Translation and mutations

Translation turns messenger RNA into a chain of amino acids. That is the work of the ribosome, the most universal machine in the living world.

The players

MESSENGER RNA   carries the message, read codon by codon
RIBOSOME        the machine: it travels along the mRNA
TRANSFER RNA (tRNA)  the adaptor: an ANTICODON on one side,
                     the matching amino acid on the other

        amino acid
             |
          [tRNA]
             |
        anticodon   U A C
                    | | |          complementary pairing
        codon       A U G
        ============================  messenger RNA
                 [  RIBOSOME  ]  --->

The tRNA is the piece that bridges the two alphabets: it, not the ribosome, is what guarantees that a given codon calls the right amino acid.

How it proceeds

1. the ribosome binds the mRNA and finds the AUG codon
2. it advances three bases at a time
3. at each codon, the matching tRNA brings its amino acid
4. the amino acids are linked together (peptide bond)
5. on reaching a STOP codon, the chain is released

   AUG  CCU  GAA  UAC  UAA
    |    |    |    |    |
   Met - Pro - Glu - Tyr  STOP        ->  a chain of 4 amino acids

From thread to machine: folding

A chain of amino acids is not yet functional. It folds in space into a precise shape, and that three-dimensional shape determines the function.

   linear chain  ->  folding  ->  functional protein
   ~~~~~~~~~~~~      in 3D        (enzyme, antibody, receptor...)

Misfolding alone can render a protein useless, even toxic: it is the mechanism of prion diseases and a factor in neurodegenerative disease. Predicting that folding from the sequence remained an open problem for fifty years, until recent advances in machine learning.

Mutations and their effects

A change in the DNA sequence propagates to the protein — sometimes harmlessly, sometimes gravely.

SILENT SUBSTITUTION
   GGU -> GGC       still glycine (code redundancy)
   ->  no effect

MISSENSE SUBSTITUTION
   GAG -> GUG       glutamic acid -> valine
   ->  altered protein, variable effect

NONSENSE SUBSTITUTION
   UAC -> UAA       a premature STOP codon
   ->  truncated protein, generally non-functional

FRAMESHIFT (insertion or deletion of a base)
   AUG CCU GAA  ->  AUG CUG AA...
   ->  everything downstream is unreadable: almost always severe

An example: sickle-cell disease

The best documented case in the history of molecular biology.

β-globin gene, 6th codon:   GAG  ->  GTG   (in the DNA)
              protein   :   glutamic acid  ->  valine

A single base changed out of the genome's three billion. Valine, being hydrophobic, makes haemoglobin molecules aggregate into long fibres that deform red blood cells into a sickle shape. The result is anaemia, pain and blockage of small vessels.

A remarkable fact: carriers of one copy of the allele are protected against malaria. This explains its high frequency in historically malarial regions — natural selection has maintained a severe allele in homozygotes because it is advantageous in heterozygotes.

Summary

• Translation converts mRNA into a chain of amino acids, on the ribosome.
• Transfer RNAs bring the amino acids via their anticodon.
• The chain folds in 3D; shape determines function.
• Mutations: silent, missense, nonsense, frameshift.
• A frameshift is almost always severe: everything downstream becomes unreadable.
• Sickle-cell disease results from a single changed base, and protects against malaria in heterozygotes.