Genetics and Genetic Diseases Overview

Genes and Genetic Diseases

• Genes influence all aspects of body structure and function.
• Defects in genes lead to recognizable genetic diseases.

Chromosomes

• Two types of cells:
  • Germline: mutations can be transmitted to the next generation.
  • Somatic: diploid cells, 23 pairs of chromosomes.
• Homologous chromosomes: 22 of the 23 pairs are virtually identical. The remaining pair (sex chromosomes) are X in females and X and Y in males.

Polyploidy

• A germline or somatic cell has more than the diploid number of chromosomes (46).
• Several types of body tissues (e.g., liver, bronchioles, epithelial tissue) are normally polyploid.
• Triploidy: A zygote has three copies of each chromosome instead of the usual two.
• Nearly all triploid conceptions are lost as spontaneous abortions or stillbirths.
• Triploidy accounts for approximately 10% of known 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 chromosomes 13, 18, and 21 can sometimes survive.
• Usually results from non-disjunction during meiosis or mitosis, where homologous chromosomes or sister chromatids fail to separate properly.

Abnormalities of Chromosome Structure

• Parts of chromosomes can be lost, duplicated, or rearranged as gametes are formed.

• Deletions: A gamete with a deletion uniting with a normal gamete results in a zygote with one chromosome having a normal complement of genes and one with missing genes.

• Duplications usually have less serious consequences than deletions.

• Inversions: the occurrence of two breaks on a chromosome followed by the reinsertion of the fragment at the original site, but in reverse order.

• Balanced: no loss or gain of genetic material. Deletions and duplications can cause disease.

• Translocations: interchanging of genetic material between non-homologous chromosomes

• Robertsonian translocation: long arms of two non-homologous chromosomes fuse at the centromere, forming a single chromosome.

• Reciprocal translocation: breaks in two different chromosomes and the material being exchanged.

• Fragile sites:Areas of chromosomes that can develop microscopically observable breaks and gaps. Fragile X syndrome is a relevant example, located on the long arm of the X chromosome.

Down Syndrome

• Most common example of aneuploidy chromosomal cells.
• ~10 cases per 800 live births.
• Typically have low IQ quotients.
• Risk increases with maternal age.
• Approximately 97% caused by nondisjunction during gamete formation or early embryonic development.
• Remaining 3% result from translocations.
• Distinctive facial appearance (low nasal bridge, epicanthal folds, large protruding tongue, and flat low-set ears).
• Congenital heart defects are common.
• By age 40, often exhibit symptoms nearly identical to Alzheimer's disease; one of the Alzheimer's genes is located on chromosome 21.

Turner Syndrome

• One of the most common single chromosome aberrations.
• ~1 in 2500 newborn females.
• Presence of a single X chromosome; no homologous X or Y chromosome. Therefore, they are female but usually sterile.
• Physical characteristics: short stature, webbing of the neck, widely spaced nipples, coarctation of the aorta (15-20% cases), edema of the feet in newborns, and sparse body hair.

Klinefelter Syndrome

• Two X chromosomes and a Y chromosome.
• Due to the presence of a Y chromosome, they have a male appearance. However, they are usually sterile.
• Physical characteristics: 50% develop gynecomastia; testes are small; body hair is sparse; stature is elevated; and voice is somewhat high-pitched.
• Moderate degree of mental impairment is often present.
• ~1 in 1000 male births.

Elements of Formal Genetics

• Locus: location of a gene on a chromosome.
• Alleles: Different forms of a gene at a particular locus. Alleles can determine differences between hemoglobin forms.
• Polymorphic: When two or more alleles occur at appreciable frequencies in a population.
• Genotype: genetic makeup at a given locus (compositions of genes).
• Phenotype: the result of the genotype and environment.
• Dominant allele: masks the effect of another allele in a heterozygote.
• Recessive allele: will only be expressed in a homozygote.
• Carrier: individual with a disease causing allele, but is phenotypically normal.

Transmission of Genetic Diseases

• Pattern in which a disease is inherited across generations.
• Mendelian traits: after Gregor Mendel.
  • Segregation principle: homologous genes separate during reproduction & each cell only carries one gene of a homologous pair.
  • Independent assortment principle: heritable factors are transmitted independently.
• Four major modes of inheritance for known single-gene diseases : Autosomal dominant, Autosomal recessive, X-linked dominant, and X-linked recessive.

Pedigree Chart

• Summarizes family relationships and the occurrence of genetic diseases.
• Proband: Individual showing the disease. Also called propositus (male) or proposita (female).

Autosomal Dominant Inheritance

• Both sexes exhibit the trait equally.
• Does not skip generations.
• Affected heterozygotes transmit the trait to approximately 50% of their children.
• Two affected individuals can produce affected offspring together, although more common for affected heterozygotes to mate with a healthy individual.

Genetic Disease Characteristics

• Recurrence risk: Chance a child will inherit a genetic disease. For one affected heterozygote parent and one healthy parent having a child, recurrence risk is 50%.
• Each birth has an independent event; If there's no genetic history of disease in a family, the child's genetic disorder is likely a new mutation.

Genetic Disease Characteristics (continued)

• Penetrance: The percentage of individuals with a particular genotype who also exhibit the expected phenotype, not all.
• Incomplete penetrance: the individuals with a disease-causing allele may not exhibit the disease phenotype.
• Age-dependent penetrance: Symptoms may not appear until later in a person's life
• Obligate carrier: Individuals who have an affected parent and an affected child and must themselves carry the disease allele but do not have the disease themselves.
• Examples of diseases: Breast cancer, colon cancer, hemochromatosis, and polycystic kidney disease.

Autosomal Recessive Inheritance

• Rare diseases.
• Individuals must be homozygous for recessive allele to express the disease.
• Carriers are phenotypically normal; however they may have various expressivity and penetrance.
• High frequency of carriers.
• Common example: cystic fibrosis (~1 in 2500 births in a white population).
• Defective Cl transporter leads to a salt imbalance and thick, dehydrated mucus secretions.

Autosomal Recessive Inheritance (continued)

• Consanguinity (marriage between related individuals): a factor for producing recessive disease offspring.
• Affected in equal proportions in males and females.
• Usually affects siblings, not parents.
• ~¼ of the offspring of carrier parents will be affected.

X-linked Inheritance

• Most sex-linked traits located on the X chromosome.
• Females receive two X chromosomes and can be heterozygous, homozyous for the disease, or homozygous for the normal allele. Males receive one X chromosome and one Y chromosome.
• Males who inherit a recessive disease allele on the X chromosome will be affected, since their Y chromosome will not have a gene to counteract it.
• Males are more frequently affected in X-linked recessive diseases.

Characteristics of X-Linked Recessive Conditions

• Seen more often in males than in females.
• Females require two copies of the recessive allele to express the disease.
• Males need only inherit one recessive allele from their mother.
• X-linked recessive traits are never transmitted from father to son.
• Affected fathers transmit to all daughters but they are usually carriers, not affected.
• Approximately half of the sons will be affected.
• Common example: Duchenne muscular dystrophy (DMD).

X-Linked Recurrence Risk

• Most common is a carrier female mating with normal male.
• The mother transmits the disease-causing allele to half of her offspring.
  • Half the daughters will be carriers, and half will be normal.
  • Half the sons will be normal and half will have the disease.

Sex Determination

• Begins during the sixth week of gestation.
• One Y chromosome is sufficient to initiate gonadal differentiation.
• The number of X chromosomes doesn't alter this process.
• SRY (Sex determining region on the Y): located on the short arm of the Y chromosome, acts as a trigger gene that initiates the action of genes involved in other chromosomes needed for male characteristics development.

Sex-Linked Traits

• Sex-limited trait: Only occurs in one sex, often due to anatomic differences (i.e., breast development).
• Sex-influenced trait: Occurs more frequently in one sex than the other, often due to the impact of hormones (i.e., male-pattern baldness).

Gene Identification

• Precise gene localization on chromosomes.
• Direct testing for disease-causing mutations is often not possible in most diseases.
• Sequencing the whole human genome is becoming more affordable allowing for scanning for gene mutations that cause diseases in individual or family members.
• Enables more accurate diagnoses.

Precision or Personalized Medicine

• Taking into account unique genetic and environmental risk factors.
• Diagnose disease by searching for disease-causing variances in patients entire DNA sequence.
• Genetic testing to guide drug administration and dosage.
• Variance in CYP2D6 gene, an example influencing drug metabolism in ~25% of prescribed drugs, through trial and error, reduce needed time for determining drug dosage requirements.

This quiz delves into the complexities of genes and genetic diseases, exploring their influence on body structure and function. It covers topics such as chromosomes, polyploidy, and aneuploidy, providing insight into how genetic defects can lead to various health issues. Test your understanding of these critical concepts in genetics.