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Linkage analysis

Linkage is the tendency of genes, which are closely located on the same chromosome, to segregate together.

The physical distance two genes on the chromosome is proportional to how frequently they cross over together during homologous recombination.

Therefore, frequency of recombination is a tool for mapping chromosomes.

Linkage analysis follows DNA regions, allowing not only mapping of a chromosome but also identification of disease genes.

Association analysis is a similar approach for identifying disease genes, but instead just analyzes which alleles are present in diseased individuals throughout a population.

Key concepts

  1. A pair of homologous chromosomes can exchange segments by crossing over.
  2. Recombination produces genotypes with new combinations of parental alleles.
  3. Two genes close together on the same chromosome do not cross over (assort) independently during meiosis.
  4. Loci on a chromosome can be mapped by analyzing recombinants.
  5. Map distances between loci based on recombination measurements are additive.

Loci cross over together in proportion to how near each other they are. Adjacent loci almost always cross over together; far-apart loci rarely cross over together. The proportion of recombinants to nonrecombinants is the recombination frequency, measured in Morgans and labeled θ (theta). The smaller θ gets, the closer the two loci. Recombination frequency can be used to draft a chromosome map.

A low recombination frequency (θ≈0) means two loci are tightly linked (close together and almost always assort together), while a high recombination frequency (θ≈0.5) means two loci are unlinked and could even be on different chromosomes. θ can be used to calculate the LOD score (determining whether two loci are linked) and the map distance (how far apart are two loci).

To determine recombination frequency, recombination events must be deduced. This requires that: at least one parent be heterozygous (informative); and the phase of the alleles must be known. The phase of an allele is simply whether it is on the maternal or paternal homologue. Two alleles on the same homologue are in coupling (they are cis) and two alleles on opposite homologues are in repulsion (they are trans). In a DdMm individual, D could have the same phase as either M or m; more information is needed to deduce which homologue bears which allele.

Linkage equilibrium

Imagine that genes HAIR and BRAIN are two genes present on Chromosome 13, and that HAIR and BRAIN each have two alleles. Alleles HAIRbrown and HAIRblonde are equally prevalent throughout the population; thus, any Chromosome 13 is equally likely to bear HAIRbrown or HAIRblonde. However, alleles BRAINsmart and BRAINdumb are not equally prevalent throughout the population. In fact, BRAINdumb is four times as prevalent as BRAINsmart; thus, any given Chromosome 13 has a 20% chance of bearing BRAINsmart and a 80% chance of bearing BRAINdumb.

When two alleles are in linkage equilibrium, then 20% of Chromosome 13's bearing HAIRblonde or HAIRbrown would also bear HAIRsmart and 80% of Chromosome 13's bearing HAIRblonde or HAIRbrown would also bear HAIRdumb. When an allele is in linkage disequilibrium, then it is more likely to associate with a certain allele of a different gene. For example, although BRAINsmart and BRAINdumb are present on 20% and 80% of Chromosome 13's, a Chromosome 13 with HAIRblonde might also bear only BRAINdumb alleles while HAIRbrown bears the remaining 30% BRAINdumb and all the 20% BRAINsmart alleles. In this case, HAIRblonde and BRAINdumb are in strong linkage disequilibrium.

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