Part 2: Linkage Analysis

That's right. Now here is the table of values that you generated.

This table provides information about the pedigree, but we must also supply the computer with genetic marker information in order to find a region where the defective gene may be located. 

What is a genetic marker? There are several types of genetic markers, and
they all have two characteristics in common. First, they are polymorphic.
This means that different normal individuals can have different versions of
the sequence in that spot. In fact, one individual can have a different
version of the sequence on each of the two chromosomes in that respective
pair. This enables one to tell which of the two chromosomes from that pair
the parent has passed to the child. The second characteristic all markers
have is that we know where that stretch of sequence lies on its chromosome. This enables us to line the markers up in their spatial order on the chromosome, and see where recombinations have occurred during meiosis. A recombination will be indicated when a child inherits a chromosome that contains markers from both of the respective chromosomes possessed by the parent. For example, a boy may have a chromosome 1 in which the markers from the p telomere to p31 have come from one of his mother's chromosome 1's, but the markers from p31 to the q telomere have come from his mother's other chromosome 1. In this case, a recombination has occurred in p31.

One type of marker is a microsatellite marker, in which 2, 3 or 4
nucleotides are repeated in a string (example, CACACACACA, CAGCAGCAGCAG or GATAGATAGATAGATA). There are a great many microsatellite markers in the human genome, scattered across all the chromosomes. Different normal individuals can have a different number of CAs, CAGs or GATAs in one of the strings, or one person can have a different number of CAs, CAGs or GATAs on each of the two chromosomes in that particular pair. Another type of marker is the single nucleotide polymorphism, or SNP. SNPs involve just a single nucleotide, and different normal individuals can have a different nucleotide in that particular position. For example, in the HOXA1 gene, there is a string of histidines in most people, encoded by a stretch of CAT's, but some people have a G substituted for one of the A's in the string, creating a CGT codon that codes for arginine in place of one of the CATs that codes for histidine. Arginine and histidine are similar enough that the HOXA1 protein functions just fine with an arginine in place of the histidine. Therefore, while the A allele is the most common allele, the G variant has persisted in the human genome, because there has been no evolutionary pressure to weed it out.

To map a disease gene, one tracks the inheritance of the disease as well as the inheritance of specific alleles of these markers. Recombination will occur between the disease and markers that are not close to the disease gene. The closer the marker is to your disease gene, the less the chance that recombination will occur between the marker and the disease. For example, imagine a mother who has 2 different length CA strings in one place (call them the 1 and 2 alleles), and has the disease in question. Imagine she has two sons, both of whom have inherited the disease, but one has inherited the 1 allele and the other has inherited the 2 allele of that marker. This means that there has been recombination between the disease gene and the marker, so this marker is not very close to the disease gene. Imagine another marker, for which Mom is also heterozygous, for which every person in the family who inherits the disease inherits the 1 allele, whereas every individual in the family who does not have the disease inherits the 2 allele. This lack of recombination between the disease and the marker suggests that this marker is very close to the disease gene.

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