The difference between homeobox and Hox genes

This is a big pet peeve. Let’s get straight to business: the terms “homeobox” and “Hox” are not interchangeable. They do mean different things. I’m correct in saying that Amphioxus (Branchiostoma lanceolatum) has 15 Hox genes. I’m also correct in pointing out that it has over 130 homeobox genes.

Gene names can be very confusing and difficult to remember, so there are many abbreviations in biology. For example, the gene insulin-like growth factor 1 is abbreviated to Igf1. Does that make it easier to remember? Who knows. But I believe the use of abbreviations is partly responsible for the incredible confusion over homeobox and Hox genes. And I do mean incredible. It’s very obviously a confusing topic for students, or anyone new to evo-devo, developmental genetics, or gene regulation… but it’s so much worse than that. Professional publications make the mistake, academics make the mistake, and they do it often. I think the reason it keeps happening is that the word “Hox” appears to be a shortened “Homeobox”. All over the internet you will see the terms used interchangeably, and sometimes with the apparently shortened version in brackets. “Homeobox (Hox)”. This otherwise decent glossary for Epigenesys manages to dump the terms homeotic, homeobox, and Hox into one single paragraph and glossary entry, which is of little help to a confused student seeking clarity. So let’s clear this up, and I’ll keep it quick. 

First, let’s go over the facts, and the answer, before we discuss why these confusing names have been chosen. Scientists discovered that there are some genes that contain a very conserved region of DNA we now call the homeobox. When I say very conserved, I mean it. You have homeobox genes, the birds outside do, the grass outside does… even yeast does. The origin of homeobox genes is ancient, definitely pre-dating the origin of animals. This 180-base-pair homeobox codes for a 60-residue chain known as the homeobox domain (or homeodomain). So the region of the gene is known as a homeobox, the region of the protein is the homeodomain. The explanation for why it is so conserved across organisms, through hundreds of millions of years of evolution, is that its function restricts its evolution. The homeobox domain binds DNA (or RNA), allowing a protein with a homeodomain to act in gene regulation. For example, these proteins can be used to turn genes on and off. It’s an invention of evolution that’s persisted through the origin of the fungi, plants, and us animals, and the homeobox itself hasn’t changed much at all. So there’s your definition of a homeobox gene. It isn’t a specific gene, it’s a huge and ancient group of genes that all contain the homeobox, a region of DNA that codes for a domain which can bind to DNA.

Every Hox gene is a homeobox gene, but not every homeobox gene is a Hox gene. The homeobox genes have diversified so much through evolutionary history that there are now distinct classes of them. The most famous is definitely the family of Hox genes. This is also where the terms come from. When scientists first discovered the homeobox domain, they found it because they were studying animals that had mutated Hox genes. These mutants often had body parts in the wrong place, and were described as “homeotic mutants”. When they identified the genes causing the mutations, they discovered that they all shared a common motif, so they named it the homeobox. This is one of the most incredible discoveries in biology, as they quickly realised that the homeobox is found in genes from humans, flies, jellyfish, daffodils, yeast, and so on. But the actual genes they had discovered were a distinct group of homeobox genes, which we now call the Hox genes. They definitely are homeobox genes, and they regulate other genes.

Think about the confusion here. Hox genes are a distinct family of homeobox genes. Scientists discovered the homeobox motif by investigating which genes caused homeotic mutations. What they had found were the Hox genes, so calling Hox genes homeotic is fine. But they didn’t understand at the time that the homeobox motif is found in many genes that aren’t Hox genes. Many homeobox genes have absolutely nothing to do with body parts growing in the right or wrong places. But when they named the homeobox, they only knew of the Hox genes they were discovering via the homeotic mutants. This is where almost all the confusion stems from. Despite being called homeobox genes, most don’t cause homeotic mutants if modified. The Hox genes, a specific family of homeobox genes, are great examples of genes that can cause homeotic mutants.

In us bilaterian animals, one of the main roles of the Hox genes is to specify anteroposterior identity to your body. It’s a complicated system, but we’ll keep it simple. The Hox genes play a role in determining which body parts grow where on the body. So by messing with them you can make limbs grow in the wrong places. But there are plenty of other non-Hox homeobox genes. There are entirely different families with entirely different roles. The Hox genes control the body plan along the anterior to posterior axis in us bilaterian animals, but there’s still some uncertainty over their precise role in non-bilaterian animals. The Hox genes do appear to be unique to animals. You don’t find Hox genes in plants and fungi. They have homeobox genes, but not the Hox genes, which appear to have arisen very early in animal evolution (there is evidence that sponges had Hox genes too, but have since lost them).

We know so much about homeobox genes, especially the Hox cluster, that we could discuss it all day. The evolution of the Hox, ParaHox, and NK clusters is quite fascinating, as are the roles of these gene families in a developing animal. I’ll save these for future entries. Today’s point is mostly just an early-morning rant. Hox genes are homeobox genes as they contain the homeobox, but homeobox genes include Hox genes, ParaHox genes etc. The terms are not interchangeable. It’s such an easy mistake to make that it appears in books, academic websites, and helpful videos on YouTube. Just keep it in mind and focus on what exactly is being discussed. It’s not necessarily wrong to describe a mobile phone as technology, but the terms aren’t interchangeable. You can’t go around describing technology as mobile phones. It makes no sense to say, “the electron microscope is a wonderful mobile phone”. Homeobox and Hox genes work the same way. You can describe a Hox gene as a homeobox gene because that’s exactly what it is. But note that the terms aren’t interchangeable.

33 thoughts on “The difference between homeobox and Hox genes”

  1. Chris G says:

    Thank you Mr Harrison. I have been looking all over the place for clarification!

    1. Not a problem, I’m glad the rant was helpful!

  2. Abeer says:

    wow u explained and clarfied this all way too beautifully.many thanks

  3. Harriet says:

    Thanks so much for this. It’s really informative and helped clear up a lot of my confusion. But I need to ask you a question. Based on your comment ‘the Hox genes appear to be unique to animals. You do not find Hox genes in plants and fungi’, I am now a little confused. I have just been set a biology essay with the title ‘Explain that the genes that control development of body plans are similar in plants, animals and fungi, with reference to homeobox sequences’. By homeobox sequences, I assume the title means HOX genes as not all homeoboxes are responsible for body plans. But if plants and fungi do not have HOX genes, how do they arrange their body plans? And how do I write the essay, bearing in mind that they must use completely different mechanisms if they don’t have HOX genes?

    1. Hi Harriet! I hope your essay goes well!

      Basically, all of these homeobox genes are related. They all came from one original gene, and that gene is ancient. So old that it predates the invention of animals, plants, fungi etc. The common ancestor of all these groups used homeobox genes (genes which code for the DNA-binding “homeodomain”) so we still find homeobox genes in all the descendents including human beings, roses, mushrooms etc. So homeobox genes are everywhere. But in those lineages over millions of years, they’ve been copied and duplicated and modified resulting in new homeobox genes. So although plants and fungi also have homeobox genes (genes with the homeobox motif), they have plant-specific ones. The rest of the gene (the bit that doesn’t code the 160 base pair homeobox part) could be very different compared to homeobox genes from animals. It’s the homeobox itself that’s conserved and similar.

      Among us animals, we’ve evolved entire groups of different homeobox genes. One group exists as a cluster in most animals: the HOX genes (or the HOX cluster). They ARE homeobox genes, and they are related to the genes in plants, but they are specific to animals. Some of the plant homeobox genes are only found in plants. The person who designed your essay title knows this. They know that we find many HOX genes in different animals, but not outside of Animalia. Same goes for The ParaHox genes and other groups that are animal specific. You’ve become confused because you’re expected to write about how homeobox genes are used in body plans in plants as well as animals. The point that they’re trying to get you to discover through research is that although we have different homeobox genes… the homeobox part is always extremely similar or identical. Remember that structure = function in proteins. You to think a little less about genes being the same or different, and think about the homeobox itself. It’s the common thing here, so if you can figure out what it actually does, physically, and understand its role in regulating how the body plan develops, you should be able to draw some conclusions about the similarities and perhaps even differences between plants and animals.

      You need to think about how animals and plants use homeobox genes (genes with the homeobox motif) in development. The HOX genes are just a class (and an important one!) of animal homeobox genes. There must be homeobox genes that have maybe similar roles in plants… But to summarise: there are thousands of homeobox genes. One cluster of genes that evolved within the animal kindgdom (after the split with the lineages that led to plants etc) we call the Hox genes. They’re just homeobox genes, but new enough that they’re only in animals. Plants have unique homeobox genes too. But for all their uniqueness, the homeobox part is the common feature, and the important thing for you.

      Note I haven’t told you anything about what the homeobox actually does or the ways it’s used in animals and plants. I’ve just tried to clear up the confusion. Your lecturers will have your essay analysed electronically using a system that looks for similar sentences etc online. Hopefully I’ve set you in the right direction but remember not to copy/paste from here! Remember biology isn’t black or white. If you can find common things between plants and animals to talk about, then great, but if there are differences then it’s worth pointing out too. Good luck!

  4. Dr. Doris says:

    Thank you so much. Really helped me. I’m a doctor and an anatomist reading developmental genetics and got really confused. Thanks for the clear guidance.

    1. Dr. Doris says:

      Btw I read that NKX 2.5 contains a homeodomain. So it means that its not a hox gene, but is a homeobox gene and it is conserved in all I lower organisms right.

      1. You’re right that the NK genes are a different family of homeobox-containing genes. But although they aren’t Hox genes, they’re closely related and relatively recent (in the grand scheme of things). So the NK genes aren’t found in all organisms. Like the Hox genes, the NK genes are only found in animals. Very ancient though, there’s evidence that sponges possessed them.

        Many homebox genes are much older and found in fungi, plants, or even bacteria. NK genes evolved within the animals. I’m sure you’ve realised already that NKX 2.5 is often associated with heart development. The NK genes have the worst nomenclature of all homeobox genes in my opinion. It’s also known as tinman (get it?) or usually Csx in mammals. Be careful with the names!

  5. Peterson Lopes says:

    This was very useful. Now, finally, things made sense!

  6. Dr. Roze says:

    Now we need to learn how different families of homeobox-containing genes are defined, what are the differences between them. Hox gene family vs NK gene family, for example. This should clarify all confusions.

    1. Thanks for the comment, when I get some time in the summer I’ll try to write up a summary!

  7. Yann says:

    Just to add a little cent of confusion…

    You wrote “The Hox genes, a specific family of homeobox genes, are responsible for the homeotic mutants”.
    But are all homeotic mutants linked to Hox genes (at least in animals) ?
    Would you call all genes controlling anteroposterior identity a homeotic gene ? What about segmentation genes (eg : bicoïd is actually a homeobox gene :o(, hunchback is a Zn-finger protein, Nanos a RNA-binding protein…), pair rule genes (at least some of them are homeobox genes too…) or gap genes ?

    Btw, plants use MADS-box genes to specify the identity of flower parts (the A of MADS comes from one of these genes : Agamous). Theses are example of homeotic-but-not-hox genes

  8. Brunno says:

    Hello there!

    Thank you so much for the text. I finally understood it correctly now!
    I was wondering if you could tell me some articles, reviews or anything that i can found this information? i really need for a essay and unfortunately they won’t accept personal blogs =(

  9. John Licwinko says:

    Wow. I am reading Endless Forms Most Beautiful and realized that I did not clearly understand the terms homeobox gene, homeobox, hox gene and homeotic gene, etc. As I researched the internet, I felt that the definitions were not consistent, and I was trying to sort all this out when I came across your blog. Exactly the information that I was looking for. I can’t thank you enough.

  10. Kevin Navarrete says:

    Hi Mr. Harrison.

    Excellent article, I have to confess that I have finally understood the function of hox genes. But according to this phrase “Every Hox gene is a homeobox gene, but not every homeobox gene is a Hox gene.” I’ve got a doubt,,, Could you give me an example of homeobox which is not a hox gene?. “The thoughts of a carbon-based biped from Scotland.” I loved that phrase. Thanks buddy!!.

    1. Thanks for the feedback. As I mentioned in the article, Amphioxus has over 130 homeobox genes, 15 of them being Hox genes. Some of the homeobox genes are from the ParaHox cluster (a sister cluster of the Hox gene cluster). There’s also the NK cluster of genes. For example, Nkx-2.5 is a homeobox gene. In the mouse we call it csx but it’s more commonly known by many biologists as tinman because of its role in heart development. There are just a handful of Hox genes, but there are plenty of homeobox genes and for good reason. Since they bind to DNA and can used in gene regulation, they’re extremely important in the development of multicellular organisms and even single-celled organisms too. Bacteria use homeobox genes to regulate gene expression for different environmental conditions.

      1. Kevin Navarrete says:

        Thanks!… You have won a new follower😀

  11. Ben Sheeran says:

    Thank you so much for this. I have an Evolutionary Biology final exam tomorrow and in the review the professor just made everybody more confused about homeotic genes, homeobox genes, and HOX genes.

    1. No worries, I hope it cleared some things up.

  12. Mike Hayes says:

    This may be a very simple question, but if the homeodomain is very conserved how is the homeobox protein able to bind to a specific region of the DNA? Why don’t they all bind to the same region?

    1. This is a brilliant question. One way they get around this involves interactions between proteins. Genes with the homeodomain usually function as transcription factors, but these proteins don’t always work in isolation. Instead they often form complexes with other transcription factors. These complexes are much more specific in their targeting than any of the TFs would be alone.

  13. etmoietmoietmoi88 says:

    Omg thank you! I was just laboring over the difference between HOM and HOX genes, so I googled it and came across your page, which is where I realized that HOX ≠ Homeobox for starters! I think it’s fair to say that my course on developpment did not give adequate definitions of these genes. Granted, the prof did say “don’t worry too much about the terminology”, but I couldn’t help worrying about it… it was bugging me. I don’t see the point in learning something halfway. Thanks for clearing this up for us all out there:)

    1. I’m glad my little rant was able to help! It doesn’t help the professors/lecturers that there are so many similar terms.

  14. etmoietmoietmoi88 says:

    So are a fruit fly’s HOM genes one of those “non-HOX” genes made of homeoboxes?

    1. No, they’re the same thing.

      1. etmoietmoietmoi88 says:

        Got it, thanks for the response:)
        Yeah, I’d imagine it’s not the easiest terminology for a professor to explain (although you manage just fine… I hope you teach wherever you are), plus I think ours thought we’d studied them before in another class.

  15. Jennifer says:

    Hi, I was wondering if you could clear up a couple of details for me.

    So the homeobox is 180 base pair sequence that is found in lots of genes and binds to DNA/RNA controlling its expression, BUT DOESN’T NECESSARILY BIND TO A GENE CONTROLLING DEVELOPMENT OF BODY PLAN. Hox genes however, contain the homeobox AND affect development (because the homeodomain binds to a gene controlling some aspect of body plan)


    1. Hi Jennifer,

      You’ve understood much of the difference but some of what you typed isn’t quite correct. The homeobox (which is the homeodomain in the resulting protein) is able to bind to DNA, as you’ve correctly stated. That’s amazing because it means genes with a homeobox can be used to turn on and off other genes. Being able to activate specific genes at specific times, or in specific cells, or in response to specific environmental stimuli is obviously important. One of the most important uses is in development, activating or deactivating specific genes in specific cells at the right time for an organism to develop normally.

      Hox genes are a group of closely related homeobox genes that are definitely involved in development. Technically a homeobox gene doesn’t need to have a role in development. E. coli use homeobox genes and they are single cells. But don’t make the mistake of thinking Hox genes are the only homeobox genes involved development. There are the ParaHox genes, NK genes, hundreds and hundreds of genes that are involved in the development of the animal body plan. Hox genes are just one group, a very important group. In most animals, the Hox genes are found very close to each other in the genome. This is why they’re described as a “cluster”. It appears there were a few Hox genes that duplicated and each was modified slightly and that’s why we have many more now. But they’re often found together in a cluster. In the fruit fly, the cluster has broken up into two clusters.

      Plants use homeobox genes for the same reason as animals, fungi, bacteria etc do. They use them to regulate genes by binding to DNA. This includes homeobox genes used in development. I hope this answered some of your questions.

  16. Jennifer says:

    also, are hox clusters groups of hox genes, or groups of homeobox genes? And what do homeobox genes do in plants? THANKS!

    1. Hox is the name given to a distinct class of homeobox genes. So the Hox cluster(s) of animals are the Hox genes. In many animals, the Hox genes are found together on the same chromosome and even in the order that correlates with where they are expressed along the anterioposterior axis of the developing embryo. The fact that they are found in clusters raises interesting evolutionary questions regarding the origin of the individual genes and why some species have broken or scattered clusters.

      Homeobox genes play the same roles in plants as they do in animals. Some are involved in morphological development, patterning where different structures grow… others have more fundamental roles in the biology of individual cells. Remember, the homoeodomain allows proteins to bind to DNA, so homeobox genes usually code for transcription factors that can turn genes on and off. The activation and repression of genes is something happening all the time in my many biological processes, not just during typical development.

  17. Jessica says:

    Very goo info. Lucky me I recently found your blog by chance (stumbleupon).
    I have book-marked it for later!

  18. AYAN says:

    Why are these genes are called as box?…I mean like Homeobox- Paired Box etc etc etc.??..
    Please clarify this and guide me to any materials to read for myself for this.

  19. Rio says:

    Rarely I wrote comment on an online article, but THIS article made me really want to do it. Well-written and packed with knowledge. Thank you for writing this article! Looking forward for other superb work!


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