HCR 240 Week 1: Genes and Genetics
Genes and Genetics
Deoxyribonucleic Acid (DNA)
DNA is the hereditary material in cells.
It has a double helix structure.
Contains four nitrogenous bases:
Adenine (A)
Cytosine (C)
Guanine (G)
Thymine (T)
Nucleotide = Phosphate group + pentose sugar + nitrogenous base.
Complementary base pairing:
A bonds with T
C bonds with G
In RNA:
A bonds with U (Uracil)
C bonds with G
DNA provides the code for the organization of amino acids, forming a polypeptide, and ultimately a protein.
There are 20 amino acids.
Triplets of nucleotides (3) code for a specific amino acid, called a codon.
There are 64 possible codon combinations.
3 of these are stop codons (nonsense codons).
Replication
The DNA strand is untwisted and unzipped.
A single DNA strand acts as a template.
DNA polymerase adds new nucleotides and proofreads.
If an incorrect nucleotide is added, DNA polymerase will excise and replace it.
Mutations of DNA
Base pair substitution (point mutation):
One base pair is incorrectly substituted for another.
Silent: Incorrect base pair still codes for the correct amino acid.
Nonsense: Incorrect base pair codes for a stop codon.
Missense: Incorrect base pair codes for an incorrect amino acid.
Mutagens (ROS, radiation, toxic chemicals) can cause errors during proofreading or changes to the parent DNA, leading to mutations.
Frame shift mutations:
Insertion or deletion of one or more base pairs.
Alters all subsequent codons, often leading to premature stop codons.
From DNA to Protein
DNA remains in the nucleus, but amino acids and proteins are formed in the cytoplasm.
Process to create proteins involves three steps:
Transcription
RNA splicing
Translation
Transcription
RNA is synthesized from a DNA template via RNA polymerase.
There are 4 mRNA base pairs (A, U, G, and C) chosen based on the complementary DNA sequence.
Transcription continues until a termination sequence is reached.
Gene expression is regulated by transcription factor proteins.
RNA Splicing
mRNA is removed from the nucleus.
Once removed, RNA matures through the removal of introns.
Extrons are combined to form functional mRNA.
Translation
Functional mRNA is converted into polypeptides with the assistance of ribosomes and transfer RNA (tRNA).
tRNA contains a sequence of nucleotides (anticodon) complementary to the triad of nucleotides on the mRNA strand (codon).
The termination signal on the mRNA sequence ends translation.
Chromosomes
Somatic cells:
Contain 46 chromosomes (23 pairs).
One from the mother and one from the father.
Diploid cells (2n).
Gametes (sperm and egg cells):
Contain 23 chromosomes.
Haploid cells (n).
Meiosis: Formation of haploid cells from diploid cells.
22 out of 23 chromosome pairs are autosomal (not sex-related).
The 23rd pair is sex-related and determines the genotypical sex of the child.
XX: female
XY: male
Genetic Diseases and Chromosomal Abnormalities
Polyploidy: Cells with 3 or more copies of each chromosome; fetuses do not survive (stillborn or miscarriage).
Aneuploidy: Cells with an abnormal number of one particular chromosome, typically a result of nondisjunction.
Down syndrome (trisomy 21)
Trisomy X (47, XXX)
Turner syndrome (45, X)
Klinefelter syndrome (47, XXY)
Down Syndrome
Trisomy 21.
Occurs 1 in 800 live births.
Incidence increases with maternal age.
Increased risk of congenital heart defects, respiratory infections, leukemia, and Alzheimer's disease.
Life expectancy is around 60 years.
Manifestations may include:
Intellectual disabilities
Low nasal bridge
Epicanthal folds
Protruding tongue
Flat and low-set ears
Short stature
Poor muscle tone
Sex-linked Aneuploidy
Turner Syndrome:
Females have only one X chromosome (45, X).
Occurs 1 in 2500 female births.
Manifestations: absence of ovaries (sterile), short stature, webbing of the neck, widely spaced nipples, high rates of fetal mortality.
Teenagers receive estrogen replacement therapy to promote secondary sexual characteristics.
Trisomy X:
1 in 1000 female births.
Females have three or more X chromosomes.
Symptoms are variable and include sterility, menstrual irregularity, and/or cognitive deficits.
May not be diagnosed until later in life.
Klinefelter syndrome:
1 in 1000 male births.
At least one Y and two or more X chromosomes (XXY).
Characteristics include: overall male appearance, gynecomastia, small testes, sparse body hair.
May also have an extra Y chromosome.
Typically have worsening symptoms with additional X chromosomes (XXXX or XXXY).
Chromosomal Structure Abnormalities
Fragile X Syndrome:
Site is on the long arm of the X chromosome; has an elevated number of repeated DNA sequences (CGG).
Manifestations include intellectual disabilities, behavioral problems, long and narrow faces, large protruding ears, hyper-extensible finger joints.
Second most common cause of intellectual disability after Down syndrome.
Fundamentals of Genetics
Allele: Different forms of a gene; typically inherit one from mother and one from father.
Homozygous: Alleles that are identical (AA or aa).
Heterozygous: Alleles that are different (Aa).
Dominant: Allele with observable effect (denoted by capital letter).
Recessive: Allele with non-observable effect in the presence of a dominant allele (denoted by lowercase letter).
Co-Dominant: Both alleles have an observable affect (example: blood type AB).
Genotype: Composition of genes at a given locus.
Phenotype: Outward appearance of an individual (genotype + environment).
Example: Phenylketonuria (PKU) - without treatment leads to intellectual disorders; with dietary restrictions, the child will have a normal phenotype.
Carrier: Individual with disease-causing allele but with a normal phenotype, most typically occurs with heterozygous alleles.
Sex Determination:
One copy of the Y chromosome is sufficient to initiate the process of gonadal differentiation that produces a male fetus.
Number of X chromosomes does not alter this process.
Sex-determining region on the Y chromosome is called SRY.
In some mutations, SRY can cross over to the X chromosome (XX karyotype but with a male phenotype) or be deleted from the Y chromosome (XY karyotype with female phenotype).
Genetic Disease Inheritance
4 major types:
Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive
Not sex-linked vs. Sex-linked (Y-linked genetic diseases do occur, but they are more rare).
Autosomal Dominant
Diseases are rare (<1 in 500).
Condition is expressed equally in males and females (not sex-linked).
Transmission of affected individuals to their offspring is not sex-linked.
No generational skipping occurs:
All affected children will have an affected parent.
Nonaffected parents cannot pass it to their children.
Exceptions may occur if there is a germline mosaicism.
Transmission is approximately 50%.
Example: Huntington’s disease.
Genetic Complications
Germline mosaicism:
Parent carries the mutation in his or her gamete cells but does not have the autosomal dominant disease in his or her somatic cells (parent with normal phenotype; asymptomatic carrier).
Disease can pass on to children despite no recorded family history.
Penetrance:
Percentage of individuals who have the diseased genotype and express the diseased phenotype.
Incomplete penetrance: 90% of people with the gene mutation for retinoblastoma (eye tumor) will have the disease, and 10% will not.
Age-dependent penetrance: People with the genes for Huntington’s disease will not show symptoms until they are in their 30-40s.
Expressivity:
Extent of variation in a phenotype associated with a particular genotype. Can be caused by modifier genes, environmental factors, and mutations.
Example: Neurofibromatosis type 1: expressivity varies from brown spots on the skin to malignant tumors, scoliosis, gliomas, and neuromas.
Autosomal Recessive
Rare to have the disease; more common to be a carrier.
Condition is expressed equally in males and females (not sex-linked).
Transmission of affected individuals to their offspring is not sex-linked.
Since the abnormal allele is recessive, the person must be homozygous to express the disease (dd) – this means that both parents must be carriers (dd or Dd).
Most commonly, both parents are heterozygous (Dd).
Carrier detection tests can help identify people who are heterozygotes.
Parents who are heterozygous carriers have a 25% chance of passing on the disease to their children, a 25% chance of not passing the disease, and a 50% chance of having children who are also carriers.
Generational skips may occur with autosomal recessive diseases.
Example: Cystic fibrosis:
Mutated gene forms defective chloride channels, which leads to a salt imbalance that results in abnormally thick, dehydrated mucus.
Affects the lungs and pancreas.
Patients typically do not survive past 40 years of age.
Consanguinity:
Mating of two related individuals (also known as inbreeding).
Proportion of shared genes depends on the closeness of the biologic relationship.
Dramatically increases the recurrence risk of recessive disorders.
X-Linked Dominant
X-linked dominant disorders are incredibly rare.
Females are more likely to be affected by X-linked dominant disorders than males.
Males who have an X-linked disorder have a 100% chance of passing the disorder to their daughters and a 0% chance of passing it to their sons.
Females who have an X-linked disorder have a 50% chance of passing it to their sons or daughters.
One example of an X-linked dominant disorder is fragile X syndrome.
X-Linked Recessive
Since males only have one copy of the X chromosome, they are significantly more likely to be affected by X-linked recessive disorders.
Males only need one copy of the recessive gene, whereas females would need two.
An affected father will:
Never be able to pass the gene to his sons (can only give Y chromosome).
Always pass the gene to his daughters (must give affected X chromosome), who will then become carriers.
Generational skips may occur due to female carriers.
Example: Duchenne Muscular Dystrophy:
Occurs 1 in 3500 males vs 1 in 50,000,000 females.
Exhibits progressive muscular degeneration.
Deletion of DMD gene causes dystrophin to not work properly; consequently, muscle cells do not survive.
X-Linked Recessive Complications
Even though females have two X chromosomes, they only need one set of X chromosome proteins.
To correct for this, each cell will select one X chromosome to deactivate.
Cells may choose different X chromosomes to deactivate.
The deactivated chromosome becomes a Barr body.
15% of the genes on the Barr body may escape deactivation.
If female cells inactivate one X chromosome, then why is Turners syndrome a problem?
If female cells inactivate one X chromosome, then why do female carriers of an X-linked recessive disorder typically not have symptoms?
Assignments
See assignments in Canvas.
Week 1 Worksheet.
You will need to use the book and complete the assigned readings.