Mutations: Changes in the Genome
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[edit] Inherited vs. de novo Mutations
Inherited mutations are those that are passed from a parent to a child during fertilization. While they might not affect the parent, inherited mutations are not newly created in the embryo. There are a number of reasons why the inherited mutation might not affect the parent who has the mutation, including (but not limited to): balanced translocations, recessive mutations, non-penetrance, parental imprinting, and trinucleotide repeat expansions.
Sporadic or de novo mutations on the other hand, occur randomly during the cellular processes that create a new embryo. These mutations can occur anywhere in the DNA sequence, at any time during cell division, and can have a variety of effects ranging from no effect to a severe genetically based disease.
[edit] The Cell Cycle
[edit] Chromosome Level Changes
[edit] Aneuploidy
Aneuploidy occurs when a cell has the wrong number of chromosomes either due to an extra or missing chromosome. This type of problem can occur during the anaphase part of M phase. Through a process called nondisjunction the chromosome pairs may not separate properly causing one of the daughter cells to receive both copies of a chromosome and the other daughter cell receives no copies of that chromosome. Therefore, one daughter cell will have an extra chromosome and the other daughter cell will have a missing chromosome. Also, this problem can occur if there is a lag during anaphase. When the pairs of chromosomes separate to each side of the cell, a chromosome may travel too slow which would cause it to not be incorporated into the new cell. This new cell would be missing a chromosome.
[edit] Deletion
Chromosome Deletions occur when the cell is missing a portion of a chromosome. This type of problem can occur during S phase if there is a problem during DNA replication or other parts of interphase if the DNA is damaged.
[edit] Duplication
Chromosome Duplications occur when a cell has a repeated portion of a chromosome which causes the cell to have extra information. This type of problem can occur during S phase if there is a problem during DNA replication.
[edit] Inversion
Chromosome Inversions occur when a piece of a chromosome breaks and that piece is reattached in the opposite orientation. This type of problem can occur during interphase if the DNA is exposed to damage that causes DNA breakage.
[edit] Insertion
Chromosome Insertions occur when a piece of a chromosome that had broken reattaches in a location where this genetic material is not typically found. This type of problem can occur during interphase if the DNA is broken and then repaired by attaching to a different location.
[edit] Translocation
There are two types of translocations: reciprocal and robertsonian. A reciprocal translocation occurs when two nonhomologous chromosomes break and then switch genetic material. A robertsonian translocation occurs when two chromosomes break on the p arm near the centromere and then the two q arms attach together while the p arms are lost. Either of these types of translocation can occur at any point during the cell cycle.
[edit] Genes
[edit] Anatomy of a Gene
[edit] Genotype to Phenotype
[edit] Products of Genes
[edit] DNA Sequence Level Changes
A number of changes can occur at the DNA Sequence level that can lead to various phenotypes or genetic disorders. These types of changes can be broadly broken down into point mutations and frameshift mutations.
Point mutations are the most common types of mutations in the DNA sequence. Point mutations occur when one base changes to a different base. (Example: adenine (A) changes to thymidine (T)). Most point mutations have little or no effect, and can arise from mutagens or a mistake in DNA replication.
In some cases, a point mutation can cause a missense mutation, where the new codon codes for a different amino acid than the original codon. Nonsense mutations are changes that result in the incorporation of a stop codon, resulting in an abnormally short protein. Abnormally short proteins can have a number of outcomes within a cell. They might be non-functional, functional in a less effective way, or acquire a new function. This could happen due to changes in protein folding, changes of interactions with the protein and other substances, or even through decay of the shortened protein.
Frameshift mutations include insertions and deletions of base pairs that alter the triplet (3-base codon) reading frame. Any number of base pairs inserted or deleted that is not a multiple of 3 will cause a frameshift mutation. These types of mutations change every subsequent codon, usually also creating a new stop codon at a different location than the original. This type of mutation can also result in truncated proteins.
Insertions occur when one or more base pairs disrupt the original sequence and are incorporated into the DNA sequence where they otherwise would not be found. Deletions occur when one or more base pairs are eliminated from the original DNA sequence. Deletions and insertions can range in size from one or two base pairs to hundreds or thousands of base pairs.
Tri-Nucleotide Expansion Mutations is a dynamic mutation involving groups of three bases of DNA and are the cause for a group of diseases known as Tri-nucleotide Repeat Expansion Diseases (TRED). The three bases repeat over and over in the gene. It is like a word being repeated over and over. There is a number of times that the word can be repeated before it causes problems. There are three stages for the repeat: normal, premutation and affected. There is a certain amount of repeats which varies per genetic condition which still allows the person to be unaffected. When a parent passes this gene on to their children, the word may repeat itself more and if the number of repeats increases enough, it may fall into the premutation range. People in the premutation range are usually unaffected but their repeats are unstable and will most likely expand into the mutation range when they pass it on their children. If the repeats are occuring in a non coding region of a gene, it is known as Type 1 Expansion. The repeats cause loss of function in the gene. They usually have a recessive inheritance. An example of a type 1 expansion disease is Fragile X syndrome. If the repeats occur in a coding region, it will result in a gain of function mutation. They typically have a dominant inheritance and an example of a type 2 expansion disease is Huntington's Disease.
[edit] Mutation Analysis
There are different ways of analyzing the genome to find the mutations mentioned above and identify genetic conditions. Genetic conditions often have different mutations associated with them. For example, CF. If the mutation has been passed on from a parent, then the scientists know which mutation to look for and will sequence that specific gene in search of that mutation. It is a lot easier to identify a mutation prenatally or in an adult when it is known. If the mutation is uknown, for example a de novo mutation or one that has not been identified in the parents, the scientists will sequence the area of the genome linked with the condition and look for any known associated mutations. In the case of Down syndrome or any other aneuploidy, a karyotype or picture of the chromosomes can be obtained in order to detect any abnormalities. These tests can be done prenatally through amniocentesis and CVS or can be done through a blood or tissue sample when the patient is a child or adult.
For more information on prenatal diagnosis: Pregnancy Screening / Reproductive Screening.
For more infromation on mutation screening:How Genetic Tests Work - Molecular (sequence, target, array), Biochemical & Cytogenetics
[edit] Links
Chromosome Abnormality: This page has additional information on various types of chromosome abnormalities such as aneuploidies, insertions, inversions, translocations, etc.
[edit] References
[edit] Chromosome Level Changes
Nussbaum, R.L., McInnes, R.R., Willard, H.F., and Boerkoel, C.F. (2004). Principles of Clinical Cytogenetics. Thompson and Thompson Genetics in Medicine, 6. (pp. 135-155). Philadelphia, Pennsylvania: Saunders.
Strachan, T. and Read, A.P. (2004). Chromosome Structure and Function. Human Molecular Genetics 3. (pp. 34-58). New York: Garland Publishing. [edit]
[edit] DNA Sequence Level Changes
Hartwell, L., Hood, L., Goldberg, M., Reynolds, A., Silver, L., Veres, R. (2000) Genetics: From Genes to Genomes. USA: McGraw-Hill.
Strachan, T. and Read, A.P. (2004). Chromosome Structure and Function. Human Molecular Genetics 3. (pp. 34-58). New York: Garland Publishing. [edit]
[edit] Mutation Analysis
Strachan, T. and Read, A.P. (2004). Chromosome Structure and Function. Human Molecular Genetics 3. (pp. 34-58). New York: Garland Publishing. [edit]
