MoBio Genome Mapping Chapter 10

Genome mapping is the process of finding the location of genes on each chromosome. It is a critical step in identifying the genes involved in a genetic disease. Once a disease gene is accurately located, we can determine its DNA sequence and study its protein product. For example, cystic fibrosis (CF) is the most common lethal inherited disease in the United States. As many as 1 in 2500 Americans of Northern European descent carry a gene with CF. In 1985, the gene was mapped to chromosome 7q31-q32 by linkage analysis. Four years later, its DNA sequence was determined by Francis Collins and colleagues. We now know that the disease is caused by the defect of a chloride channel encoded by the CFTR gene.

There are two types of genome mapping:

Genetic Mapping uses linkage analysis to determine the relative position between two genes on a chromosome.

Physical Mapping uses all available techniques or information to determine the absolute position of a gene on a chromosome.

Linkage Analysis

The genetic mapping is based on the linkage between "loci" (locations of genes). If two loci are usually inherited together, they are said to be "linked". The linkage of two loci depends on their recombination frequency during meiosis, as explained below.

A locus (singular of loci) may have different sequences, referred to as alleles. Consider two loci A and B, each having two alleles (one from mother, another from father). A1 and A2 are the two alleles of locus A ; B1 and B2 are the two alleles of locus B. Initially, A1 and B1 are located on the same chromosome. A2 and B2 are located on a different chromosome.

Image

Figure 10-A-1. Illustration of recombination between two loci A and B. (a) Two pairs of sister chromatids align during meiosis. A1 and B1 are located on the same chromosome. A2 and B2 are located on a different chromosome. (b) DNA crossover leads to recombination if the chiasma is located between the two loci. (c) DNA crossover does not lead to recombination if the chiasma is not located between the two loci.

The DNA crossover may cause recombination of loci A and B. Namely, A1 and B2 (or A2 and B1) are located on the same chromosome. The recombination frequency depends on the distance between the two loci and the position of crossover (the chiasma). The closer they are, the less likely the recombination will occur, because recombination occurs only when the chiasma is located between the two loci.

Although linkage analysis has been quite successful in identifying single-gene diseases, it has not fared as well for diseases resulting from mutations in multiple genes throughout the genome. To study such diseases, a more powerful method has been developed, which is discussed in the next section.