Variant Effects

Variant Effects

Every time DNA is copied, small mistakes can creep in. A change in the DNA base sequence is called a variant, or a mutation, and they happen constantly. So does every variant cause a disease? Almost never, and that is the interesting part. This module (Higher tier, Biology-only) works out when a variant matters and when it changes nothing at all, which turns out to depend almost entirely on where in the DNA it lands.

Most change nothing

The great majority of variants have no effect on the organism at all, and there are two separate reasons for that. Much of our DNA is non-coding. A change there alters no amino acid in any protein, because no protein is being spelled out at that point. The genetic code is degenerate. Several different codons code for the same amino acid, so even a change inside a gene often produces a codon that means exactly what the old one meant. The protein comes out identical. Keep this in view for the whole module. "Mutations cause disease" is the sentence to avoid: some do, most do not, and knowing why is what the marks are for.

A change that says the same thing

A single base changes inside a gene. The new codon codes for the same amino acid as the old one. What happens to the protein?

• Nothing changes: the amino acid sequence is identical, so the protein folds and functions exactly as before
• The protein folds differently, because the DNA is different
• Less of the protein is made
• The protein is not made at all

Two places, two routes

When a variant does matter, it matters in one of two quite different ways, and which one depends on where it landed:

What would each one do?

Trace the variant

Four single-base changes happen in four different places. Work out what each one does.

• The first falls in a coding region and changes one amino acid, right inside an enzyme's active site. What follows?
• The second also changes an amino acid, but in a part of the protein far from the active site. What is the likely effect?
• The third falls in a non-coding region where RNA polymerase binds, and makes the binding stronger. What follows?
• The fourth falls in a stretch of non-coding DNA that is not a binding region and does nothing else. What follows?

Two routes, in words

A variant in a _____ region can change the amino acid sequence, which changes how the protein folds and therefore its _____. A variant in a non-coding region changes no amino acids, but it can alter how well _____ polymerase binds, and so change how _____ of the protein is made.

Where, not what

Take one enzyme, and imagine the same kind of single-base change happening at three different points in the gene that codes for it. In the third base of a codon, where the new codon happens to code for the same amino acid: the enzyme comes out identical. Nothing has happened at all. In a codon well away from the active site: one amino acid differs. The chain may fold almost exactly as before, and the enzyme usually goes on working. In a codon at the active site: one amino acid differs again, and this time the shape the substrate has to fit into is the shape that changed. The enzyme may stop working entirely. Same kind of change, three outcomes. This is why an exam answer that begins "a mutation changes the protein" has already gone wrong: it depends where.

Away from the active site

A variant changes one amino acid in an enzyme, in a region well away from the active site. Which is the most scientifically careful thing to say?

• It often has little or no effect, because the shape at the active site may be unchanged, but a large enough change to the folding could still alter it
• The enzyme is destroyed, because any changed amino acid changes the protein
• It can never have any effect, since only the active site matters
• Less of the enzyme is made

From base to phenotype

Put the chain of consequences in order, for a variant that does end up mattering.

• One DNA base is changed
• The codon containing it now reads differently
• A different amino acid is placed in the chain
• The chain folds differently, so the protein has a different shape
• The protein's function changes, and the phenotype changes with it

The words for it

Five terms carry this topic, and using the right one is often the difference between a mark and a near miss:

Which are true?

Select ALL THREE statements that are TRUE.

• Whether a variant matters depends more on where it lands than on how large the change is
• A variant can change the phenotype without changing a single amino acid
• Most variants persist without ever being noticed, because they change nothing observable
• Every variant causes a genetic disease
• A variant outside a gene can never affect the phenotype
• A changed base always changes the amino acid it helps to code for

Explain the nuance

Exam practice. In about 50 words, explain why most DNA variants have no effect on the phenotype. Include:

• the point about non-coding DNA
• the point about the genetic code being degenerate
• a sentence making clear that SOME variants do matter, and what decides which

Variant summary

A variant is a change in the DNA base sequence. Most have no effect, because much DNA is non-coding and the genetic code is _____. A variant in a coding region can change an amino acid, altering how the protein folds and therefore its _____ and function. A variant in a non-coding region can change how well RNA polymerase _____, altering how _____ protein is made. Whether a variant matters depends on where it lands.