Mendelian types of inheritance

August 12, 2017 17:51 | Genetic Diseases

known quite a number of inherited diseases caused by a change in the DNA, which, however, do not have the Mendelian inheritance of character.The following will be considered mitochondrial inheritance and mitochondrial disease, as well as imprinting.

Mitochondrial inheritance and mitochondrial disease

Mitochondria are cellular organelles.Mitochondria have two highly specialized membranes - outer and inner, circular DNA molecule, as well as its own system of transcription and translation.Each cell contains several hundred mitochondria.They carried out a number of important biochemical chain reactions, of which the most important are the energy cells metathesis.

As already noted, have their own mitochondrial DNA in each mitochondrion contains 10 or more DNA molecules.Genome mitochondrial DNA (mgDNK) completely deciphered.

Disruption of interaction between mitochondrial and nuclear genomes of diverse causes of mitochondrial disease.

Since mtDNA found in the cytoplasm of cells, it is inherited only

through the maternal line.In the cytoplasm of the egg, there are thousands of mitochondria and therefore, tens of thousands of mtDNA molecules.At the same time the sperm There are only a few mtDNA molecules, which do not fall within the egg is fertilized.Therefore, men inherit mtDNA from their mothers, but did not pass it to their offspring.This type of inheritance is called maternal inheritance or inheritance on the maternal side.

Usually all copies of mtDNA are identical, and this condition is called gomoplazmiey.Sometimes mtDN By having the mutation.As a result of the work is not very perfect mitochondrial DNA polymerase mutations and reparative systems in mtDNA occur 10 times more frequently than in nuclear DNA.The appearance of a mutation in one of mtDNA molecules may result in two populations of mtDNA in the cell is called geteroplaziey.As a result, cell division mutant mtDNA gets into other cells, where it continues to reproduce.

energy requirements of the different tissues of the body are different.The most energy-consuming is the nervous system.That is why this system is primarily affected in mitochondrial diseases.

classification of mitochondrial diseases is based on two principles:

1) mutant protein involved in energy reactions of oxidative phosphorylation;

2) whether the mutant protein encoded by mtDNA and nuclear DNA.

Class I of mitochondrial disease include optic atrophy Leber.The disease is manifested acute or subacute loss of central vision due to optic atrophy.The disease can begin in childhood and in old age.Some patients with optic nerve atrophy combined with symptoms encephalomyopathies.Leber optic atrophy is caused by mutations in mtDNA genes encoding subunits of complex I.

This class applies Leigh's disease (subacute necrotizing encephalomyelopathy).Leigh's disease occurs only when the mutant mtDNA is not less than 90% of the mtDNA.If the percentage is lower than the mutant DNA, the syndrome manifests neuropathy, ataxia and retinitis pigmentosa.

syndrome neuropathy, ataxia and pigmentary retinal dystrophy (NARP) can manifest in infancy and later, up to the 2nd decade of life.Besides pathology, which went down in the name of the syndrome, patients can be dementia, seizures, motosensornaya neuropathy, hearing loss.

syndrome myoclonic epilepsy and ragged-red muscle fibers (MERRF), which is manifested epilepsy, dementia, ataxia, and myopathy occurs when mutations in the gene for the tRNA.The syndrome may occur in childhood and adulthood.In addition to these symptoms, when MERRF syndrome in patients with sensorineural hearing loss is sometimes observed, dementia, optic atrophy, spastic diplegia.Typically, this syndrome is detected heteroplasmy expressed so expressive syndrome varies dramatically.

Another syndrome caused by point by replacing the gene tRNA - a syndrome Mitochondrial encephalomyopathies and stroke-episodes (MELAS).If it is also observed heteroplasmy, and, as a consequence, the expressiveness of the syndrome is quite variable.The main clinical manifestations include encephalomyopathies, stroke-state, usually transient, with restoration of function, seizures, ataxia, myoclonus, epilepsy, migraine headaches.

By mitochondrial diseases caused by deletions or duplications include Kearns-Sayre syndrome (myopathy, cerebellar disorders and heart failure), Pearson syndrome (pancytopenia, lactic acidosis, and pancreatic insufficiency), and chronic progressive external ophthalmoplegia, which is shownomitting the century.

Disruption of interaction between nuclear and mitochondrial genomes explain mtDNA depletion syndrome and syndrome of multiple divisions of the mtDNA.Both of these conditions are inherited as an autosomal dominant trait, so the reason, probably the nuclear gene mutations.

Diseases mitochondrial respiratory chain due to mutations in nuclear genes, can be divided into two groups - mitochondrial myopathy and mitochondrial encephalomyopathies.These diseases are inherited as Mendelian traits but due to lack of enzymes, belonging to one of the complexes of the mitochondrial respiratory chain.

Genomic imprinting

There are currently three known classes of exceptions to the rule of Mendelian hybrids identity in the 1st generation.The first exception has long been known, and it is associated with X-linked inheritance.

second, only that the consideration relates to traits determined by genes of mtDNA, which have a so-called maternal inheritance.At the heart of these two classes of deviation from Mendelian inheritance are differences in the genetic contribution of parents in the genotype of the offspring.When the X-linked inheritance progeny may receive only X chromosome from their mother, while the father's chromosome by either X, or Y. In succession mitochondrial zygote formed by the merger of gametes, and receives mitochondria mtDNA contained therein only in the egg.

Recently, genetics and embryologists described a third exception - genomic imprinting, where both parents transmit descendants absolutely identical genes but these genes are specific imprint sex parents, paternal and maternal genes are activated or suppressed (suppressed, blocked) during gametogenesis in different ways.Thus, in some cases it is important from a parent who inherit the gene.

term "imprinting» (imprint - «mark») first proposed in 1960 Crows from Columbia University, USA.

Genomic imprinting has a special place among the specific mechanisms of regulation of gene activity in the early stages of development, leading to differences in the expression of homologous maternal and paternal alleles.Subsequent genetic modification can lead to changes in gene expression will be transferred stably into cell lineages during development.Genomic imprinting, for example, may change the dose of genes that control embryo growth, cell proliferation and differentiation.

example of imprinting in human whole-genome is a true molar pregnancy, which occurs when the fertilized egg cell, deprived of maternal chromosomes, two sperm.Despite the availability of a full set of diploid, early embryogenesis of zygotes occurs abnormally: embryo tissue itself does not form.In the case of two sets of maternal chromosomes developed teratoma - embryonal tumor.Only the mother or only the father's genomes are not able to ensure the normal development of the embryo.

at the organismal level imprinting effect observed in connection with the presence of chromosomal fragments or whole chromosomes single (paternal or maternal) origin - the so-called uniparental disomy (OSA), namely there is a qualitative rather than a quantitative chromosome imbalance.

In recent years intensively investigated the effect of genomic imprinting in connection with various pathologies in humans.Examples of diseases which are based on the disorder function of imprinted regions of the genome, quite a lot, so we can talk about a special class of human diseases - "imprinting diseases", of which there are more than 30.

most convincing data obtained with Prader-Willi syndrome (IPS)and Enzhelmena syndrome (SE), which, having substantially different clinical manifestations, basically have similar molecular cytogenetic changes.

Beckwith-Wiedemann (SBV) has been well studied in terms of imprinting as a syndrome having the following main features: macrosomia, macroglossia, umbilical hernia, increased susceptibility to tumors.

Communication genomic imprinting with other human genetic disorders on chromosomes or individual genes level also clearly apparent and is now widely studied.So, for example, Huntington's chorea and spinnomozzhechkovoy ataxia disease occurs earlier and is more severe if the genes are inherited paternal origin.In neurofibromatosis, myotonic dystrophy, on the contrary, the disease has an earlier onset and a heavy flow in the inheritance of the mutant gene from the mother.There is no doubt the involvement of genomic imprinting in the etiology of tumor growth.

In recent years, using molecular genetic techniques the phenomenon of genomic imprinting watch and multifactorial diseases.For example, a pronounced paternal imprinting found in atopic dermatitis, the mother - in bronchial asthma and atopy in children.In insulin-dependent diabetes mellitus revealed a higher probability of paternal imprinting.


above described methods of molecular genetics, which are used to identify the gene Mendelian hereditary human diseases, such techniques are part of the international program "Human Genome".Below are the main provisions of genetic engineering and the essence of the project "Human Genome".

In February 2001, simultaneously in two journals, "of Nature" and "Science", presented the results of the draft project of all, regardless of the human genome obtained from each other by an international consortium "Genomcheloveka" project and the private company "Celera", for which the projectthe human genome is a commercial enterprise.These publications, despite the incompleteness of the project, is a significant achievement across biology and medicine.

Recombinant DNA technology

Indeed, at the time of announcement of the program "Human Genome" formed a whole new trend in molecular genetics, which became known as "genetic engineering" or "recombinant DNA technology".The latter may be divided into two broad areas: DNA cloning techniques and DNA analysis methods, especially in the determination of the nucleotide sequence of the DNA molecule.

DNA Cloning

Cloning of DNA in vivo (in vivo) includes six steps:

1) obtaining DNA fragments including genes or parts thereof with a restriction enzyme;

2) recombination of fragments;

3) insertion of DNA fragments into a vector;

4) transformation with a vector of the host organism;

5) screening a recombinant vector;

6) selecting clones of interest to researchers.

notion of restriction enzymes

In each human chromosome, there is only one continuous strand of DNA.It is hard packed to fit into the chromosome.Manipulated DNA molecule of this length is practically impossible.Therefore, the opening of the 70-ies.XX century.specific bacterial enzymes cut the DNA into fragments, was very important.Enzymes were called restriction enzymes or endonucleases.In bacteria, these enzymes serve to protect against the penetration of foreign DNA into a cell.

Recombination of DNA fragments

Restriction enzymes cut both strands of DNA, which form as a result of either blunt or sticky ends.DNA from one organism specific restriction enzyme cut in well-defined locations, so this DNA after restriction (also called digestion) will always give the same set of fragments.If one type of restriction enzyme used to cut the DNA from different organisms, a set of fragments that would be different, but the sequence of nucleotides in the field of cutting all fragments will be the same and thus complementary to each other in the formation of fragments of the sticky ends.Recent called sticky because of complementarity they may combine with other fragments, formed by the same restriction enzyme or another restriction enzyme, the ends of the same generatrix.Combining fragments having complementary cohesive ends is accelerated and stabilized by a specific enzyme, which is called ligase.Thus, if a restriction enzyme to cut the DNA of two different types of fragments and mix, it may be formed entirely new, not existing in the natural environment of the recombinant DNA molecule.

order to interest researchers DNA fragment could be investigated, it must be propagated.This can be done by two different methods, moving it into a host cell and replicate it in vitro (in a test tube).

introduction of DNA fragments into a host cell using a vector

to move the DNA fragment into a host cell is typically used special designs, which are called vectors.The most frequently used as vectors in bacterial substances, bacteriophages, yeast and bacterial artificial chromosomes.It has recently been proposed to use as a human artificial chromosome vectors.

Create genomic libraries

Restriction fragments of genomic DNA and cloning fragments using different vectors created a basis for the formation of genomic libraries.For this purpose genomic DNA is cut or, say, a particular restriction enzyme digested and the resulting fragments cloned through various vectors which are used for recombinant DNA techniques.Genomic library should contain not only the genes, but all non-coding DNA, located between the genes.Since the restriction enzyme digestion produce incomplete, so that DNA fragments are formed with partially overlapping sequences of nucleotides.This facilitates subsequent recovery arrangement pattern of fragments in native DNA (DNA in vivo).Furthermore genomic libraries, cDNA libraries exist.

cloning DNA sequences using the polymerase chain reaction (PCR)

Furthermore the described method of cloning DNA sequences in vivo, there is also a method for in vitro cloning, called polymerase chain reaction (PCR).

prerequisite for PCR is the knowledge of the sequence of nucleotides that define cloned sequence.For the PCR must first synthesize a pair of so-called primers, which are short nucleotide sequences complementary to the sequences of the DNA fragment propagated.

After separation of the two strands of DNA fragment studied the reaction mixture was added substances which bind to corresponding complementary portions of these strands.This is followed by the separation of newly formed DNA strands using heat treatment.To the newly formed DNA strands again being finished fragment complementary strands using a DNA polymerase enzyme.

example can be repeated indefinitely or until exhaustion of free nucleotides in the reaction mixture, but usually 20-30 cycles is enough to obtain sufficient DNA fragment studied for any subsequent manipulation of this fragment.