Hox genes found freedom - and snakes lost their legs

The Genes We Have Lost The evolution of hominids has been accompanied not only by gains, but also losses. Some genes that work normally in chimpanzees and other monkeys have turned off in humans, turned into silent pseudogenes. In 1999, Maynard Olson from

Scientists from the United States have created an algorithm that can predict from the genome how transcription factors work in a living organism - proteins that control the synthesis of other proteins. Research published in PNAS.

Although the DNA sequences of many organisms have already been read, scientists still do not fully understand how they work. One of these mysteries has long been the Hox genes, which control the growth of an organism and the development of its parts in the right places. It is they who "command" the head of the Drosophila larva to grow in front, determine where and in what quantity the wings and legs will appear. This group of genes is also present in mammals.

Hox genes do not encode simple proteins, but special ones called transcription factors. These proteins act as "switches" for many other genes, attaching to specific regions of DNA to amplify or inhibit the reading of a sequence. This allows the Hox genes to "orchestrate" the development of the embryo. However, scientists have noticed a strange feature: although each Hox gene is responsible for the growth and development of different parts of the body, they all bind strongly to the same DNA sequences.

In 2015, geneticists at Columbia University found that these transcription factors bind to many other regions of DNA, but much weaker. Scientists have realized that these weak bonds are the key to understanding how the Hox genes work. However, finding them all in the genome was not easy. For this, geneticists created a new sequencing method (reading DNA sequences), which they called SELEX-seq. This approach required sequencing the same region many times in a row, but it did not provide information on important regions with weak binding. “It was like running the same paragraph through Google Translate over and over again, but at the end only getting 10% of the words neatly translated,” commented Richard Mann, one of the technology's authors, Higgins Professor of Biochemistry and Molecular Biophysics at Columbia University. ...

The researchers created a new algorithm to understand why DNA sequences behaved in this experiment in this way. The algorithm was named No Read Left Behind, or NRLB (literally "no reading is forgotten"). This algorithm was the first quantitative method capable of assessing the strength of binding of DNA regions to transcription factors. In addition, he was able to accurately predict the effect of certain mutations on the level of gene expression in Drosophila embryos, even for weakly binding sites.

There are about 10% of transcription factors in the genome, and their binding strength to different sequences can vary thousands of times. Therefore, the work is important not only in the context of studying Hox genes, but also for our understanding of how the genome functions.

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Hox genes determine the body pattern of animals. It is very important that they are expressed in the right amount, in the right place and at the right moment of embryonic development, otherwise the whole body circuit will be disrupted. It turns out that for these genes there is a special kind of translation regulation, which makes it possible to separate one type of protein from all others. Their mRNA has IRES-like regions that can trigger translation. In this case, the cap-dependent translation for these proteins is turned off.

Hox genes are an important subject for study

Broadcast initiation is different

So, the genetic material of a cell is encoded in DNA. A certain type of RNA is read from DNA, and a protein is read from RNA. This type of RNA is called messenger RNA, in it has a definite structure. This is a linear molecule, respectively, it has 2 ends, which are called 5'- and 3'-ends. There is a special structure at the 5′-end - ... It is necessary to start protein synthesis on the RNA matrix, as it attracts the protein factory - .

This happens with us, but not with viruses. More precisely, not all viruses. Some have other structures in RNA that initiate protein synthesis - ... So it turns out that in mammalian RNA, structures similar to IRES viruses are sometimes found. At the same time, the cap is also present. It turns out RNA with two signals of attraction of the ribosome. This interesting phenomenon often has important biological implications. For example, under stress, cap-dependent translation initiation is suppressed. But some proteins must also be synthesized under stress. That's when the cell uses IRES. And how such a mixed system works under normal, non-shock conditions is a big mystery. Cellular IRES are not alike, and their role in the development of the organism is not clear. Scientists studying the regulation of Hox genes tried to find an answer to this question.

Do mRNA of Hox genes have IRES viruses?

Interestingly, some Hox genes in the mRNAs suggest the presence of IRES. Moreover, it is IRES that attracts the ribosome and triggers protein synthesis. The first experimental evidence in favor of this hypothesis has already been presented. Scientists also discovered another special regulatory element - translation inhibitory element (TIE), which blocks cap-dependent protein synthesis. The appearance of the blocking element explains why, with both a cap structure and an IRES, only IRES works.

Why is IRES better than a cap?

The importance of the region of RNA where the putative IRES is located was experimentally confirmed in this case. It has been shown that if one of the Hox genes of mice is mutated by removing the IRES, the mouse will develop abnormally (see Figure 1).

Figure 1. Pathologies in the development of the skeleton of mice with deletions in the 5'-untranslated region in one of the Hox genes - Hoha9. Scientists have developed a line of mice in which IRES is damaged in one of the Hox genes. These mice develop abnormally. Their skeletal structure is disrupted: for example, there are not enough ribs (black arrows indicate the missing ribs). Other pathologies are also observed. Picture from.

For very important proteins that are encoded in the Hox genes, it is believed that IRES is better than cap. This may be due to the fact that the cap structure is the same for all mRNAs. And the IRES are different. That is, to the proteins that determine the structure of the body, an individual approach is needed. Even the beginning of synthesis is an important stage of regulation and must be unique for each such protein.

Glossary of terms:

• IRES (Internal Ribosome Entry Site) - site of internal ribosome planting.
• Hox genes are a family of genes that encode transcription factors that regulate the formation of organs and tissues during the development of an organism.
• Deletion is the removal of a fragment of a DNA molecule.
• Cap - 7-methylguanosine - structure at the 5'-end of messenger RNAs.
• Ribosome is a complex consisting of RNA and proteins and serves for the synthesis of protein from amino acids according to a given template based on genetic information provided by messenger RNA (mRNA).
• Translation - protein synthesis on an RNA template.
• Chromosome is a structure consisting of DNA and proteins located in the nucleus of a eukaryotic cell. Designed for storage, implementation and transmission of genetic information.
• Eukaryotes are living organisms whose cells contain nuclei.

Literature

1. Alexander, T., Nolte, C. & Krumlauf, R. (2009). Hox genes and segmentation of the hindbrain and axial skeleton. Annu. Rev. Cell Dev. Biol. 25 , 431–456 ;
2. Genes from which wings grow. And legs. And everything else ;
3. Wikipedia: «

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Homeotic genes determine growth and differentiation processes. Homeotic genes encode transcription factors that control the programs for the formation of organs and tissues. Mutations in homeotic genes can cause the transformation of one part ... ... Wikipedia

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- (English evolutionary developmental biology, evo devo) a field of biology, which, comparing the ontogeny of various organisms, establishes kinship ties between them and reveals the development of ontogenetic processes in the course of evolution. She ... ... Wikipedia

Transcription factors (transcription factors) are proteins that control the transfer of information from a DNA molecule into the mRNA structure (transcription) by binding to specific regions of DNA. Transcription factors fulfill their function ... ... Wikipedia

HOXB7 protein complex with DNA. Legend ... Wikipedia

- (transcription factors) proteins that control the process of mRNA synthesis on the DNA template (transcription) by binding to specific regions of DNA. Transcription factors perform their function either independently or in combination ... ... Wikipedia

Books

• The evolution of ontogeny, ND Ozernyuk, The evolution of ontogeny is considered as the main problem of evolutionary developmental biology, since the evolutionary transformations of organisms are caused by changes in their ontogenesis. Integration ... Category:

Hox genes are a large family of genes that regulate the development of various body parts in multicellular animals. It has long been known that these genes are very evolutionarily conservative: many of them are common even in such distant organisms as insects and mammals. However, this conservatism is not absolute. A detailed study of the fate of one of the groups of Hox genes, carried out by German geneticists, showed that new genes in this group arose several times in different evolutionary branches. Even in such relatively related animals as chordates and echinoderms, their set is different. And the ancient common ancestor of all bilaterally symmetric animals had significantly fewer Hox genes than most modern representatives.

Family genes Hox are known as regulators of the individual development of animals that control the differentiation of parts of their body (see: Programs of the work of Hox genes in larvae and adults of annelids are fundamentally different, "Elements", 05/27/2013). Most animals have several of these genes, and they have two important properties. First, mutations in the Hox genes cause a special type of deformity associated with the transformation of some parts of the body into others. In insects, for example, this can be the transformation of the abdominal segments into thoracic segments or antennae into legs (Fig. 1). Genes with this effect are commonly called homeotic (see also Homeotic gene). Second, Hox genes are extremely evolutionarily conserved. As early as 30 years ago, it was shown that, for example, in insects (fruit fly) and in vertebrates (mouse, human), their nucleotide sequences are very close.

Insects and vertebrates are not at all close relatives. They are located from each other on the evolutionary tree as far as is generally possible for two bilaterally symmetric animals (see: New data made it possible to clarify the pedigree of the animal kingdom, "Elements", 04/10/2008). That is, their common ancestor was at the same time a common ancestor of mollusks, echinoderms, flat, round and annelids, and in general all, without exception, members of a huge group of bilaterally symmetric, or bilateria (Bilateria). If a mouse and a fly have some common gene, then this means that this common ancestor already had it.

The fruit fly, meanwhile, has eight Hox genes, all of which have precise one-to-one correspondences in vertebrates (Figure 2). At least, this opinion has been widespread for a long time.

Another feature of Hox genes is that the regions of activity (expression) of these genes are usually located along the body of the animal in the same order in which the genes themselves are physically located on the chromosome (Fig. 2). This is called the principle of collinearity. For convenience, Hox genes are usually divided into groups: "front", "central" and "back". In accordance with the principle of collinearity, these names mean both the location of the genes themselves on the chromosome and the location of their expression regions in the body.

The new work done in the Applied Bioinformatics Lab, Department of Biology, Universität Konstanz, is devoted to the evolutionary fate of the central group of Hox genes. Both in the fruit fly and in vertebrates, this group includes three genes; in Drosophila they are called Antp, Ubx and abd-A, and in vertebrates - Hox6, Hox7 and Hox8(fig. 3). Based on their relative position, one can expect a one-to-one correspondence: the gene Antp will match the gene Hox6, gene Ubx- gene Hox7, gene abd-A- gene Hox8... But is it really so?

Geneticists from Constance decided to understand the relationship of the central Hox genes by comparing them directly. As you know, the product of each gene is a protein, and a protein is a chain of amino acids, the sequence of which can be deciphered and written down. There are many known Hox protein amino acid sequences. With the help of special programs, German geneticists in pairs compared with each other just absolutely all available sequences of proteins - products of the central Hox genes, "without looking" either at the gene number or at what animal it is from. A series of such objective comparisons would reliably show which genes have a common origin and which do not.

It turned out that of the three central Hox genes, insects and vertebrates actually have only one in common. This is the gene that insects call Antp, and in vertebrates - Hox7... Only this gene was probably in their common ancestor. The other central Hox genes of insects and vertebrates have nothing in common; they arose in these groups in different ways, as a result of independent gene duplications (doublings). For example, genes Hox6 and Hox8 is present only in vertebrates: they are not similar to any genes of other animals.

The fate of the gene in Drosophila turned out to be interesting abd-A... It (or its close "relative") is found not only in insects and even not only in arthropods, but also in several other types of animals, including mollusks, annelids and flat worms. Apparently, this gene is common to a huge group of Protostomia. This group includes arthropods, molluscs and almost all worms. But vertebrates are not included, and they do not have this gene.

Two unusual central Hox genes have been found in echinoderm and hemichordate animals. These two types are considered closely related, and indeed, the unique Hox genes - apparently newly acquired evolutionarily - are very similar. But in chordates (which include, in particular, vertebrates) these genes are not. Hemichordates, echinoderms and chordates together are part of the Deuterostomia group. The results obtained apparently mean that not only the common ancestor of bilaterally symmetric animals, but also the common ancestor of deuterostomes, had only one central Hox gene.

True, the common ancestor of deuterostomes lived a very long time ago - more than 500 million years ago. So the high conservatism of Hox genes is generally confirmed by these results. But we now clearly see that it is not absolute. In the hypothetical "protoworm", which was the ancestor of all bilaterally symmetric animals, the set of Hox genes was not the same as in a mouse or a fly (although in the wake of the first discoveries one might think so). It was still noticeably simpler. And its complication went gradually, in different groups in different ways, through events, many of which are now known to us.

The work of geneticists from Constance shows that detailed descriptions of the evolutionary fate of individual genes can be very plot-like, no worse than, for example, analyzing the biographies of historical characters. In the coming years, more and more such studies are likely to appear, based on vast databases and on the use of the most modern software. Evolutionary genetics is entering a new stage of its development before our eyes.

Sources: Stefanie D. Hueber, Jens Rauch, Michael A. Djordjevic, Helen Gunter, Georg F. Weiller, Tancred Frickey. Analysis of central Hox protein types across bilaterian clades: On the diversification of central Hox proteins from an Antennapedia / Hox7-like protein // Developmental biology(2013, preprint).