From Anonymous Qtl To Identified Gene In Animals

Increasingly, the laborious steps of positional cloning have become easier due to the ongoing sequencing of the entire human genome. A rapidly increasing database on all polymorphic DNA is now available as are appropriate data mining algorithms to combine this wealth of genetic data with existing protein and mRNA databases. Homology searches in DNA, mRNA, or protein databases for possible genes in the region identified by linkage analysis can aid in identification of the candidate genes. Although this will speed up gene hunting immensely, the need to first identify the region of interest in a genomic search and to narrow that region by (repeated steps of) fine mapping remains. Only after the region is sufficiently small (e.g., < 100 genes) does the positional candidate gene approach becomes feasible. Repeated fine mapping is expensive and laborious, particularly when the low statistical power of each repeated search step is taken into account. Not surprisingly, most QTL mapping has been conducted in animals. Animal QTL studies have the clear advantage that the environment can be controlled, and that a sufficient number of progeny and types of crosses can be performed. The latter advantage is ofgreat importance if the chromosomal region containing a QTL is still very large. Various strategies are available, including constructing congenic strains. They are produced by repeatedly backcrossing the strain with the mapped QTL (donor) to another strain (recipient) while checking each backcross for the presence of the QTL using flanking DNA markers. After a number of predefined backcrosses, a strain is developed that is genetically almost identical to the recipient strain except for the QTL area. Phenotypic comparisons between congenic and recipient strains might verify the existence of the QTL, its impact, and possible interactions with other QTLs. Once the existence of the QTL has been proven by means of congenic lines, the actual fine mapping can commence. This is done by pheno-typing substrains that are recombinant at various places in the QTL area.

Other strategies to fine map QTLs are the production of recombinant congenic strains, advanced intercross lines, or interval-specific congenic strains.

Also, exclusively in animals, transcript mapping techniques such as reverse transcriptase polymerase chain reaction and exon trapping can be used to locate genes. For a detailed review of these strategies, the reader is referred to the suggested reading.

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