20 July 2020

ECO by Science

Preimplantation genetic diagnosis

Denis Rebrikov, Post-science

Nature combines different combinations of genetic information, thus creating a variety of phenotypes. But people also have different predispositions to certain diseases. What technologies are used to determine genetic disorders and identify hereditary diseases?

Why are people different?

Sometimes we meet people who look the same – they are monozygotic (identical) twins. They are very similar, and sometimes even parents have difficulty distinguishing them. But why are monozygotic twins so similar, and all the people around are different? Monozygotic twins have exactly the same DNA. They developed from a single cell due to the fact that inside the mother's womb, she divided into two embryos, and each then developed independently.

A person has 23 pairs of chromosomes, which are DNA fragments in which genetic information about the structure of the body is recorded – in about 25 thousand different genes distributed across 23 pairs of chromosomes. We are diploid organisms, with two sets of chromosomes, one of which we inherited from our father, and the other from our mother. Nature has come up with such duplication so that in the event of a breakdown of one of the sets, it would be possible to take information from another. The diversity of genotypes that we observe in the population, and, consequently, the diversity of phenotypes, is due to the fact that when a set of chromosomes is created, transmitted from parent to child, it is randomly generated: we have 23 pairs of chromosomes, and one chromosome is randomly dropped from each pair into the gamete. It turns out 223 combinations of chromosomes – about 8 million genetically different gametes, differing in the whole chromosome. And this is only one of the parents, and therefore, the probability of consecutive birth of identical children in a particular pair of parents is the lowest possible – one divided by 64 trillion.

Genetics and hereditary diseases

Combinations of genes that are transmitted to a child determine the structure of his body, biochemical processes and health. All people have a different predisposition to diseases of various organs and systems: for someone, the cardiovascular system "breaks down" faster, for someone - the system of functioning of the brain, neurons, and so on. In addition, combinations of genes cause monogenic and orphan diseases – hereditary diseases associated with a violation of a particular gene and often leading to the death of a child at a fairly early age.

Today, knowing the genetics of parents, we can predict some moments for the child they will have. We can screen the genetics of the parents and see that in their body the combination of broken genes in the chromosomes coincided so that they themselves are healthy: although one of the two copies is broken, it's not scary, because the second copy works, and the body is healthy. But if a child gets one broken copy from each parent, then both of them will be broken, and he will not be able to compensate for the function: he will be missing a whole gene. As a consequence, a monogenic disease will develop. The probability of a sick child being born to such parents who have a mutation for a specific gene, but they themselves are healthy, is 25%, and this is quite serious.

Preimplantation screening technologies

In such cases, it is recommended to conduct an in vitro fertilization (IVF) procedure with the selection of embryos by genetic screening before their transfer to the uterus. What is IVF? Since it is necessary to collect a lot of oocytes for the procedure – usually one or two of them ripen - a woman is first of all given a drug that helps to mature more oocytes in one ovulation. Then, during the natural cycle, oocytes are collected from a woman, and spermatozoa are collected from a man. During the IVF procedure, several oocytes are fertilized independently, these embryos in specialized incubators, outside the woman's body, grow up for five days to the blastocyst stage – this is about 250 cells in each embryo. On the fifth day, 5-7 cells of the embryo are biopsied – it does not cause damage to it – and these cells are given for genetic analysis.

There are several methods of genetic screening. The first is to conduct a point diagnosis by polymerase chain reaction, when we know in advance where to look, which gene is broken, which mutation in this gene is present in the parents. This is a fairly cheap test that costs 2-3 thousand rubles.

The second method is a micromatrix analysis, with which you can view a more complex structure of rearrangements: DNA is hybridized onto a chip on which there are a lot of pieces of DNA corresponding to human chromosomes, and a full genomic screening is carried out. A micromatric analysis is usually done if a woman is over 40 years old, because in this case the risk of a violation by the number of chromosomes (and not just by a mutation in the chromosome) is quite high. One of the frequent diseases associated with a violation of the number of chromosomes is Down syndrome, in which a child has chromosomes of the 21st pair instead of the normal two are represented by three copies – this is the so-called trisomy on the 21st chromosome. With the help of DNA hybridization on a chip, we can determine the presence of an extra chromosome for a particular pair or its absence. If the disease is severe, then such an embryo is not transferred to the uterus.

And the third method is high–performance sequencing (NGS – next generation sequencing), when we can determine either all the protein-coding regions of the genome (exome), or the entire genome. Usually, such technology is not used for screening, but the exome can be determined, and then it becomes possible to view all the gene sequences and tell which combination of genes got into a particular embryo.

Today, such technologies are increasingly used in clinical practice. If earlier there were strict indications for this – for example, for patients older than 40-45 years or when parents absolutely have a hereditary disorder that can be transmitted to a child with a probability of 25% – then today we can already look at specific genes associated with a predisposition to the development of oncological diseases, disorders of the cardiovascular system, and so on. Such technologies of preimplantation screening (PGS) and preimplantation diagnostics (PGD) are the future of genetic technologies in medicine.

About the author: Denis Rebrikov – Candidate of Biological Sciences, RNIMU named after Pirogov.

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