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Skip to 0 minutes and 7 secondsWe've now seen how errors in recombination and segregation can cause problems. But before either of those things happen, DNA has to be copied. That's about 20,000 genes, or 3 billion bases, that need to be copied. Imagine if you were given the task of copying 120 books, word for word. That's three billion letters you had to write out correctly and accurately. That's what happens when DNA is copied, over and over again, in cell division. With such a large number of bases, it is inevitable that copying mistakes will happen from time to time. We call these "errors in replications." A replication error can affect a single DNA base, several bases, or sometimes larger chromosome regions.

Skip to 0 minutes and 52 secondsSo how do these errors cause genetic conditions? First of all, it is important to realise that not all errors of replication are disease-causing or pathogenic. Indeed, as we discussed in week 1, many errors of replication are responsible for normal human variation and drive evolution. Whether a replication error results in disease depends on its size, its position, and its effect on protein production. When we talk about gene mutations, we generally group them into base substitutions or frame-shifting mutations. Base substitutions involve the substitution of a single base and can cause synonymous, nonsynonymous, or stop gain mutations. Where there is a synonymous change, there is a change in the base, but it results in the same amino acid being encoded.

Skip to 1 minute and 37 secondsThis is exemplified by the word "cat"-- C-A-T. If it changes to "kat" with a K, the word sounds the same although is spelled differently. Although synonymous changes often don't cause disease, if they occur at one of the essential splice sites which dictate how the introns are removed during protein production they can be pathogenic. A nonsynonymous change, also known as a "missense mutation," is where base substitution results in a different amino acid being incorporated into the protein encoded by the gene. The effect of the amino-acid substitution will depend upon whether the newly incorporated amino acid significantly alters the structure and function of the resultant protein.

Skip to 2 minutes and 16 secondsThis is exemplified by the example here, where C has been substituted initially for B, where the sentence makes sense, and subsequently for G, where it no longer makes sense. A stop gain mutation was previously known as a "nonsense mutation" and is where the altered DNA sequence prematurely tells the cell to stop building the protein. This means that the protein is shorter than it should be and may not function properly. Finally, insertions and deletions change the number of bases in a gene. One or many bases may be inserted or deleted. If the number of bases inserted or deleted is not a multiple of three-- the size of the codon-- then the reading frame of the gene will be disrupted.

Skip to 2 minutes and 58 secondsThis usually results in a shortened, abnormal protein, which may or may not be destroyed by the cell.

Errors in replication

When DNA is copied, over and over again in cell division, errors will inevitably be introduced. We call these errors in replication. A replication error can affect a single DNA base, several bases or sometimes larger chromosome regions.

Not all the errors introduced into the genome are pathogenic, or disease-causing. Indeed, as we discussed in week one, genomic variation is often completely normal and is what drives evolution and makes us unique. Whether a replication error results in disease depends on its size, its position and its effect on protein production.

When we talk about gene mutations, we generally group them into point mutations or insertions / deletions.

Point mutations involve the substitution of a single base and can cause

A) synonymous,

B) nonsynonymous or

C) stop gain mutations.

Point mutation © YourGenome

Where there is a synonymous change there is a change in the base but it results in the same amino acid being encoded.

For example:

Synonymous mutation © St George’s University of London

Although synonymous changes often don’t cause disease, if they occur at one of the essential splice sites, which dictate how the introns are removed during protein production, they can be pathogenic.

A nonsynonymous change (also known as a missense mutation) is where a change in one DNA base pair causes a different amino acid to be substituted in the protein made by the gene:

Nonsynonymous mutation © St George’s University of London

The protein resulting from the nonsynonymous change will therefore have one different amino acid incorporated which, depending upon how vital that amino acid is to the protein structure and function, may be pathogenic.

A stop gain or nonsense mutation is where the altered DNA sequence prematurely tells the cell to stop building the protein. This means that the protein is shorter than it should be and may either be destroyed by the cell or may not function properly:

Stop gain mutation © St George’s University of London

Insertions and deletions change the number of bases in a gene.

Insertion mutation Deletion mutation © YourGenome

One or many bases may be inserted or deleted. If the number of bases inserted or deleted is not a multiple of three (the size of the codon) then the reading frame of the gene will be disrupted. This usually results in a shortened, abnormal protein which may or may not be destroyed by the cell:

Frameshifting del mutation © St George’s, University of London

If the number of bases inserted or deleted is a multiple of three, then the insertion or deletion will not alter the reading frame and may be less deleterious:

In-frame insertion mutation © St George’s, University of London

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This video is from the free online course:

The Genomics Era: the Future of Genetics in Medicine

St George's, University of London

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Find out what this course is like by previewing some of the course steps before you join:

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