What does phasing mean?

Question

What does phasing mean in genetics/informatics? I've heard that a phased file is a file that has genes separated by chromosome, but can someone give a concrete definition of what phasing actually means?

Answer 1

Phasing is a way to identify the location of genetic mutations. Mutations can be in cis (on the same copy of a gene) or in trans (on different copies of the gene). The location tells us who is a carrier of a genetic condition and who is affected by a genetic condition.

Let's say John and Jane wants to have a child. As they prepare to conceive, they want to reduce genetic risk to their child to the greatest extent possible. Thus, they undergo genetic testing to determine if they are carriers of the same genetic conditions (this is called "carrier screening").

We have two copies of every gene. To be affected with a genetic condition means that both copies of a gene are nonfunctional (two mutations, one on each copy of the gene). To be a carrier of a genetic condition, only one copy is nonfunctional (mutation(s) on one copy) and the other is functional (no mutation on the other copy).

When the couple's results come back, John is found to have two mutations in a gene. John is nervous: "If I have two mutations, doesn't that mean I have this awful condition?"

Whether or not John actually has the condition depends on the phasing of the mutations. Are they on the same copy or different copies? We can ask the following:

1. Are both mutations on the same copy of the gene? In other words, are the mutations in cis? This would mean that one copy is nonfunctional, and the other copy is functional. This person would be a carrier.
2. Is one mutation on one copy of the gene, and the other is on the other copy of the gene? In other words, are the mutations in trans? This would mean that both copies are nonfunctional. This person would be affected with the genetic condition.

Genetic testing on John can tell us how many mutations are present in a gene, but not on which copies of the gene they are present on. So, phasing is required to determine location. To do phasing, we test John's parents. We know that John (and everyone else for that matter) inherited one copy of this gene from his biological mother and one copy from his biological father.

1. If we find that each parent has one mutation, we know that both copies of the gene are mutated, and John has the genetic condition.
2. If we find that one parent has two mutations, and the other has none, we know that only one of John's copies has both mutations, and the other does not. Thus, John is a carrier of this condition, because one copy is not working and the other one is working.

Phasing is very important in modifying risk recurrence in children and diagnosing people with genetic conditions.