Mutations

• Mutations are alterations in a cell's genetic material.
• Mutations occurring in gametes or gamete-producing cells can be passed on to future generations.

Types of Mutations

• Spontaneous mutations
• Mutations caused by mutagens

Session Learning Outcomes

• To describe how environmental factors can cause mutation
• To recognize different kinds of mutations like frameshift, insertions, deletions, and point mutations
• To describe the effects of different point mutations on protein structure and function

Spontaneous Mutations

• Errors can arise during DNA replication, repair, or recombination.
• These errors can lead to base-pair substitutions, insertions, or deletions, impacting longer stretches of DNA.
• Approximately 1 in every 10^10 nucleotides is altered and inherited by daughter cells.

Genes Accumulate Mutations

• Genes change when one base is changed to another
• Genes change when one base is deleted up to a large segment
• Genes change via insertions of one base up to a large segment
• More drastic changes are more likely to inactivate the gene or genes involved.

Mutations Caused by Mutagens

• Mutagens are chemical or physical agents that interact with DNA, causing mutations.
• Chemical agents include hydroxylamine and alkylating agents.
• Physical agents include high-energy radiation like X-rays and ultraviolet light.

Chemical Mutagens

• Chemical mutagens fall into several categories
• Base analogues may be substituted into DNA, but they pair incorrectly during DNA replication.
• Some interfere with DNA replication by inserting into DNA and distorting the double helix.
• They can cause chemical changes in bases that alter their pairing properties.

Classification of Mutation Types

Based on effect on structure:

• Small-scale mutations (point mutations)
• Large-scale mutations (alterations of chromosome structure) Based on effect on function:
• Loss of function mutations result in less or no function
• Gain of function mutations result in a new or abnormal function
• Lethal mutations result in the death of the organism

Point Mutations

• Point mutations involve changes in a single base pair of a gene.
• Point mutations fall into thee classes: base-pair substitutions, base-pair insertions, base-pair deletions

Base-Pair Substitutions

• They are replacements of one base nucleotide with another.
• Transitions involve the replacement of a purine base with another purine or a pyrimidine with another pyrimidine.
• Transversions involve replacement of a purine with a pyrimidine or vice versa.
• There are 12 possible substitution mutations.

Base-Pair Insertions

• Insertion mutations add an extra base.

Base-Pair Deletions

• Deletion mutations remove a base.

Impact of Base-Pair Substitutions on Protein Function

• Some base-pair substitutions have little or no impact on protein function.
• Silent mutations code for the same amino acids with no detectable change
• Missense mutations code for different amino acids.
• Other base-pair substitutions cause a readily detectable change in a protein.
• Nonsense mutations change an amino acid codon into a stop codon, leading to a nonfunctional protein.

Missense Mutation Example

• Sickle-cell disease is caused by a mutation of a single base pair in the gene that codes for one of the polypeptides of hemoglobin.
• A change in a single nucleotide from T to A in the DNA template leads to an abnormal protein.
• In sickle cell anemia, valine is replaced with glutamic acid.
• The mutant mRNA has a U instead of an A in one codon.

Sickle Anemia

• In sickle cell anemia, valine is replaced with glutamic acid.
• Normal hemoglobin molecules do not associate with one another, and each carries oxygen.
• Sickle-cell hemoglobin molecules interact with one another to crystallize into a fiber, leading to greatly reduced oxygen-carrying capacity.

Base-Pair Insertions or Deletions (Frameshift Mutations)

• Insertions and deletions are additions or losses of nucleotide pairs in a gene.
• These have a disastrous effect on the resulting protein more often than substitutions do.
• Insertion or deletion mutations cause a frameshift mutation.
• All the nucleotides downstream of the deletion or insertion will be improperly grouped into codons.

Impact of Insertions and Deletions on Protein Function

• Frameshift mutations can cause immediate nonsense
• Frameshift mutations can cause extensive missense
• Insertion or deletion of 3 nucleotides lead to no frameshift but extra or missing amino acids

Chromosome Mutations

• Two main types of chromosome mutations exist: structural aberrations and numerical aberrations.
• Structural aberrations are qualitative
• Numerical aberrations are quantitative
• Types of chromosome mutations include deletion, ring chromosome, duplication, isochromosomes, inversion (paracentric & pericentric), and translocation (Robertsonian & reciprocal).

Types of Chromosomes

• Metacentric: centromere in middle
• Submetacentric: centromere distant from middle
• Acrocentric: centromere at end

Deletion

• A chromosomal segment is removed.

Ring chromosome

• Breaks occur in both arms of a chromosome
• The two broken ends anneal, the two acentric fragments are lost
• This results in double deletion

Isochromosome

• Mirror image chromosome
• Loss of one arm with duplication of other

Inversion

• Inversions require two breaks in one chromosome
• The fragment generated rotates 180 degrees and reinserts into the chromosome
• Inversions don't change number of gene
• Pericentric - involves p and q arm, includes centromere
• Paracentric - involves only one arm, don't include centromere

Translocation

• Involves exchange in fragments between different chromosomes
• Reciprocal translocation involves chromosomes exchange fragments
• Nonreciprocal translocations chromosome transfers a fragment without receiving a fragment in return.

Robertsonian Translocation

• Named after W. R. B. Robertson who first identified them in grasshoppers in 1916
• The most common structural chromosome abnormality in humans, frequency is 1/1000 livebirths
• Involves two acrocentric chromosomes
• Two types: Homologous acrocentrics involved, and Non-Homologous acrocentrics involved

Alterations of Chromosome Structure

• Deletion: removes a chromosomal segment
• Duplication: repeats a segment
• Inversion: reverses a segment within a chromosome
• Reciprocal translocation: moves a segment from one chromosome to another

Abnormal Chromosome Number

• Nondisjunction is when pairs of homologous chromosomes do not separate normally during meiosis
• Gametes contain two copies or no copies of a particular chromosome
• Fertilization of gametes in which nondisjunction occurred results in offspring have an abnormal number of a particular chromosome called Aneuploidy
• Trisomic zygote has n+1 chromosomes
• Monosomic zygote has n-1 chromosomes

Human Disorders Due to Chromosomal Alterations

• Alterations of chromosome number and structure cause serious human disorders.
• Two main categories: Autosomal aneuploidy and Sex Chromosomes aneuploidy

Autosomal Aneuploidy: Down Syndrome

• The result of an extra chromosome 21, trisomy 21
• Karyotype 47, XX +21 or 47, XY+21
• Affected individuals have characteristic facial features, heart defects, susceptibility to respiratory infection, an increased risk of developing leukemia and Alzheimer's disease, and are mostly sexually underdeveloped and sterile.
• Occurs in approximately 1 in 600 births
• The frequency of Down syndrome increases with the age of the mother.

Patau's Syndrome (Trisomy 13)

• The result of an extra chromosome 13, trisomy 13
• Most common Karyotype is 47, XX +13 or 47, XY+13
• Occurs in approximately 1 in 10,000 births

Sex Chromosomes Aneuploidy

• Nondisjunction of sex chromosomes produces a variety of aneuploid conditions

Klinefelter Syndrome

• The result of an extra chromosome in a male, producing XXY individuals
• Most common Karyotype is 47, XXY
• Affected individuals have abnormally small testes and are sterile although the extra X is inactivated, some breast enlargement and other female characteristics are common
• Affected individuals have normal intelligence.
• Occurs in approximately 1 in every 2,000 live births.

Turner Syndrome

• The result of monosomy X, producing an X0 karyotype
• X0 individuals are phenotypically female but are sterile because their sex organs do not mature.
• With estrogen replacement therapy, secondary sex characteristics can develop.
• Most affected individuals have normal intelligence.
• Monosomy X or Turner syndrome (X0) occurs once in every 5,000 births.

Disorders Caused by Structurally Altered Chromosomes

Deletion

• Cri du chat syndrome is attributed to deletion in chromosome 5.
• Affected individuals have mental retardation, small heads, unusual facial features, and a cry like the mewing of a distressed cat.
• This syndrome is often fatal in infancy or early childhood.

Translocation

Chromosomal translocations have been implicated in certain cancers:

• CML (chronic myelogenous leukemia) occurs when a large fragment of chromosome 22 switches places with a small fragment from the tip of chromosome 9.
• The resulting short, easily recognized chromosome 22 is called the Philadelphia chromosome.
• The chromosome is defective and unusually short because of reciprocal translocation of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1.
• This gene is the ABL1 gene of chromosome 9 juxtaposed onto the BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signaling protein that is "always on", causing the cell to divide uncontrollably.