Mutations and Genetic Variation

Q: What is a polymorphism?

A: A polymorphism is any genetic difference among individuals that is present in multiple individuals in a population. It is a variation in the DNA sequence that is common enough to be found in a significant portion of the population.

Q: What is the fundamental role of mutation in genetics?

Mutations are ultimately the source of all genetic variation, providing the raw material upon which evolutionary forces like natural selection can act.

Q: What are the three possible effects a mutation can have on an organism's phenotype?

A: Mutations can be harmful (deleterious), beneficial (advantageous), or neutral (having no effect on the organism's survival or reproduction).

Q: Describe the harmful mutation associated with Huntington's disease.

A: The mutation occurs in the HTT gene. Mutant alleles contain an excessive number of repeats of the CAG codon, which codes for the amino acid glutamine (Q). This results in a mutant HTT protein containing 36–250 consecutive glutamines, compared to the nonmutant range of 6–35.

Q: What is the phenotypic effect of the Huntington's diseas mutation?

A: The mutant protein leads to neurodegeneration, causing atrophy of cerebral tissue and the basal ganglia, enlarged ventricles in the brain, and the progressive symptoms of Huntington's disease.

Q: What is lactase persistence and why is it a beneficial mutation?

It is is the continued expression of the lactase enzyme into adulthood, allowing individuals to digest the lactose in milk. This is a beneficial mutation because it provides a nutritional advantage from dairy consumption, improving chances of survival and reproduction in populations with a history of dairy farming.

Q: Where are the mutations for lactase persistence typically located?

A: The mutations are primarily found in enhancer elements of the gene, not the coding sequence itself. These mutations increase the rate of transcription and mRNA production, allowing lactase expression to continue in adults.

Q: How can the environment alter the effects of a mutation?

A: The environment can influence how a mutation is expressed. For example, the negative effects of the sickle-cell allele are present regardless of environment, but the benefit of being heterozygous (resistance to malaria) is only realized in regions where malaria is present.

Q: How can other genes alter the effects of a mutation?

A: The expression can modify the phenotype caused by a mutation. This is known as the genetic background, where genes elsewhere in the genome can either suppress or enhance the effect of a mutant allele.

Q: What mutation causes sickle cell anemia and what is its effect?

A: A single base-pair mutation in the hemoglobin gene causes a nonsynonymous (missense) change, replacing glutamic acid with valine. This changes the shape of hemoglobin, causing red blood cells to sickle under low oxygen conditions.

Q: Compare the phenotypes of homozygous (SS) and heterozygous (AS) individuals for the sickle cell allele.

A: Homozygous (SS) individuals have sickle-cell anemia and suffer from severe anemia. Heterozygous (AS) individuals have sickle-cell trait, which causes mild or no anemia.

Q: How common are mutations for a single nucleotide versus across the entire genome?

A: The mutation rate for any specific nucleotide is very rare. However, because genomes are so large (billions of nucleotides in humans), mutations are common across the entire genome of an organism.

Q: Are mutations directed to fulfill an organism's "needs"?

A: No. Mutations are spontaneous and occur randomly without regard to any perceived "need" by the organism. They are not purposeful.

Q: What is a mutation "hotspot"?

A: A specific nucleotide or region in the DNA that is more prone to mutation than other areas.

Q: In humans, which sex has a higher mutation rate and why?

A: The mutation rate is greater in males than in females. This is partly because male germ cells (sperm) undergo more cell divisions over a lifetime, increasing the chance for replication errors.

Q: What is a somatic mutation?

A mutation that occurs in the DNA of a nonreproductive cell (any cell not involved in gamete production). These mutations are passed on to all daughter cells derived from that cell but are not inherited by the organism's offspring.

What is a germ-line mutation?

A: A mutation that occurs in the DNA of a reproductive cell (egg or sperm). These mutations can be passed on to the organism's offspring and will be present in every cell of the offspring's body.

What type of mutations lead to cancer?

Cancer results from an accumulation of somatic mutations.

Q: How can a personal genome reveal cancer risk?

A: If an individual inherits a germ-line mutation in a cancer-related gene (like Ras), every cell in their body carries that mutation from birth, significantly increasing their overall cancer risk. Personal genome sequencing can identify such inherited risk factors.

Q: When do mutations become permanent?

A: When errors during DNA replication are not repaired by the cell's proofreading and repair mechanisms.

Q: What are the two broad classifications of mutations based on scale?

A: They are classified as small-scale (affecting a single gene or a few nucleotides) or large-scale (affecting entire chromosomes or large segments of them

Q: What is a point mutation?

A: A type of mutation that  is a change in a single nucleotide base pair in the DNA sequence.

Q: What is a silent (synonymous) mutation?

A type of mutation that is a nucleotide substitution that changes the DNA sequence but does not change the amino acid sequence of the resulting protein due to the redundancy of the genetic code. It has no effect on the protein's function.

Q: What is a missense (nonsynonymous) mutation?

A type of mutation that is a nucleotide substitution that changes a single amino acid in the protein. The mutation in the beta-hemoglobin gene that creates the sickle-cell allele (S) is a classic example.

Q: What is a nonsense mutation?

A type of mutation that is a nucleotide substitution that changes a codon for an amino acid into a stop codon. This results in a prematurely truncated protein that is typically nonfunctional or unstable.

Q: What causes a frameshift mutation?

A type of mutation that is caused by the insertion or deletion of a number of nucleotides that is not a multiple of three (e.g., 1, 2, 4, 5 base pairs).

Q: What is the effect of a frameshift mutation on the resulting protein?

A: It shifts the ribosomal reading frame during translation. This changes every subsequent amino acid downstream from the mutation, usually resulting in a completely different and nonfunctional protein, often with an early stop codon.

Q: What happens if an insertion or deletion involves exactly three nucleotides?

A: This is an in-frame mutation. The reading frame is preserved, but one amino acid is either added to or deleted from the protein. This can be less disruptive than a frameshift but can still impair protein function if the amino acid is critical.

Q: What mutation causes the most common form of Cystic Fibrosis?

A: It is caused by an in-frame deletion of three nucleotides in the CFTR gene, which results in the loss of a single amino acid (phenylalanine) at position 508 in the CFTR protein.

Q: What is the effect of this deletion?

A: The deletion causes the CFTR protein to misfold. This misfolded protein cannot properly transport chloride ions out of cells, leading to the thick mucus secretions that affect the lungs, pancreas, and other organs, characteristic of cystic fibrosis.

Q: What is a transposable element?

A: A “Jumping gene”, a DNA sequence that can move from one location in the genome to another.

Q: What is transposition?

the process by which a transposable element moves or "jumps" from one location in the genome to another.

How can a transposable element disrupt gene function?

When a transposable element jumps into a gene, it can insert itself within the coding sequence, disrupting the gene and preventing the production of a functional protein.

How can a transposable element restore gene function?

If a transposable element that had disrupted a gene subsequently jumps out of that gene, the original DNA sequence can be restored, and the gene can function normally again.