Mapping Genomes

Core Concepts

Genetic (linkage) maps: distance from recombination

During meiosis, homologous chromosomes pair up and swap segments in a process called crossing over. When two genes lie close together on the same chromosome, a crossover rarely occurs between them, so their alleles are usually inherited as a unit — the genes are linked. When two genes are far apart, crossovers between them are frequent, and their alleles sort nearly independently.

This relationship turns recombination into a measuring tool: the farther apart two loci are, the higher the recombination frequency between them. By convention, 1% recombination = 1 map unit = 1 centimorgan (cM), named in honor of Thomas Hunt Morgan, whose fruit-fly studies established linkage mapping (commonly taught history). The calculation is:

recombination frequency = (number of recombinant offspring ÷ total offspring) × 100%

Recombination frequencies are then used to order genes and estimate the distances between them, just as surveyors triangulate positions from measured angles.

Two caveats matter for exams. First, map units are relative distances based on crossover probability — they are not physical distances, and the number of base pairs per map unit varies across a genome (in humans, a commonly cited rough average is about 1 million bp per cM, but the true value varies by chromosome region). Second, crossing over is suppressed near centromeres (commonly taught), so maps built from recombination are compressed in those regions.

Physical maps: distance in base pairs

Genetic maps give order and approximate spacing, but not true distances. Physical maps measure the DNA itself:

• Restriction maps use restriction enzymes — bacterial proteins that cut DNA at specific recognition sequences — to produce a set of fragments whose sizes reveal the spacing of cut sites.
• Sequence-tagged site (STS) mapping uses short, unique DNA sequences that occur exactly once in the genome as landmarks; their positions can be detected by PCR.
• Clone-based maps assemble overlapping cloned fragments — commonly large inserts carried in bacterial artificial chromosomes (BACs) — into long continuous stretches called contigs that tile across a chromosome.

Only a physical map can ultimately be converted into the letter-by-letter sequence of A, T, G, and C.

From maps to genomes: the combined approach

The Human Genome Project used maps at every stage (commonly taught strategy): build a low-resolution genetic map, refine it into a physical map of ordered clones, then sequence each clone and use the clone order to assemble the whole chromosome. This hierarchical approach made assembly tractable because every sequenced piece already had a known home. (The alternative — whole-genome shotgun sequencing without a prior map — is covered in the next topic.)

Positional cloning: finding genes by location

Once a region is mapped, a disease gene can be found without knowing what it does. In positional cloning, researchers track the inheritance of mapped markers through affected families. A marker that always travels with the disease must sit near the responsible gene. Each round of testing narrows the interval, until the region is small enough to examine gene by gene and identify the culprit — the strategy behind the discovery of many single-gene disease genes (commonly taught examples include cystic fibrosis and Huntington's disease).

Common Confusions