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The long-lasting success of forward genetic screens relies on the simple molecular basis of the characterized phenotypes, which are typically caused by mutations in single genes. Mapping the location of causal mutations using genetic crosses has traditionally been a complex, multistep procedure, but next-generation sequencing now allows the rapid identification of causal mutations at single-nucleotide resolution even in complex genetic backgrounds. Recent advances of this mapping-by-sequencing approach include methods that are independent of reference genome sequences, genetic crosses and any kind of linkage information, which make forward genetics amenable for species that have not been considered for forward genetic screens so far.