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Homeotic genes

Homeotic genes control development of whole body segments or structures. When they are overactive or missing, weird things can happen!

Key points

  • Homeotic genes are master regulator genes that direct the development of particular body segments or structures.
  • When homeotic genes are overactivated or inactivated by mutations, body structures may develop in the wrong place—sometimes dramatically so!
  • Most animal homeotic genes encode transcription factor proteins that contain a region called the homeodomain and are called Hox genes.
  • Hox genes are turned on by a cascade of regulatory genes; the proteins encoded by early genes regulate the expression of later genes.
  • Hox genes are found in many animals, including fruit flies, mice, and humans. Mutations in human Hox genes can cause genetic disorders.


How many legs does a fruit fly have? Even if you're not particularly into fruit flies, you may know that insects tend to have six legs total—as compared to, say, the eight legs of spiders. Also, you may have noticed that a fly's legs usually grow out of the middle part of its body—its thorax—and not, say, out of its head.
Image credit: modified from Drosophila melanogaster, by Madboy74 (CC0/public domain)
What's responsible for this orderly organization of body parts in something as tiny as a fly? As it turns out, a set of master regulator genes are expressed in different regions of a fly's body during development. These genes turn on the right genetic "program" for development of each section of the body. They make sure, for example, that the fly's thorax carries legs while its head does not.
In this article, we'll take a closer look at these and other homeotic genes, also called selector genes. By definition, these are genes that "select" the identity of entire segments or structures in the bodies of developing organisms.

Homeotic mutations in fruit flies

Homeotic genes are responsible for determining the identity of particular segments or structures of the body. So, when homeotic genes are inactivated or expressed in unusual locations due to mutations, they may cause body segments to take on new—and sometimes startling!—identities.
As an example, let’s look at a homeotic gene called Antennapedia. Normally, Antennapedia is expressed in what will become the second segment of a fly's thorax, starting when the fly is a tiny embryo and persisting into the adult fly. There, the gene acts as a master regulator, turning on the genetic program that makes the fly's second pair of legs and other segment-specific structures.
Image credit: modified from Hox genes of fruit fly, by PhiLiP, public domain
If Antennapedia stays where it's supposed to and does its job, we get a nice, normal-looking fly with all its appendages in the right place. But what happens if a genetic mutation causes expression of the Antennapedia gene to expand into the fly's head? This type of mutation causes legs to grow from the fly's head in place of antennae! In other words, the gene activates its normal, second-segment leg development program, but in the wrong part of the fly.1
Image credit: modified from Antennapedia mutation by toony, CC BY-SA 3.0. The modified image is licensed under a CC BY-SA 3.0 license
Another fly homeotic gene with dramatic effects is the Ultrabithorax gene. This gene is expressed strongly in the third segment of the thorax, which bears the fly's rearmost pair of legs. Ultrabithorax expression in this region of the fly starts early in development and continues throughout the fly's life.
Image credit: modified from Hox genes of fruit fly, by PhiLiP, public domain
Wings usually form only in the second segment of the thorax, not in the third, which instead makes small structures called halteres that help the fly balance. The job of Ultrabithorax is to repress second-segment identity and formation of wings in the third segment. When Ultrabithorax is inactivated in the developing third segment due to mutations, the halteres will be converted to a second set of wings, neatly positioned behind the normal set.1
Image credit: modified from Drosophila melanogaster, by Madboy74 (CC0/public domain); based on similar image by P. A. Otto2

Overview of fruit fly Hox genes

Antennapedia and Ultrabithorax are not the only homeotic genes in a fruit fly. In fact, a whole set of different homeotic genes act in different regions of the fly's body, ensuring that each segment takes on its correct identity. These genes are typically expressed in the regions they regulate, starting early in embryonic development, and they continue to be expressed in the adult fly.
The diagram below shows eight major homeotic genes in flies. The upper part of the diagram shows where each gene is most strongly expressed in the mature fly, while the lower part of the diagram shows where the genes are located on the chromosome. The order of the genes on the chromosome more or less mirrors their order of expression along the head-tail axis of the fly.
The break mark (//) in the chromosome indicates that these two clusters of genes are separated by a long intervening region that's not shown. Image credit: modified from Hox genes of fruit fly, by PhiLiP, public domain
What exactly are these homeotic genes? Each gene encodes a transcription factor that is expressed in a specific region of the fly starting early in its development as an embryo. The transcription factors change the expression of target genes to enact the genetic “program” that's right for each segment.
The homeotic transcription factors shown in the diagram above all contain a DNA-binding protein region called the homeodomain, which is encoded by a segment of DNA called the homeobox. Because they contain a homeobox, homeotic genes of this class are sometimes called Hox genes for short.

How are fly Hox genes turned on?

Hox genes need to be carefully regulated. As you learned above, a little sloppy regulation can result in things like extra wings or legs instead of antennae—both of which would be pretty bad for the survival of a fruit fly in the wild! So, how are these genes expressed in the right parts of the developing embryo?
To answer this question, let's take a quick look at the early steps of fly embryo development. Genetic patterns laid out in the fly egg—before the embryo is even an embryo—lay the groundwork for the fly’s body plan. During development, the fly’s body is first roughed out very generally, starting with head end over here, tail end over there. Then, the structure is gradually refined, first into broad sections, then smaller sections, then finally into actual body segments.
This process involves different classes of genes with increasingly narrow and specific patterns of expression. Broadly speaking, earlier-acting groups regulate later-acting groups in a sort of molecular domino effect. Hox genes are turned on in specific places through the activity of genes in this cascade.
Genes in the early developmental cascade include the following groups:1,2
  • Maternal effects genes, which are genes whose mRNAs are placed in the egg cell by the mother fly before fertilization. Some of the mRNAs are “tied” to the head or tail end of the embryo and are responsible for setting up the head-tail polarity. The maternal effects genes encode regulators of transcription or translation that control each other as well as other genes.1
    Image credit: modified from Figure 6. Module Predictions within the Segmentation Gene Network by Mark D. Schroeder et al.3, CC BY 4.0
  • Gap genes are named appropriately. If gap genes are missing due to a mutation, there is a big gap in the fly larva—it is missing a large chunk of its normal segments.1,4 Gap genes are activated through interactions between the protein products of the maternal effects genes, and they also regulate each other. They're responsible for defining large, multi-segment regions of the fly, the ones that are missing when the gene is mutated.
    Image credit: modified from Figure 6. Module Predictions within the Segmentation Gene Network by Mark D. Schroeder et al.3, CC BY 4.0
  • Pair-rule genes are turned on by interactions between gap genes, and their expression patterns are refined by interactions with one another. They appear in multiple “stripes” along the embryo, similar in pattern to the segments of the mature fly but slightly offset.5 When a pair-rule gene is missing due to mutation, there is a loss of structures in the segment regions where the gene is normally expressed.
    Image credit: modified from Figure 6. Module Predictions within the Segmentation Gene Network by Mark D. Schroeder et al.3, CC BY 4.0
So, where do the Hox genes come in? Hox genes are turned on in specific patterns by the protein products of the gap genes and pair-rule genes. Their expression patterns are refined—by the products of these genes and through interactions with other Hox proteins—as the embryo develops.
Image credit: modified from Figure 6. Module Predictions within the Segmentation Gene Network by Mark D. Schroeder et al.3, CC BY 4.0

Many animal species have Hox genes.

Hox genes are not unique to fruit flies. In fact, Hox genes are found in many different animal species, including mice and humans. Yes, you have your very own Hox genes! The presence of similar Hox genes in different species reflects their common ancestry: a Hox gene cluster was likely already present in a common ancestor of mice, flies, humans, and other animal groups.
Not only are Hox genes found in many different animal species, but they also tend to have the same order on the chromosome in all of these species. As in flies, this order roughly maps to the parts of the body whose development is controlled by each gene. Because this is so consistently the case, scientists think it is likely not a coincidence and may have functional importance.5
In vertebrates like humans and mice, Hox genes have been duplicated over evolutionary history and now exist as four similar gene clusters labeled A through D:
Image credit: modified from Features of the animal kingdom: Figure 4 by OpenStax College, Biology, CC BY 4.0, with edits based on Lappin et al.6
In general, the genes of the different clusters work together to establish the identity of body segments along the head-tail axis. That is, the genes towards the beginning of the cluster—closer to one in the diagram—tend to specify structures at the head end of the organism, and the genes toward the end of the cluster—closer to 13 in the diagram—tend to specify structures near the tail end.
However, gene duplication has allowed some Hox genes to take on more specialized roles. For instance, many Hox genes towards the end of the cluster act specifically in the development of vertebrate limbs—arms, legs, or wings—as shown in the diagram of the woman above. Mutations in HoxD13 in humans can cause a genetic condition called synpolydactyly, in which people are born with extra fingers or toes that may also be fused together.7
Image credit: modified from Synpolydactyly by S. Malik, CC BY 2.0; originally from publication by Malik et al.3
The Hox cluster is a great example of how developmental genes can be both preserved and modified through evolution, particularly when they are copied by a duplication. Hox genes also show just how powerful a developmental gene can be, especially when it is a transcription factor that that turns many target genes on or off to activate a particular genetic "program."

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