Homeotic genes in mammalian genomes appear to have been duplicated over evolutionary time. If you line them up using DNA sequence as a guide, you can see that the genes' organization is conserved.

In each case, the corresponding genes between each cluster (for example, A4, B4, C4, D4) are more closely related to each other than to the genes within a cluster (for example, A4, A5, A6). Some clusters have lost genes. Other genes are retained in all four clusters.

Genes that correspond to each other in each duplicated cluster (i.e. A4, B4, C4, D4) are called paralogs. Studies have shown that paralogs have similar, and often overlapping, functions in the animal. For this reason, it is difficult to study the function of a homeotic gene by making a mutation in the gene and studying its effects - in many cases, the effects are hidden by the normal functions of other genes in the same paralogous group.

To remove the function provided by a group of paralogs, a mutation must be made in every gene in the group. If the function is removed in this way, dramatic effects can be observed.

Mice with mutations in paralogous genes

This picture, provided by Mario Capecchi's research group at the University of Utah, shows the effects of mutating two of the three genes in one paralogous group in the mouse HOX cluster. These are the forelimb bones from mice with mutations in two genes from the Hox-11 group.

The capital letters A and D represent the normal HOX A-11 or HOX D-11 genes. The small letters a and d represent mutated genes. For each picture, the genotype of the animal at these two genes is shown. For example, "aa; DD" represents a mouse carrying two mutated copies of the HOX A-11 gene and two normal copies of the HOX D-11 gene.

• (a) is a normal forelimb. The letters h, r, and u indicate the three main bones of the forelimb: r=radius, u=ulna, h=humerus.
• (b) shows the forelimb from a mouse carrying two mutated copies of HOX A-11 and two normal copies of HOX D-11.
• (c) shows the forelimb from a mouse carrying two mutated copies of HOX D-11 and two normal copies of HOX A-11. Note that the structure and arrangement of the bones in (b) and (c) are both approximately normal. Therefore, mutation of a single gene in this paralogous group has only a mild effect on the animal.
• (d) shows the forelimb from a mouse carrying mutations in both copies of both genes. Note that two of the forelimb bones, the radius and ulna, are almost completely missing. The mutations in both genes have produced a striking change in body shape.

In insects, the phenotypes of mutations in homeotic genes are much easier to observe, since only one copy of each homeotic gene exists. If this single gene is mutated, no other normal gene can mask the effects of the mutation.