What are Hox genes: how mutants arise

We are all a little mutants, and each has its own DNA, unique and - not counting twins and clones - unique. However, the general public was accustomed to being afraid of mutants, imagining some unfortunate inhabitants of Mars from the movie “Remember Everything”: with an extra hand, missing ribs or a badly deformed body. Such mutations are also known, and today it is possible to artificially grow flies with legs on the head or mice with two upper jaws. The main thing is to choose the right target - a small group of very important genes that determine the body structure of animals.

Since Thomas Morgan, one of the founding fathers of modern genetics, began to cultivate fruit flies in 1906, they have become one of the most studied animals on the planet. Small size, unpretentiousness, and most importantly - a short life cycle made Drosophila a popular model for genetic research. By the middle of the twentieth century, myriads of flies with the strangest manifestations of mutations, with violet or white eyes, without bristles on a naked body passed before the eyes of scientists ... But what Edward Lewis of California Institute of Technology saw in his eyes caught his eye for a long time . The fly had an extra pair of wings, like some butterfly had.

The formation of the Drosophila segmented body begins long before the Hox genes work - even with messenger RNA, which is introduced into the egg even before fertilization, at the maturation stage. Some of them are concentrated in the front of the cell, others in the back, so that in the first hours of embryo development, when proteins are actively synthesized on these mRNAs, a concentration gradient appears in it: there is more Bicoid protein in the front pole and Nanos in the back pole. A different concentration of proteins launches different genes of the Gap and Pair-Rule families, which are responsible for segmentation of the embryo. It is only when the segments are sufficiently formed that Hox homeosis genes related to the specialization of the segments come into play. For the discovery of these mechanisms in 1995, Eric Vishaus and Christian Nyuslein-Volhard shared with the Edward Lewis the Nobel Prize in Physiology or Medicine.

The story of a fly: development

Lewis was not the first to pay attention to such ugliness - and there was something to think about. The animal’s body develops from one cell, and each new generation of cells carries the same initial set of chromosomes and genes (minus germ cells, which do not appear immediately). In different tissues and parts of the body, a slightly different set of genes is activated - and the cells develop according to a different scenario. Some form the legs of Drosophila, others form its antennae, others form wings, obeying the genes that conduct their growth. A malfunction of the genes is fraught for the fly with serious violations, for example, the appearance of an additional pair of wings or legs that have grown between the eyes, in place of the antennae.

Our expert Pavel Elizariev, junior researcher at the Laboratory for the Regulation of Genetic Processes of the Institute of Gene Biology, Russian Academy of Sciences: “It so happened that the complexes of homeosis genes became one of the most studied in the fruit fly and other organisms - probably the fly with legs on its head was very remarkable. But over time, the story became even more interesting. When about 30 years ago they began to accurately map mutations leading to transformations of the body of a fly, it turned out that not one of them was inside the Hox genes themselves. Most affect the wide genomic regions around that do not encode anything: here are the sequences that regulate the activity of the surrounding genes. These sequences do not work on their own, but due to binding to activator proteins or repressor proteins. A whole new level has opened up in the regulation of body structure - and the complexes of homeosis genes have become a testing ground for non-coding DNA, which in our genome occupies about 98%. ”

There are many such violations of the correct development of the body in Drosophila. Lewis noted that they are associated with the incorrect formation of a whole segment - as if the third segment of the chest suddenly began to consider itself second and hastily grew extra wings. The Ubx gene was also found, mutations in which started development in the wrong direction. And soon Ubx also found relatives - two more genes located on the same third chromosome, next door to it. And since they make one segment similar to another, they were called so, only in Latin - homeosis (Hox).

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By the early 1980s, the work of Lewis and other scientists helped find all the Hox genes in which mutations make some segments of the body of the fly look like others. There were eight of them, and they form two close groups. Ubx and two others make up the Bithorax complex, which is activated in the nine posterior segments of the Drosophila body. The five others work in the segments of the chest and head, forming the Antennapedia complex - the Antp gene turned out to be the most significant in this group: disrupting its work, you can grow legs in place of the head antennas. The most interesting thing was that the Hox genes are located in the genome in exactly the same order as their segments in the body - from the head to the tip of the abdomen.

An ancient fragment of homeobox is found even in plant genes that act in conjunction with genes containing a similar MADS box. Moreover, MADS was found in almost all studied eukaryotes, including yeast and humans, although the functions of all of them are different. In plants, they control all the main development programs, so that they can be considered analogues of the Hox genes of animals.

Animal History: Evolution

In 1983, Swiss biologists found an unexpected common feature in Drosophila homeosis genes: they all had a small, only about 180 nucleotides in length, but characteristic sequence, "homeobox". This amazing fragment encodes a protein domain of approximately 60 amino acids, which binds to DNA and is found in almost all animals, from starfish to pop stars. The order of the location of Hox genes on the chromosome is preserved with almost the same rigor in animals. Such conservatism indicates the important role that Hox genes play and their dizzy antiquity.

Small changes in homeobox, which distinguish one group of animals from another, made it possible to trace their possible history down to a common ancestor, who most likely had a basic group of four Hox genes. The intestinal cavities do not need such complexity, and they have lost half of them. But already at the ancestor of bilateral animals, who lived about 600 million years ago, they doubled, and each took on its own, slightly different from the other functions. Such complications occurred several times, so if there are eight such genes in Drosophila and other insects, then in the chordate lancelet - already 14. The maximum number of Hox genes was reached in vertebral tetrapods - amphibians, reptiles, birds and mammals. We have this complex of genes in four copies similar to each other, so even with a few losses their total number exceeded 30. In fact, although the segmentation of our body from the side is not as noticeable as that of worms or insects, it exists, and Hox genes determine whether the vertebrae will connect to the ribs or even grow together in the coccyx. The mutation in Hox10 in mice causes them to grow ribs even on the abdomen.

Lizard Story: Regeneration

Several years ago, St. Petersburg biologists studied the work of the Hox genes of the ringworm Nereis in the state of the larva and adult organism. It turned out that if in the larva their work is carried out according to the classical scheme familiar from flies, then in the adult worm it abruptly changes the program. Instead of activating each Hox gene in its segment, they are included everywhere and differ only in the degree of activity. It is assumed that this allows the Nereis, which has lost tail segments, to safely grow new ones.

When genes “get sick” Human embryonic development is an incredibly complex process. Therefore, violations in the work of Hox genes, as a rule, end in miscarriages in the early stages of pregnancy. However, occasionally children are still born - one of the results of mutations in Hox clusters may be Goldenhar syndrome (hemifacial microsomy). This is a serious disease that is associated with multiple malformations and, of course, remains incurable. There are indications of the possible role of Hox genes in the development of certain types of cancer, such as leukemia or breast cancer. Usually almost silent in an adult, some of the Hox genes can again show activity in tumor cells, “waking up” under the influence of signaling molecules and growth hormones.

Such a picture is not news at all, even for much more complex vertebrates. Many reptiles and amphibians, known for their ability to regenerate lost tails and even limbs, use the same homeosis genes for this. The details of this mechanism are still poorly understood, but it is known that even almost identical duplicated Hox clusters in salamanders carry different introns - non-coding inserts inside genes that provide more wide possibilities for regulating their activity. Perhaps such "improvements" play an important role in the work of Hox genes in the regeneration of limbs. In general, despite small differences, Hox genes are extremely conservative and remain very similar even in such close groups of animals as insects and mammals. Replacing one of them in Drosophila with a homologous one taken from a mouse, you can grow a completely normal fly. They are even more similar in humans and reptiles.

And if lizards, thanks to them, are able, without blinking an eye, to grow a new tail instead of a bite, will the precise regulation of Hox genes help people? Research in this direction is already underway, and if someday a person is restored a lost finger or even a whole hand, it is worth remembering that the story of flies with legs on their heads began.

The article “Mutant Stories: Homeosis Genes” was published in the journal Popular Mechanics (No. 6, June 2016). Do you like the article?

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