1.4 Linkage and partial linkage for genetic mapping

Genetic mapping is based on the use of genetic techniques to construct maps showing the positions of genes and other sequences features on a genome. Historically, the first markers used to construct genetic maps were genes coding for mendelian traits (qualitative traits that are highly heritable) with distinguishable phenotypes for each allele (see (Sturtevant 2001) for more details on early gene mapping works). Although genes are useful markers, genetic maps based only on them are not precise in large genomes due to the gaps existing between successive coding region. Furthermore, only a part of the genes exist in allelic forms that can be distinguished conventionally. That is why DNA markers having at least 2 alleles are preferable, i.e. RFLP, SSLP or SNP previously described.

Genetic mapping makes use of the principle of inheritance at first described by Gregor Mendel (Mendel 1865) and the resulting genetic linkage properties to estimate the relative position of each DNA markers on a chromosome. The principle of genetic linkage arises from the fact that, while chromosomes are inherited as intact units, the alleles of some pairs of genes located on the same chromosome should also be inherited together. However, this principle, deriving from the Second Law of Mendel which states that pairs of alleles segregate independently is not what we observe in reality. Indeed, genetically linked genes are sometimes inherited together and sometimes are not, resulting in what we call partial linkage.

This partial linkage property is explained by the behaviour of chromosomes during meiosis, where homologous chromosomes can undergo physical breakage and exchange fragment of DNA in a process called crossing-over (or recombination). These recombination events explain why linked genes and therefore linked DNA markers are sometimes not inherited together. This allows to develop a way to map the relative position of DNA markers since markers which are close together will be separated less frequently than two markers that are far away. Furthermore, the frequency with which markers on a same chromosome are unlinked by crossovers will be directly proportional to the distance between them. The recombination frequency is therefore a measure of the distance between two markers and if we estimate the frequencies for several pairs of markers, we can construct a map of their relative positions.

Comparisons between genetic maps and the actual positions of genes on DNA molecules, as revealed by DNA sequencing, have shown that some regions of chromosomes, called recombination hotspots, are more likely to be involved in crossovers than others. This results in shared chromosomic region among individuals of the same population, although each individual has a unique DNA sequence, and is known as haplotype structure. We will see in Section 1.7 that different populations have their own haplotypic structure.

References

Mendel, Gregor Johann. 1865. “Versuche ãœber Pflanzen-Hybriden” [Experiments Concerning Plant Hybrids].” Proceedings of the Natural History Society of BrÃŒnn IV: 3–47.

Sturtevant, A.H. 2001. A History of Genetics. G - Reference,Information and Interdisciplinary Subjects Series. Cold Spring Harbor Laboratory Press. https://books.google.fr/books?id=wDIisw1ZqAMC.