The mutant gene that causes FFI is often written as “D178N 129M”. What is this string of numbers and letters? Is it an address? A compressed DNA base pair sequence? Simply a random unique identifier? This post sets out to answer this question as best I have come to understand it.
First off, a review of some basic genetics. DNA comes in double helices, but only the 5′ to 3′ side of each helix gets transcribed into RNA and therefore translated into protein. The 3′ to 5′ side is complementary and doesn’t contain any additional information. A length of double helix makes up a chromosome, and chromosomes come in pairs. Humans have 23 pairs of chromosomes. The haploid human genome contains about 3 billion base pairs, so the diploid genome contains about 6 billion base pairs. No one explains it all better than Salman Khan.
Within this sequence of 6 billion base pairs, each gene has a particular place, or locus, where it is expected to be found. The gene that codes for human prion protein, PrP, is located at 20p12-ter along with a couple of related genes. This locus, the genetic equivalent of an address in computer memory, means that PrP is coded on Chromosome 20, on the short (p = petit) half of the chromosome, i.e. “north” of the centromere, and 12-ter is the specific location (ter refers to the telomere, meaning the locus is very close to the end of the chromosome).
This address, 20p12-ter, refers to either one of the two copies of Chromosome 20 that each person has. Each of the two Chromosome 20s will have at this position an allele, or version, of the PrP gene.
Two alleles for PrP exist in the healthy human population (aka “wild type” alleles). Each version is 209 amino acids long. 3 DNA base pairs (= one “codon”) code for an amino acid, so the gene for PrP must be at least 209*3 = 627 base pairs long, plus start and stop sequences. A handy chart shows how the codons map (with some redundancy) onto amino acids. It turns out that the two healthy PrP alleles only actually differ in one amino acid– the 129th one, to be exact. One allele has methionine (M) at that position, while the other has valine (V) at that position. Though this is just one amino acid, for simplicity, the whole alleles are referred to as the “M” allele and “V” allele respectively. So a person’s genotype could be MM, MV or VV.
Both of the healthy alleles have aspartate (D) at the 178th codon. FFI is caused by a mutation wherein asparagine (N) substitutes for aspartate in position 178, specifically in an “M” allele where M occupies position 129 . Hence, the FFI gene is referred to as “D178N 129M”. To expand this, one might say “[a prion protein gene where the] D [in codon] 178 [is replaced by an] N, [and codon] 129 [is an] M.” All this tells you nothing about what allele the person’s other Chromosome 20 might have– it could be a healthy M or a healthy V allele. If we denote the FFI mutant gene as “M*”, then the possible genotypes are M*M and M*V. Some people refer to the former as being “homozygous” and the latter as “heterozygous”, though neither is homozygous for the mutant gene. So far it appears no human has ever been homozygous for the mutant gene, though homozygous M*M* knock-in mice have been created.
As it turns out, aspartate is GAC or GAT and asparagine is AAT or AAC. So the whole thing is caused by one base pair mutation: A instead of G. (FML).
Incidentally, the “V” allele can also be mutated from a D to an N at codon 178, and this results in a different disease phenotype known as sCJD.
I’m no expert. Corrections most welcome.