User:Supriyabehl/sandboxGene Dosage

Gene Dosage

Currently, the Gene dosage page has a brief definition of the topic, along with an explanation for the risks when gene dosage is unbalanced (Down Syndrome).

Mechanisms of Increase/Decrease

Duplication

An increase in gene dosage is due to one or more duplication events. Duplication can occur through a number of mechanisms. One of these mechanisms is known as slippage. Slippage occurs when DNA polymerase prematurely disjoins from a growing strand, and then rejoins in an improper location during the replication of repetitive DNA. Duplication may also arise through retrotransposons; these proteins function by copying a DNA strand into RNA, reverse transcribing it back to DNA, and then randomly inserting this sequence into the genome. Another common mechanism of duplication is through unequal recombination during meiosis, when repetitive DNA sequences pair up in an incorrect location, resulting in a duplication in one strand and a deletion in the other. Meiotic or mitotic nondisjunction can lead to aneuploidy (the duplication/deletion of one chromosome) or euploidy (the duplication/deletion of every chromosome), which also results in alteration of gene dosage.

Deletion

A decrease in gene dosage is due to deletion events. Slippage can also cause deletions; if DNA polymerase skips nucleotides when rejoining the template strand, then it will result in a deletion. Certain environmental factors, such as X-ray radiation, damage DNA by creating double stranded breaks. Occassionally, the cell cannot close this gap, resulting in a loss of genetic material and a decrease in gene dosage. Additionally, gene deletions arise through unequal recombination and meiotic or mitotic nondisjunction, as previously explained.

Dosage Compensation

Dosage compensation is a mechanism that occurs to maintain a steady gene expression level, regardless of gene dosage. This occurs in sex chromosomes; due to the fact that females have two X chromosomes and males only have one, females have a doubled X-linked gene dosage. Mammals, including humans, overcome this issue through X-inactivation in females. Females will randomly inactivate one of their X chromosomes through methylation and turning them into Barr bodies, which are tightly condensed chromosomes. Barr bodies are difficult to "unwrap", which prevents genes on this chromosome to be transcribed into RNA. This allows for a single gene dosage for both sexes in mammals. Drosophila melanogaster (the common fly) takes a different approach from mammals; dosage compensation occurs through the overexpression of the X chromosome in males, to allow for a gene dosage of two in both males and females.

Haplosufficiency & Haploinsufficiency

Haplosufficiency occurs when an individual is able to function normally with a lower gene dosage for a particular gene. For example, if a mutation in one chromosome led to only having one functional gene present, haplosufficient genes would be able to still produce enough gene product to sustain a viable cell. The decreased gene dosage of that particular gene has little to no effect on the overall function of the cell. Haplosufficiency is not common in nature.

However, haploinsufficiency occurs when an individual's phenotype is greatly affected by a lower gene dosage. Using the same example as above, if the resulting single functional gene could not produce enough gene product to produce a wild-type phenotype, then it is considered haploinsufficient. Haploinsufficiency oftentimes leads to human disease, such as some cancers and frontotemporal dementia (see haploinsufficiency). Haploinsufficiency is naturally more common than haplosufficiency.