The homeodomain is a sixty amino acid long motif that is found in organisms from yeast to humans. It is comprised of three alpha helices, the first two stacked antiparallel to each other and the third running perpendicular across the other two. The third helix, is called the "recognition helix", which specifically interacts with the major groove of the target DNA. Homeodomains are part of large proteins, the homeotic proteins, which are transcription factors during development. The homeodomain itself has the DNA binding activity and determines specifically where on DNA this protein can bind.

Homeotic proteins, are encoded by the homeobox genes. Homeotic proteins are morphogens which determine the spatial arrangement of the body during development. They are often involved in body patterning and segment identification. For example, in Drosophila (fruit flies), mutations in the Ultrabithorax homeobox gene cluster cause large scale mutations such as extra sets of wings. Mutating the Antennapedia gene can result in legs growing out of a fly's head where the antennae should be.

The arrangement of the homeobox genes on the chromosome mirrors their spatial expression in the embryo, leading researchers to hypothesize that the current complement of homeotic proteins evolved by gene duplication from a common ancestor.

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