Genetics

Genes and Genetic Diseases

• Genes influence all aspects of body structure and function.
• Defects in genes can lead to recognizable genetic diseases.
• Learning objectives include describing gene influence and comparing gene defects leading to genetic diseases.

Chromosomes

• Two types of cells:
  • Germline: Mutations can be transmitted to the next generation.
  • Somatic: Diploid cells with 23 pairs of chromosomes.
• Homologous chromosomes: 22 pairs are virtually identical.
• Sex chromosomes: 1 pair, X in females, X and Y in males.

Polyploidy

• A germ line or somatic cell with more than the diploid number (46) of chromosomes.
• Several types of body tissue (liver, bronchioles, epithelial) are normally polyploid.
• Triploidy: A zygote has three copies of each chromosome instead of two.
• Nearly all triploid conceptions are spontaneously aborted or stillborn.
• Accounts for 10% of miscarriages.

Aneuploidy

• Cells that do not contain a multiple of 23 chromosomes.
• Monosomy: A diploid cell with only one copy of a given chromosome. (Always lethal)
• Trisomy: An aneuploid cell with three copies of one chromosome. (Trisomy of 13, 18, and 21 can survive)
• Results from non-disjunction of homologous chromosomes or sister chromatids during meiosis or mitosis.

Abnormalities of Chromosome Structure

• Parts of chromosomes can be lost or duplicated as gametes are formed.
• Deletions: One chromosome with a normal complement of genes and one with missing genes.
• Cri du chat syndrome: Duplications usually have less serious consequences than deficiencies.
• Inversions: The occurrence of two breaks on a chromosome, followed by reinsertion in an inverted order.
• "Balanced" abnormalities: No loss or gain of genetic material.
• Translocations: Interchange of genetic material between non-homologous chromosomes.
• Robertsonian translocation: Long arms of two non homologous chromosomes fuse;
• Reciprocal translocation: Breaks take place in different chromosomes and the material is exchanged.
• Fragile sites: Areas on chromosomes with observable breaks/gaps, but the majority have no relation to disease (some exceptions like fragile X syndrome)

Down Syndrome

• The most well-known example of aneuploidy chromosomal cells.
• 10 in 800 live births.
• Typically have low IQ quotients.
• Risk greatly increases with maternal age.
• Approximately 97% caused by nondisjunction during gamete formation.
• Remaining 3% result from translocations.
• Distinctive facial appearance (low nasal bridge, epicanthal folds, large tongue, flat low-set ears).
• Congenital heart defects occur in 1/3 to 2/3 of cases.
• Significant symptoms of Alzheimer's disease develop around age 40.
• One of the genes that can cause Alzheimer’s is located on chromosome 21.

Turner Syndrome

• One of the most common single chromosome aberrations.
• 15 to 20% of spontaneous abortions.
• One in 2500 newborn females is affected.
• Presence of a single X chromosome results in a total of 45 chromosomes.
• Affected individuals are always female, but typically sterile.
• Physical characteristics: Short stature, webbing of the neck, widely spaced nipples, coarctation of the aorta(15-20%), edema of the feet in newborns, sparse body hair.

Klinefelter Syndrome

• 2 X chromosomes and a Y chromosome.
• Due to the presence of a Y chromosome, affected individuals have a male appearance, but usually sterile.
• Physical characteristics: 50% develop gynecomastia, small testes, sparse body hair, tall stature, somewhat high-pitched voice.
• Moderate degree of mental impairment is often present.
• About 1 in 1000 male births.

Elements of Formal Genetics

• Locus: The location each gene occupies on a chromosome.
• Alleles: Genes at a particular locus can take different forms. (example: hemoglobin S or hemoglobin A).
• Polymorphic: When two or more alleles each occur with appreciable frequencies in a population.
• Genotype: The composition of genes at a given locus.
• Phenotype: The result of both genotype and environment.
• Dominant allele: The allele whose affects mask another on a heterozygote.
• Recessive allele: To be expressed, it must exist in a homozygote form.
• Carrier: An individual who has a disease-causing allele but is phenotypically normal.

Transmission of Genetic Diseases

• Mode of inheritance: The pattern in which a disease is inherited through generations of a family.
• Mendelian traits (after Gregor Mendel).
• Principal of Segregation: Homologous genes separate during reproduction; each reproductive cell carries only one of the homologous genes.
• Principle of independent assortment: Hereditary transmission of one gene has no effect on the transmission of another.
• Known single-gene diseases can be classified in the following major modes of inheritance:
  • Autosomal dominant
  • Autosomal recessive
  • X-linked dominant
  • X-linked recessive
• Pedigree chart: Summarizes family relationships and shows which individuals are affected by a genetic disease. Proband/propositus is the individual diagnosed.

Autosomal Dominant Inheritance

• Both sexes exhibit the trait in equal proportion.
• No skipping generations.
• Affected heterozygous individuals transmit the trait to approximately 50% of their children.

Genetic Disease Characteristics

• Recurrence risk: The chance a child will have a disease when one parent is heterozygous affected.
• If a child has an autosomal dominant disease without a family history, it is likely a new mutation.
• Penetrance: The percentage of individuals with a genotype who also exhibit the expected phenotype.
• Incomplete penetrance: Individuals with the disease-causing allele might not exhibit the disease phenotype.
• Age-dependent penetrance: Disease symptoms might not appear until a certain age.(example: breast cancer)

Autosomal Recessive Inheritance

• Diseases caused by autosomal recessive alleles are rare.
• Individuals must be homozygous for the recessive allele to express the disease.
• Carries are phenotypically normal.
• Characteristic of incomplete or age-dependent penetrance and variable expressivity
• Examples include cystic fibrosis.

X-linked Inheritance

• Most sex-linked traits are located on the X chromosome, except for some fragile X syndrome traits.
• Females receive two X chromosomes (can be homozygous for disease, homozygous for normal allele or heterozygous).
• Males inherit a recessive disease on the X chromosome and will be affected because the Y chromosome does not carry a normal allele.
• Males are more frequently affected by X-linked recessive diseases.

Characteristics of X-linked Recessive Conditions

• X-linked recessive conditions generally affect males more than females.
• Traits are often seen in every generation
• Affected fathers will transmit to all daughters who then will be phenotypically normal carriers.
• Example: Duchene muscular dystrophy (DMD)
• X-linked recurrence risk: The affected mother can pass the disease-causing allele to approximately half of her offspring; half of the daughters will be carriers, and half of the sons will be affected if the father is normal.

Sex Determination

• Begins during the sixth week of gestation.
• One Y chromosome is sufficient to initiate gonadal differentiation.
• The number of X chromosomes does not affect this process.
• SRY (Sex determining region on the Y) on the short arm of the Y chromosome acts as a trigger for gene action on other chromosomes. Sex-linked traits occur in only one sex because of anatomic differences, and sex-influenced traits appear disproportionately in one sex.

Gene Identification

• Locating gene positions on chromosomes is a crucial endeavor in human genetics.
• For most genetic diseases, direct testing for the disease-causing mutation might not be possible.
• Whole genome sequencing has become a more accessible and cost-effective way to search for disease-causing mutations in individuals or families.

Precision or Personalized Medicine

• Each person's unique genetic and environmental factors influence disease diagnosis and management.
• Genetic testing is becoming increasingly common for diagnosing diseases and guiding therapeutic drug prescription.
• Variance in genes like CYP2D6 impact drug metabolism and dosing recommendations, requiring personalized strategies.