Finding function

Kettleborough, R.N.W. et al. Nature 496, 494–497 (2013).

Howe, K. et al. Nature 496, 498–503 (2013).

Although cataloging all genes in model organisms is no longer a bottleneck, assigning function to genes still is. Despite the availability of several good gene-targeting tools, a large number of the 22,000 genes in mouse and of the 26,000 in zebrafish remain uncharacterized. Replacing the current gene-by-gene approach with an effort to phenotype disruptive mutations exome wide, Kettleborough et al. combined chemical mutagenesis with high-throughput sequencing. Aided by the latest well-annotated zebrafish genome (from the work of Howe et al.), the researchers designed exome-wide baits and used them to enrich exomes of the F₁ generation of a chemically mutagenized parent for sequencing. From 808 sequenced exomes, they found mutations in 75% of protein-coding genes. For rapid phenotypic analysis of the mutant alleles, the researchers examined the frequency of homozygous mutations in F₃ embryos of incrossed F₂ individuals.