Linkage


Linkage is the phenomenon where alleles at different loci are inherited together due to their physical attachment on a chromosome. The phenomenon of genetic linkage is a key exception to Mendel's second law of inheritance, which states that 'members of different gene pairs' (i.e. alleles) are transmitted independently of one other. Linkage is often the cause of aberrant segregation ratios that significantly diverge from the expected Mendelian ratio since the Mendelian ratio is based on a prediction that each allele is independently inherited. On a chromosome where two loci, A and B are linked:

A----------B
a----------b

A and B, and a and b, are in coupling;
A and b, and a and B, are in repulsion.

A block of alleles that are inherited together (which could range from a single allele to an entire chromosome) is called a haplotype. For the purposes of inheritance, it is often useful to treat a haplotype as if it is a single genetic locus.

Haplotypes can be crucial in homing in on the location of alleles that cause disease phenotypes. Single nucleotide polymorphisms (SNPs) can be identified by microarrays. Oligonucleotides (approx. 20-25 bases in length) called features are attached to a glass plate called a chip. Each oligonucleotide feature is able to hybridise to a specific SNP. If DNA from a subject is isolated, fluorescently labelled and washed over the chip, then SNPs in that subject's DNA can be identified by which feature(s) the DNA was hybridised to. This can be used in association studies to link a specific haplotype to a disease state (and thus help us to locate the disease allele).

Recombination can occur between loci causing them to be reshuffled, and thus breaking the linkage between certain alleles. However, recombination events are rare and thus the closer together two loci are, the less likely they are to be separated by recombination (i.e. they have a high degree of linkage). The further apart two loci are, the higher the expected recombination frequency. Map distance on chromosomes is sometimes measured in centimorgans (cM) - 1cM represents a distance over which there is an expected 1% recombination frequency.