Genetics - Genetic mutations

Sense mutations

A stop codon is converted to one coding for an amino acid, and it will keep translating until it finds another stop codon. This usually results in a slightly longer than normal protein. Most non-coding DNA contains a number of stop codons. This usually isn't a big deal since there isn't a huge amount of extra protein put on, but sometimes it CAN cause functional problems for the protein. Disease caused by sense mutation: Thalassemia (lbood disorder).

Consequences of frameshifts

Amino acid sequence is completely altered. These usually have large-scale, severe effects on the protein. Everything after the frameshift is messed up, which often results in a premature stop codon - a shortened peptide. Effect can be minimal if it occurs near the end of the sequence - a base pair inserted here would not cause too many amino acids to be messed up.

Types of genetic mutations

Base pair substitutions: Swapping out one or more bases for another. Ex. T for C. Alteration in nucleotide sequence: Sequence is changed but not the number of them. Most codons are read correctly, but one base pair is changed to something else. Transition: Purine can be swapped for another purine. Ex. A for G. Transversion: Purine swapped for pyrimidine (or vice versa). Ex. A for C.

Base pair position and severity

Base position affects severity of the mutation. Third base pair is pretty flexible in most cases and the amino acid will not change. If you mutate the coding sequence there is a 1/3 chance nothing bad will happen, but changing the first or second amino acid in a codon is bad and will usually result in a problem.

Huntington's Disease

CAG repeat expansion in the Huntington (HTT) gene: Creates a neuron in the brain. Normal: 6-37 copies Diseased: 35-121 copies. There is variance from individual to individual as there is some overlap (close to 35 may have it). CAG code is for glutamine: The disease leads to a chain of glutamine residues (PolyQ tract). Q is associated with glutamines, so this means many glutamines. This causes the glutamines to stick together and crystalize Huntington protein in the middle of a neuron, which leads to degeneration of certain types of neurons (late onset) due to crystallized forms. Late onset: Takes time for this aggregation to occur, with the average age of onset ~50. Symptoms: Personality changes, moodiness, abusive, depressive behavior, cognitive problems. This is a DOMINANT trait: If parents have Huntington's there is a 50% chance that offspring will have it. If offspring have it they will get it earlier than the parents.

Why do genes mutate?

Errors in DNA replication: DNA polymerase messes up 1:1 million base pairs and puts in the wrong one. Though there are proofreaders, sometimes errors still happen. Radiation/UV light: Causes pyrimidine dimers in DNA, so the wrong base pairs are often put around these structures. Chemical exposure: Chemicals can cause a change in base pairs or alteration of the appearance of base pairs to look like others. Can also make replication difficult.

Fragile X syndrome

Expansion of CGG repeat in the FMR-1 gene on the X chromosome. Normal: 6-52 repeats Diseased: 230-72,000 repeats. Causes inactivation of FMR-1, which leads to mental retardation, cognition delays, speech delays, motor delays. Fragile X chromosomes have a characteristic stalk at the end of their long arms. These fragile parts can actually break, though it usually doesn't cause many more problems because the FMR-1 gene is already messed up. Men: Much more severe symptoms. Women: Still have symptoms, but not as severe because they have 2 X chromosomes, so 50% of cells produce normal FMR-1.

Trinucleotide repeats

Expansion of trinucleotide repeats can commonly cause disease. Usually the more repeats present = greater disease severity. Number of repeats tends to increase with each successive generation and offspring have an earlier onset of disease. Anticipation: Disease gets progressively worse with each generation.

Mutations in the promoter region and splice site muations

If the promoter region is mutated, RNA polymerase might not come in and land anymore, so the gene may not be transcribed. Missense mutations do not always change an amino acids, but mutations in the promoter region can influence the protein. Splice site: Mutations here can result in the loss of exons or gain of introns. Splice acceptor mutation: Accidentally cuts out an extra exon. Goes from exon 1-3 because 2 was cut out. The effect on the protein varies: May be severe, some not. Splice site = usually pretty severe unless it is only part of a structural component.

What is mutation?

Mutation: A heritable change in DNA, though technically it is not always heritable. Typical mutation: Double strand of DNA splits into two pieces to make two new strands of DNA. One strand may be normal, but the other is mutated. The body will normally catch this error, but if it doesn't one strand will copy correctly, but the mutated one will copy incorrectly and replicate the mutation in every cell it creates, thus spreading the mutation. Transition: T to C base pair change.

When did the germline mutation occur?

Mutations can be inherited generation to generation OR de novo, where they arise spontaneously in an individual. Must identify the mutation in the affected individual and then test the parents/grandparents. Ex. If the mutation is found in a child, test parents, but if neither parents has it it is considered de novo as the child is the first to have it. Family histories can provide clues. If no one else in the family has had the disease but the child has it it is either de novo in the child or de novo in one of the parent's gametes. If other family members have the disease or similar symptoms, it is more likely that it was passed down from previous generations.

Somatic mutations

Occur in non-gametic cells and are not passed onto offspring, but all daughter cells from this mutation will receive the mutation through mitosis. This mutation occurs AFTER the person has been created, but still be in development. Generally localized to one tissue or organ, depending on the time of the mutation. NOT FOUND IN SPERM OR EGGS. The earlier the mutation occurs, the the larger the area of the body is affected by it. Often results in cancer OVER TIME, but cancer is caused by many, many, many mutations. This is why the risk of cancer rises with age.

Frameshift mutations

Occur when the "frame" of the sequence is altered. When altering the "reading" frame of a gene, adding or deleting a base causes a shift. Due to insertions or deletions of base pairs, the base pair number is affected. NOTHING after the frameshift occurs makes sense and is messed up.

Germline mutations

Occurs in gametes (sperm and eggs). Usually only one copy is mutated and the other is normal. If you give the normal gamete to offspring, then offspring = normal. Giving the mutated copy = offspring have the mutation. Passed onto offspring 50% of the time since only one copy is usually affected. Usually no phenotype is present in the original individual, but will show in the offspring if the mutated sperm or egg are passed on. If the phenotype appears in offspring, all of their cells are affected.

Missense mutations

One amino acid is changed to another. Because amino acids have unique properties, some may be very similar and some may be very different (hydrophobic, hydrophilic, polar, non-polar, etc.). This can change how the protein folds. Position in the protein can affect severity: If a protein has a particular job, depending on the domain it is in, the protein may be affected greatly or not. No effect: Similar amino acids. Large affect: Altering amino acid to a very different one, or altering an amino acid in a very crucial domain. Changes can cause a loss or change of function, which can result in a phenotype in offspring.

Examples of somatic mutations

Orange petals on a flower. Feo melanin makes golden retrievers yellow, umelanin causes black patch of fur (mutation). Horse with black botches: This is the agouti gene mutated, so black was allowed to show. Heterochromia: Occurs very early in development.

Hemophilia and the British royal family

Sex-linked recessive. Some women are carriers, but only men are affected. Queen Victoria was a carrier and likely had a mutated X chromosome, but no hemophilia was in the family beforehand. Trait was spontaneously eradicated.

Synonymous and non-synonymous changes

Synonymous: Sometimes nothing happens. If a nucleotide is changed but the codon is the same, then the amino acid will be the same and then it does not affect the protein. Non-synonymous: Change a nucleotide which changes a codon, which changes the amino acid and affects the proteins. 3 categories: Missense, nonsense, and sense mutations.

Repeat expansion

The genome has many areas of repeated nucleotides. Microsatellites: Sections repeated over and over. Errors in replication can result in extra repeats being added. Di: Usually found in introns. Used as genetic markers. Found outside of genes. Tri: Can be found outside or inside genes. Recall that three nucleotides are a codon. Overt time, repeat expansion becomes greater and can lead to disease, especially from generation to generation -- an offspring's repeats are longer than their parents, so each generation can have increased problems/disease.

Nonsense mutations

Usually VERY severe because the proteins are usually very short/small, which results in a loss of function of the protein. Function can be retained if the mutation happens late in the sequence - the mutation is less severe in this case, but this is RARE. Diseases caused by nonsense mutations: Cystic Fibrosis, Hemophilia, Duchenne's (muscular dystrophy).