Genes and enhancers

The Great and daring genome 

Svetlana Utkina, "Science in Siberia"

"Darwin Week" — a traditional marathon of popular science lectures from leading scientists of Akademgorodok - ended with a lecture on the genome and genomics. Over the past 50 years, geneticists have made many unexpected discoveries related to DNA. In his lecture "The origin of complexity from the point of view of genomics", a leading researcher at the Institute of Cytology and Genetics SB RAS, Candidate of Biological Sciences Nariman Rashitovich Battulin compared the genome with the cosmos. As in space, there is a lot of black matter in the genome, and new discoveries sometimes give rise to new questions and difficulties.

I'll buy a genome

Genomics is a relatively young science, which was formed as a special direction in the 1980s and 1990s, along with the emergence of the first projects on sequencing the genomes of some species of living organisms. Curiously, back in 1869, Francis Galton, Charles Darwin's cousin, in his book "Hereditary Genius" described the results of a study of many generations of musicians, judges, statesmen, scientists, generals, writers and artists as representatives of a class of outstanding personalities. He found that the talent of relatives of a famous person decreases with a decrease in the degree of kinship with her. Galton considered this pattern to be proof of the genetic transmission of extraordinary abilities from ancestor to descendant.

A large-scale project to decode the human genome began in 1990. In the USA, under the leadership of James Watson and under the auspices of the US National Health Organization, a working draft of the genome structure was released. In parallel, private business also joined the decryption process. The bulk of the sequencing was performed at universities and research centers in the USA, Canada and the UK. Geneticists were able to understand the genetic code — a system for recording information about the order of amino acids in proteins in the form of a sequence of nucleotides in DNA or RNA. Each amino acid in DNA is encoded in DNA by a triplet — three consecutive nucleotides. However, even today, additional analysis of some sites has not yet been completed. It can be said that the specialists have only learned musical notation, but how to play is still to be learned.

However, the breakthrough is that today any of us can go and buy our genome in a medical clinic, that is, order the sequencing of our DNA. 

In some countries, this work is scaled up, national DNA banks are being created. For example, the Icelandic company deCODE genetics owns the genetic information of two-thirds of the population of Iceland. This data is also used for the development of personalized medicine — individual therapy based on the patient's genetic data. Many laboratories and medical centers in most countries have their own sequencers. Although the procedure is not cheap. 

The most famous portrait of the human genome in numbers: 23 pairs of chromosomes, the longest is the first chromosome. One DNA molecule is a thread about the length of a human. At the same time, inside the cell, this long thread is packed in a special container — a core with a diameter of a tenth of the thickness of the hair. The DNA double helix is the most famous biological molecule, and its structure inspires many creative people. For example, a bridge in the form of a DNA molecule has been built in Singapore, ladders similar to it are being erected, decorations are being made. 

Helix Bridge is a futuristic bridge in Singapore, shaped like DNA

There are three billion letters in the genome-the nucleotides that compose it. To understand the logic of reading them, to understand how this or that information is written in DNA — that's the task for the future.

"What do we know for today? There are genes that encode protein. There are not so many of them, only 20,000, and the sequence in which DNA is recorded is only 1.5% of the genome. However, there are areas that do not encode protein, and we simply do not know what is between these areas, for us this is the first difficulty," Nariman Battulin says. — The second problem in the genome scheme is how do enhancers adjust the activity of genes? And all living organisms are born due to the complexity inherent in enhancers." 

Daring enhancers 

Enhancers (English enhancer — amplifier, magnifier) — switches, a kind of toggle switches. They are not always in close proximity to the genes whose activity they regulate, and not even necessarily on the same chromosome as the gene. To find out the function of enhancers, scientists use genetic engineering experiments. 

"To find out where a particular enhancer works, they make an artificial gene in which this enhancer is connected to a gene, the product of which can be easily noticed, for example, a luminous protein. As a result, the schedule of the enhancer's work becomes clear for those parts of the body in which the glow appeared. Several experiments were conducted with mice. An enhancer was isolated from the genome and combined with an artificial blue gene. As a result of the experiment, he colored parts of mice. One mouse had colored paws, another had a brain, and the third had a liver. That is, with the help of an enhancer toggle switch, the mouse was painted in the specified places. Thus, enhancers set the temporal and spatial pattern of gene activity," Nariman Battulin explains. 

Interestingly, the size of the genome can be different. Birds have it three times less than humans, frogs have it ten times more than humans. A very complex genome in flowering plants. And the number of enhancers in mammalian genomes is several times higher than the number of protein-coding genes. Why there are so many is another difficulty.

Trying to understand this difficult question, scientists from the Lawrence Berkeley National Laboratory with colleagues from scientific institutions in the USA, Switzerland and Spain experimentally studied the properties of ten enhancers involved in the regulation of limb development in a mouse embryo.

In two out of three cases (for Gli3 and Shox2), simultaneous removal of a pair of enhancers led to serious defects. The loss of two regulators of the Gli3 gene led to a decrease in the expression of this gene, which at the phenotypic level manifested itself in the splitting of the thumbs on the front paws. The loss of two enhancers of the Shox2 gene also led to a decrease in the expression of this gene, and at the phenotype level — to underdevelopment of the femurs.

Thus, although each enhancer individually is not vital, the removal of two enhancers regulating one gene at once leads to gross developmental disorders. 

Gave birth to a mole in the night… 

"What gender is the mole from the famous Czech cartoon? When I ask this question to students, many answer that it is a boy, since in the cartoon the mole met with a mole girl. But this is fiction. Moles do not differ in appearance. Why am I interested in moles? Yes, it's all about the article from Science," Nariman Battulin notes. 

The journal Science has published a study by an international team of scientists that female moles are intersex. Intersexuality refers to the mixed manifestation of male and female sexual characteristics in individuals of segregated species. 

The team of scientists found out that female moles develop tissues of both ovaries and testes. So who is the mole: a girl or a boy? 

"The CYP17A1 gene is an enzyme that produces testosterone in all animals. All animals have one such gene. And the moles turned out to have as many as three! — N. Battulin explains. — As a result of some random mutations, the gene tripled, its treplication led to an increase in expression in the gonads. Therefore, female moles have the same strength as males. At the same time, it should be noted that moles retain fertility." 

The mice became stronger after the introduction of the enhancer from the mole

Like all mammals, female moles have two X chromosomes, but despite this, functional tissues develop, both ovaries and testes, which are combined into one organ - ovotestis, which is a very rare phenomenon for mammals. The testicular tissue of a female mole produces a large amount of male sex hormones, including testosterone. After the story with moles, scientists decided to put an experiment on mice. Rodents were given an enhancer from a mole and their strength was measured in a special simulator. The "physical education" consisted in the following: the animal was held by the tail, the mouse clung to the bars and pulled the bars for five approaches. The strength of the animals was recorded in nanonewtons. The result: genetically modified female mice after the introduction of the enhancer from the mole became stronger, had the same high level of androgens as the males. In fact, the differences between the male mouse and the female mouse were leveled. 

Feet in hands

Another example of an interesting mutation is also described in Science. "Among the pigeons there are those who have pubescence on their legs. The leg turned into a wing. How? It is clear that the changes did not occur in the genes themselves, but the enhancers turned on the genes in certain areas. It turned out that a combination of two genes is responsible for the presence or absence of feathers on the paws. In birds, the Pitx1 gene is responsible for the development of the forelimb, and the Tbx5 gene is responsible for the development of the posterior limb. At the same time, when the Tbx5 gene is inactive, and the activity of the Pitx1 gene, on the contrary, is pronounced, feathers develop on the hind limbs of birds. That's how enhancers turned legs into arms and vice versa. Of course, examples of mutations are studied on pigeons for a reason. Unfortunately, human mutations lead to a result that does not promise anything good to their carriers," N. Battulin states. 

One of the questions of work for the future for geneticists: which genomes are responsible for the formation of facial features? In search of an answer to this question, scientists have sequenced about 8,000 genomes. In addition to DNA analysis, a 3D photograph was taken for each of the people tested, and a face profile was determined. Then the features of a person's face and the features of his DNA were compared to understand how genes make a nose with a hump or form narrow cheekbones. It turned out that there are areas in the gene enhancers responsible for creating our unique profile. For example, the first gene is responsible for the length of the chin, others for various features in the appearance of the nose, the structure of one gene can determine the position of the base of the nose, the width of the bridge of the nose. 

"I want to believe that in the near future we will be able to reconstruct the face of the person who left it somewhere using DNA. Speaking about the future scope of research in genomics, I want to quote Douglas Adams, author of my favorite book, The Hitchhiker's Guide to the Galaxy: “Space is great. Terribly big. You just won't believe how mind-bogglingly big it is. For example, you complain about how far away a pharmacy is from you — but compared to space, this is sheer nonsense.” All this can be applied to the genome. The genome is big, it's terribly big. Genes encode proteins. The schedule of genes is determined by enhancers, and it is the change in enhancers that is the driver for generating diversity, which is then supported or not supported by selection," Nariman Battulin summarizes. 

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