Linkage analysis

Having established that a cancer is familial, the next step is to identify the gene which governs susceptibility. The most practical approach is by 'linkage analysis', in which the segregation of a defined 'genetic marker' in affected and unaffected family members is compared. During meiosis there is considerable crossing over of genes between chromosomes, which are reassorted and recombined. Genes on different chromosomes segregate independently, so that four possible combinations of alleles appear with equal frequency in the gametes (Fig. 9.8). If a disease and marker gene lie close together on the same chromosome, they will segregate together and be 'linked' in the daughter chromosomes (Fig. 9.9). There is a between state when the distance between disease and marker gene allows some degree of separation and independent segregation. Those that break the link and are reassorted independently are known as 'recombinants'; their proportion in the total pool is the 'recombinant fraction' (Fig. 9.10), and the size of this allows assessment of the likelihood of linkage. Having identified the distribution of the marker gene in each family member, the probability that the observed pattern occurs by chance can be calculated. This is represented by a function known as the 'lod' score, 1 of +3 or more demonstrating significant linkage.

There is generally no functional relationship between the disease and marker genes and different alleles of the marker gene may be associated with the disease gene. Even if a strong linkage can be demonstrated between a marker and disease gene in one family, it does not follow that this will cross family boundaries or be suitable for population screening. Only a few functional marker genes have been identified, such as that coding for glutamic-pyruvic-transaminase which is linked with breast cancer (BRCA1).

Linkage studies may concentrate on individual suspect chromosomes or on areas of the genome in which 'candidate'

Parent

Dffi D ri

Dffi D ri

Gametes

Figure 9.8. Independent segregation of genes to form combinations with equal frequency.

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