Mapping

Genetic maps are created by measuring the amount of recombination that occurs between two or more loci. The easiest way to do this is to use families with a large number of children, since this provides a large number of recombination events to look at. Scientists have collected a panel of forty such families, called the CEPH families (pronounced "sef," from the French Centre d'Étude du Polymorphisme Humain—the Center for the Study of Human Polymorphisms). These families are measured (genotyped) for the variations at each locus, and the inheritance of each allele at each locus is compared.

An example of a CEPH family is shown in Figure 1. Using the father as an example (although in other families this could easily occur in the mother), allele a at locus 1 and allele b at locus 2 are always inherited together. Similarly, allele A at locus 1 and allele B at locus 2 are inherited together. There has been no recombination between locus 1 and locus 2, and therefore these loci are likely to be close together. In contrast, allele a at locus 1 and allele c at locus 3 are only inherited together half the time. There have been several recombination events between them, and therefore these loci are likely to be far apart.

The actual distance between two loci is measured using the recombination fraction, which is just the number of recombination events divided by the total number of events that are looked at. In the family diagrammed in the figure, the recombination fraction between locus 1 and locus 2 is 0 recombination events divided by 8 total events, or 0 ÷ 8 = 0. The recombination fraction between locus 1 and locus 3 is 4 recombination events divided by 8 total events, or 4 ÷ 8 = 0.50. Recombination fractions can vary between 0.00 and 0.50. To generate a complete genetic map of a chromosome, a large number of markers (between 50 and 200, depending on the size of the chromosome) are genotyped in many families, and more complex statistical analyses are used to compare the inheritance across all markers.

There is an additional complication in the analysis of recombination events. The further apart two loci are, the more likely it is that two recombination events could occur between them. The first event will shuffle the alleles, but the second event will reshuffle the alleles back to the way they were. Thus it will look like there were no recombination events when in fact there were two.

Another complication arises from the fact that the occurrence of one recombination event on a chromosome tends to inhibit the occurrence of a second recombination event, especially in regions close to the first one. This is called "interference" and will generally make the map smaller. To account for this, "map functions" have been created that are used to better estimate the true recombination distance between two markers.

Map functions are mathematical equations that are based on assumptions about how much recombination and how much interference exists on a chromosome. Map function distances are measured in units called centimorgans, named for Thomas Hunt Morgan, the first person to develop the techniques of genetic mapping. There are several map functions that have been proposed. Each is named for its originator. The most commonly used Figure 1. A typical CEPH family with genotypes from three genetic markers. Loci one and two are completely linked to each other, while loci one and three are not linked to each other. map function is the Haldane map function (named after John Burdon Sanderson Haldane), which assumes that there is no interference between loci. A second map function, the Kosambi map function (named after Damodar Kosambi), assumes a moderate level of interference and seems to more accurately reflect experimental data. Thus the recombination fraction is modified by the map function. Generally the recombination fraction and the centimorgans are very similar for distances from 0.00 to 0.10.