Homeosis genes

Homeobox

Homeosis genes contain homeobox , a sequence of 180 pairs of DNA nucleotides that forms a homeodomain in the encoded protein.

The homeo domain was first discovered in the composition of genes that control development, and, in particular, in the composition of homeoise genes, in Drosophila. However, many genes containing homeobox are not homeotic. Thus, homeobox is a special sequence of nucleotides, while homeosis is the potential for the formation of a homeosis mutation. ^[four]

The nucleotide sequence in the homeodomain is highly conserved. The functional equivalence of homeosis proteins can be proved by the fact that the development of a fly with the corresponding chicken homeosis genes proceeds normally. ^[5] Despite the fact that the common ancestor of chicken and flies existed about 670 million years ago, ^[6] homeosis chicken genes are similar to similar fly genes to such an extent that they can replace each other.

Due to the degeneracy of the genetic code, the sequence of amino acid residues in proteins is more conservative than the sequence of nucleotides in DNA, since different codons can encode one amino acid . A single mutation in the DNA of homeosis genes can lead to striking changes in the body (see homeosis mutations ).

Homedomain

Protein products of homeosis genes belong to a special class of proteins - transcription factors that bind to DNA and regulate gene transcription . The homeobox sequence consists of 60 amino acid residues and forms a helix-rotate-helix structure, known as a homeodomain . In Drosophila, the protein product of the Antennapedia homeosis gene activates genes that determine the structure of the second thoracic segment containing legs and wings and represses the genes involved in the formation of eyes and antennas. ^[7] Genes that are regulated by proteins containing homeobox are called sales genes, and they are protein products of segment polarity genes that encode tissue- and organ-specific proteins.

Enhancer sequences that bind to a homeodomain

The DNA sequence to which the homeodomain binds contains a TAAT nucleotide TAAT at the 5 ' end, with T most important for binding. ^[8] This nucleotide sequence is conserved in almost all homeodomain binding sites. Since many proteins containing a homeodomain have the same recognition sites, base pairs following this initiator sequence are used to distinguish between these proteins. For example, the nucleotide sequence after TAAT recognized by the ninth amino acid of the protein containing the homeodomain. The protein encoded by the maternal effect gene, Bicoid , contains a lysine residue in this position, which serves to recognize and bind guanine . In the Antennapedia protein, glutamine is located in this position, which recognizes adenine and binds to it. If the lysine residue in the Bicoid protein is replaced with glutamine, the altered protein will recognize Antennapedia-specific enhancer sites. ^{[9] [10]}

Hox genes

Hox genes are located on one or several (up to four) chromosomes, usually in tight groups (clusters), within which a more or less strict order is maintained: the “head” genes are in front, the “tail” genes are in the back. In more primitive representatives of multicellular organisms, such as ctenophores ( Ctenophora ) and intestinal ( Cnidaria ), there are only four of these embryonic regulatory genes; in mammals, there are already 48 of them.

The family of Hox genes is divided into 14 classes. It is believed that these 14 classes arose by duplication of one or a few of the original genes, the replicas then mutated and acquired new functions. In primitive intestinal and ctenophores, there are only 4 classes of Hox genes; in the supposed common ancestor of bilaterally symmetric animals, there should have been at least 8 of them; in mammals, all 14 classes are present. The principle of operation of these genes is the same. Their products are transcription factors whose function is to “turn on” or “turn off” other genes. As a result of the work of Hox factors, a cascade of reactions is triggered, leading to the appearance of the desired proteins in the cell.

Over the past decade, the DNA sequences of Hox genes in many animal groups have been decoded: annelids, flatworms, echinoderms, nematodes, arthropods, tunicaces, lancelets, not to mention mammals.

Regulation

Homeosis genes regulate the functioning of sales genes, and, in turn, are regulated by gap and pair-rule genes , which are controlled by morphogen proteins of a number of genes with a maternal effect . As a result of this, a cascade of transcription factors is formed : maternal effect genes include gap and pair-rule genes; gap and pair-rule genes include homeosis genes; finally, homeosis genes include marketing genes that lead to segmentation and differentiation of the embryo.

Such regulation is carried out by concentration gradients of morphogen proteins. A high concentration of one of the mother proteins and a low concentration of the others includes a certain set of gap and pair-rule genes. In flies, the second lane of expression of the Even-skipped embryo gene is activated by the maternal proteins Bicoid and Hunchback and is repressed by the gap Giant and Kruppel proteins . ^[11] .

MicroRNA molecules in hox clusters more strongly inhibit anterior homeosis genes, probably for more precise regulation of their expression. ^[12]

In clusters of homeosis genes, non-coding RNAs (ncRNAs) are widespread. One of the non-coding RNA genes in humans, HOTAIR, reduces the level of transcription of homeosis genes (transcribed from the HOXC cluster and inhibits late HOXD genes) by binding to the Polycomb group proteins (PRC2). ^[13]

The structure of chromatin is necessary for transcription , but also requires the weaving of the chromosomal territories on which the cluster is located. ^[14] Quantitative PCR showed some patterns of collinearity: the system is in equilibrium and the total number of transcripts depends on the number of genes presented in a linear sequence. ^[15]

Homeosis mutations

Errors in the expression of homeosis genes lead to major changes in the morphology of an individual. Homeosis mutations were first described in 1894 by William Batson , who described the appearance of stamens in place of petals.

In the late 1940s, Edward Lewis studied homeosis mutations at the Drosophila melanogaster model site, which led to the formation of bizarre organs. Mutations in genes involved in limb development can lead to malformations or even death. For example, mutations in the Antennapedia gene lead to the formation of limbs on the head of a fly in place of antennas. ^[sixteen]

Another well-known example in Drosophila is the mutation in the Ultrabithorax homeosis gene, which determines the development of the third thoracic segment. Typically, a pair of legs and a pair of ground beetles (reduced wings) are represented in this segment. In mutant individuals that do not have the functional protein Ultrabithorax, the same structures are formed on the third segment as on the second thoracic segment, which carries a pair of limbs and a pair of fully developed wings. Such mutants are sometimes found in wild Drosophila populations, and the study of such mutants has led to the discovery of animal homeosis genes.

Collinearity

Homeosis genes in the chromosomes of many animals are very close to each other, forming clusters. In this case, Drosophila collinearity is observed - the sequence of the arrangement of genes on the chromosome corresponds to the sequence of their expression along the anteroposterior axis of the body.

Classification

Different taxa have been given different names for homeosis genes, leading to confusion in the nomenclature. In the case of some primitive ( Ecdysozoa - arthropods, nematodes) homeosis genes comprise two clusters of Antennapedia and Bithorax , which together are called HOM-C (Homeotic Complex, Homeotic Complex). In the case of secondary (echinoderms, chordates), homeosis genes are called Hox genes and four clusters are distinguished: Hoxa, Hoxb, Hoxc and Hoxd. In primitive ones, the genesis genes are also often called Hox genes, although this is not entirely true.

Phylogeny of homeosis genes

Ecdysozoa has about ten homeosis genes. Vertebrates have four sets of paralogs of the ten genes Hoxa, Hoxb, Hoxc, and Hoxd. These clusters of paralogs formed as a result of two duplications of vertebrate genomes. ^[17]

Both duplications occurred after the ancestors of the lancelet and shell were separated from the common trunk with vertebrates, and before the evolutionary lines of mammals and cartilaginous fish were separated. Most likely, the first duplication occurred shortly before the separation of the lines of the maxillary and maxillary, and the second - shortly after (the separation of these lines probably occurred about 530 million years ago). ^[18]

Although vertebrate homeosis genes are copies of Ecdysozoa genes, these copies are not identical. As a result of the accumulation of mutations over a long period of time, proteins perform various functions. In different groups of vertebrates, some genes are lost or duplicated.

Hoxa and Hoxd determine limb development. Hox expression in a limb has two stages: the limb itself develops on the first, Hoxd 8 - 13 works on the later and fingers form, and a separate regulatory region is involved at the 5 'end of the Hoxd 13 gene, which is not found in Teleostei . ^[nineteen]

History

The importance of mutations in homeosis genes for the development of the theory of heredity was first indicated by the author of this term, William Betson, in 1894 . In the 1920s, the student of S. S. Chetverikov, E. I. Balkashina , studied homeosis mutations (including Drosophila ). Balkashina described the aristopedia mutation in Drosophila and established the parallelism of the phenomena of homeosis during regeneration and mutation of homeosis genes, and also mapped three Drosophila genes known at that time.

Edward Lewis in 1948 began a systematic study of homeosis genes that control the development of the imaginal discs of the larva in the organs of the imago . Lewis found collinearity in the space between the arrangement of the genes of the bithorax complex in the chromosome and the arrangement of the imaginal discs (segments), for the development of which they are responsible, along the anteroposterior axis of the body.

Christiana Nyuslein-Volhard and Eric Vishaus classified 15 genes that determine body structure and segmentation in Drosophila melanogaster . Researchers received the Nobel Prize in medicine in 1995 .

In January 2013, Spanish scientists conducted an experiment to introduce the hoxd13 gene into the fish genotype of the Danio-rerio , which is responsible for the development of limbs for movement on land, borrowed from mice. A similar gene exists in the fish themselves, but does not show sufficient activity for the development of paws. As a result of the experiment, fish, instead of fins, received the rudiments of limbs that could provide movement on the ground. ^[20]

The expression of genes that regulate plant development is controlled by internal and external factors. The internal factors affecting their activity include hormones , sucrose and some mineral elements, and the external factors include temperature and light. An important role in the regulation of differentiation and development processes belongs to genes that contain promoters that are sensitive and specific to phytohormones and environmental factors such as light and temperature. The promoters of so many genes whose activity is regulated by phytohormones revealed transcriptional elements that determine the hormonal specificity of plant growth reactions.

Currently, key genes have been identified that control embryogenesis , aging, and photomorphogenesis, regulate the functioning of the apical, lateral, and floral meristems , and are responsible for the formation of the root, leaves, and blood vessels. The expression of the genes that regulate the development of flowers is best studied. Based on the currently available genetic information, mathematical apparatus, and computer programs, it has become possible to build the so-called genetic regulatory networks, which make it possible to evaluate the entire spectrum of interactions between various regulatory genes in the process of cell differentiation and plant organ formation. Individual elements of these networks are capable of controlling several processes at different stages of development. Therefore, mutations affecting different parts of one regulatory gene may differ in their phenotypic manifestation.

In higher plants, the functioning of two types of developmental control genes is best studied: homeobox-containing and genes with a MADS box .

Genes Containing Homeobox

Genes containing homeobox are determined by the presence of a characteristic DNA sequence of approximately 180 nucleotide pairs (homeobox) encoding a homeodomain - a conservative site of a number of transcription factors. This nucleotide sequence is typical for genes of the cascade type of development regulation.

The first cloned plant gene encoding a homeodomain protein was maize KNOTTED1 (KN1). The knotted 1 mutation causes the KN1 gene to be expressed at the wrong time and in the wrong place. In kn1 mutants, groups of cells appear around differentiated leaf cells that still continue to divide. Groups of dividing cells located along the vascular elements throughout the leaf blade form the so-called knots. Later, a whole family of genes like KN1 was discovered, called KNOX (KNOTTED1-like HOMEOBOX). Overexpression of genes of the KNOX family also distorts leaf development.

Among the plant KNOX genes, the largest group that is involved in the regulation of the apical meristem of shoots and in the development of leaves: KN1 and RS1 in corn, KNAT1, KNAT2 and STM in Arabidopsis thaliana , HvKNOX3 in barley and OSH1 in rice was studied in most detail. The KN1, STM genes and their functional analogues are responsible for maintaining cell division of the meristems, repressing their further differentiation. These genes are expressed in the apical shoot meristems, as well as in the floral meristems.

Genes containing the MADS box

The term “MADS box” is formed by the initial letters of four genes: MCM1 yeast, AG Arabidopsis, DEF snapdragon and SRF mammals. Genes containing the MADS box include, in particular, AG ( AGAMOUS ), DEF (DEFICIENCE), AP1 (APETALA1) and AP3 (APETALA3), TFL1 (TERMINAL FLOWER), PI (PISTILLATA). Genes of this type regulate florogenesis and determine the fate of cells in the ovule; their expression is detected in the embryo, roots and leaves. Most homeosis plant genes, in particular, flower organ identity genes, are MADS box genes. It is assumed that the emergence of new organs in the process of progressive evolution of plants, for example ovules and seeds, was accompanied by the appearance of new subfamilies of exactly MADS box genes.

Transcription Factors

Direct control over the development of plant organs and tissues is carried out by transcription factors (TFs) - proteins that, after moving into the cell nucleus, regulate transcription, specifically interacting with DNA or with other proteins that can form a protein-DNA complex.

• Homeobox
• Homeosis
• Morphogenesis

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