = dominant allele, a = recessive allele.

Practice and Review

  • Today’s session is for practice; next class continues the concept review.

Autosomes vs Sex Chromosomes

  • Genetic diseases can be located on autosomes or sex chromosomes.
  • Autosomes: the 22 pairs of non-sex chromosomes.
  • Sex chromosomes: X and Y chromosomes.
  • Notation examples in slides show chromosomes numbered (e.g., 20, 17, 10, 12, 16, 18, 22) and sex chromosome designations (X, Y).

Autosomal Dominant Inheritance

  • Basis: a single copy of the disease-causing allele is sufficient for expression in most cases.
  • Pedigree pattern (example notation): Aa × aa results in offspring with approximately 50% affected (Aa) and 50% unaffected (aa).
  • Key characteristics
    • On average, half of children with one affected parent are affected.
    • No skipped generations are typical (though exceptions occur due to reduced penetrance or small family size).
  • Examples
    • Achondroplasia: caused by a mutation leading to changes in a protein essential for skeletal development.
    • Marfan syndrome: mutation in a gene coding for a collagen protein affecting elastic tissue.
    • Huntington’s disease: trinucleotide repeat disorder (CAGCAGCAG…) causing a change in a specific protein leading to brain cell death in adulthood; the function of that protein is still not fully understood.
  • Genotype and phenotype considerations
    • Homozygous individuals (AA) generally have a more severe or often fatal condition than heterozygous individuals (Aa).
    • Heterozygous condition can still manifest disease in most autosomal dominant disorders shown in the examples above.
  • Notable example details
    • Huntington’s disease described as a trinucleotide repeat disorder; an expanded CAG repeat alters a protein with unknown function.

Autosomal Recessive Inheritance

  • Pedigree pattern: both parents must be carriers ( Aa × Aa ) to have affected offspring.
  • Typical outcomes when both parents are carriers
    • 25% affected (aa)
    • 50% carriers ( Aa )
    • 25% unaffected non-carriers ( AA )
  • Key characteristics
    • Affected individuals often cluster among siblings.
    • Skipped generations are common.
    • Consanguinity can increase the risk of autosomal recessive diseases.
  • Examples
    • Cystic fibrosis: a mutation in a gene encoding a protein channel found in epithelial cells; results in thick mucus obstructing airways, pancreatic ducts, and other organs.
    • Sickle cell anemia (sickle cell disease): a single base pair mutation in the hemoglobin gene; RBCs become sickled under hypoxic or stress conditions.
  • Phenotypic notes
    • Carriers are typically asymptomatic.
    • Affected individuals are homozygous recessive (aa).

Sex Chromosomes & X-linked Inheritance

  • X-linked inheritance focuses on genes on the X chromosome.
  • X-linked Recessive Inheritance (basis): XX, XY with X-linked alleles.
  • Pedigree patterns
    • Male offspring are more frequently affected than female offspring.
    • Females can be carriers, while males usually express the disease if they inherit the mutant allele.
    • No transmission of an X-linked recessive disease from father to his sons (since fathers pass their Y chromosome to sons).
    • Skipped generations are common in females due to carrier status and X-inactivation dynamics.
  • Examples
    • Hemophilia A: clotting factor deficiency (Factor VIII).
    • Hemophilia B: Factor IX deficiency (also X-linked).
    • Hemophilia C is autosomal recessive (not X-linked) despite similar naming.
    • Duchenne muscular dystrophy: mutation in the dystrophin gene on the X chromosome.

Chromosome Disorders

  • Karyotype: a full set of an individual’s chromosomes; used for diagnostic purposes.
  • Prevalence and impact
    • Chromosome abnormalities occur in about rac{1}{150} live births.
    • About 50% of miscarriages have a major chromosome abnormality.
    • The vast majority (about 95%) of conceptions with chromosome disorders are spontaneously aborted.
  • Down Syndrome (Trisomy 21)
    • Definition: presence of an extra copy of chromosome 21 (trisomy 21): 47,XX,+21 or 47,XY,+21.
    • Nondisjunction is responsible for ~95% of Down syndrome cases.
    • Maternal age effect: risk increases after age 35.
    • Prenatal diagnosis and screening: amniocentesis (around 16 weeks) and chorionic villus sampling (CVS) at 9–10 weeks; Quad Screen may be used as a less invasive preliminary assessment.
    • Karyotype example image: Down syndrome karyotype (described in slides).
  • Down Syndrome: characteristics
    • Developmental delays
    • Distinct facial features
    • Congenital heart defects
    • Increased risk of leukemia
    • Premature aging
  • Aneuploidy notes
    • Autosomal aneuploidy: monosomies are typically lethal; some trisomies survive.
  • Sex Chromosome Aneuploidy
    • Turner syndrome: 45, X karyotype (monosomy X) – the only monosomy that is not universally lethal.
    • Klinefelter syndrome: 47, XXY karyotype.
    • XXX syndrome: 47, XXX karyotype.
    • XYY syndrome: 47, XYY karyotype.

Prenatal and Diagnostic Implications

  • Prenatal testing options mentioned
    • Amniocentesis: typically performed around 16 weeks gestation.
    • Chorionic villus sampling (CVS): typically performed around 9–10 weeks gestation.
    • Prenatal Quad Screen: blood test to assess risk for certain conditions, potentially reducing the need for invasive testing.

Miscellaneous Notes and Concepts

  • The terminology and concepts above are foundational for understanding genetic diseases, including the differences between autosomal and sex chromosome patterns, dominant vs recessive inheritance, and chromosomal abnormalities.
  • Practical implications include family planning considerations, carrier testing, prenatal diagnosis, and the management of conditions with varying expressivity and penetrance.
  • Ethical and practical implications include genetic counseling, screening decisions, and considerations around maternal age and reproductive choices.

ext{Probability Examples (summary)}

  • Autosomal dominant, one affected parent (Aa × aa):
    • P( ext{affected}) = rac{1}{2}
  • Autosomal recessive, both carrier parents (Aa × Aa):
    • P( ext{affected}) = rac{1}{4}
    • P( ext{carrier}) = rac{1}{2}
    • P( ext{unaffected}) = rac{1}{4}
  • Down syndrome prevalence: approximately rac{1}{150} live births, with ~95% due to nondisjunction.
  • Chromosome disorders prevalence in conceptions: ~95% spontaneously aborted; ~50% miscarriages involve major chromosome abnormalities.
  • Karyotype notations to remember: 45, X (Turner), 47, XXY (Klinefelter), 47, XXX, 47, XYY.

Key Terminology Recap

  • Allele: different version of the same gene.
  • Locus: specific site on a chromosome where a gene/allele is located.
  • Homozygote: same allele on both chromosomes (e.g., AA or aa).
  • Heterozygote: different alleles on the paired chromosomes (e.g., Aa).
  • Pedigree: a family tree diagram used to track inheritance patterns.
  • Nondisjunction: failure of chromosome pairs to separate properly during meiosis, leading to aneuploidies.
  • Aneuploidy: abnormal number of chromosomes (e.g., monosomy or trisomy).
  • Karyotype: full set of chromosomes used for diagnostic assessment.