High Informativeness of Molecular-Biological Markers
About the author:
Kharchenko A. V.
Type of article:
Relative saturation of genomes with any mictosatellite sequences is the result of influence of many factors, which all in all determine composite, structural and thermodynamic features of genomic mictosatellite sequences. Mictosatellites may be formed in two ways. One of the resources of evolution of simple repeats in eukaryotes is poly (A)-tracks. The latter are located at the 3’ends of such mobile elements. The second potential possibility of formation of mictosatellite sequences consists in replicative extension or shortening of protomicrosatellites, which can be formed in the genome due to mutative events. Such mictosatellites must have minimal number of repeats (3-5) to change its length due to formation of bulges during the transcription. Generally, the number of long mictosatellite repeats is not big. Only 12 % of all mictosatellites in human genome, for example, have more than 40 nucleotides. But there is a possibility of transformation of single mictosatellite repeat into composite one, consisting of two sequences with different replicable motives. This may occur due to mutations in one of the repeats and its duplica- tion due to replication errors. Mictosatellites can be presented in the genome everywhere, both in noncoding and coding sequences, affecting transcriptional activity. Polymorphism of mictosatellites can be identified by their morphological characteristics. The difference in the degree of polymorphism between various mictosatellites may depend first on the length of mictosatellite sequence itself. The majority of mictosatellite mutations are associated with insertions or deletions of specific repeats, emerging during replication. Such disorder of stability of mictosatellites more often occurs due to formation of bulges on DNA during replication (“slippage”). Intensive extension of mictosatellite sequences due to replication errors is called mictosatellite expansion. The ability of repeats to expansion depends on the length of mictosatellite sequence. The relations between mutative events, leading to expansion of mictosatellite sequences due to addition of a repeat, correlates with number of mutations, which lead to reduction of repeats in human mictosatellites as 10:4. In some of mictosatellite repeats the replication errors are mostly associated with 3’-end: (GA)n and (CA)n, and in another ones with 5’-end – (CG)n and (CT)n. In trinucleotide GC-multiple repeats the proximal 3’-end, relative to the direction of replication, has positive impact on the frequency of replicative error. Despite the fact that a bulge at the 3’-end originates during each replicative tour, this error 99 % is corrected by the system of reparation. Change in length of mictosatellite sequence is occurred once per 100 replications. Among trinucleotide repeats these properties are ultimately presented by GC-multiple repeats, too, such as (CAG)n, (CTG)n, (GGC)n and (GCC)n. The pattern and regularities of distribution of these trinucleotide microsatel- lites in the genome is of special interest due to the role they play in the development of oncologic diseases. Cur- rently, they are the most examined mictosatellite sequences. They are assigned to the number of most expressed in the coding regions of human genome. Likewise, instability of dinucleotide mictosatellites is connected with development of certain oncologic disease. Replicative errors in dinucleotide repeats are more often related to deletions, which lead to reading frame shifting. Study of the mechanisms, which lead to mutative events in mictosatellite sequences, showed that these events, both in normal and malignant cells, are based on the same mechanisms. Number of point mutations is confirmed in the mictosatellite DNA at one level, regardless of its characteris- tics. But in mictosatellites themselves, there are zones where such mutations emerge more often. There are three mechanisms, producing mutations in these sequences: insertion, deletion, replacement and disorder of replicable motive. Polymorphism of mictosatellites can be identified by their localization and orientation in genome. The secondary structure of DNA is currently viewed as the cause of expansion of mictosatellite sequences. The secondary struc- ture of DNA itself is the derivative of thermodynamic characteristics of its sequence. The secondary bulge-type structures in mictosatellite sequences, identified by their thermodynamic character- istics, can initiate the phenomenon of expansion of mictosatellite repeats. The more stable these bulges, the lower is the risk of formation of new mictosatellite repeats. CAG/CTG and GAC/GTC- triduplex sequences have equal number of hydrogen couplings, but are distinguished by the strength of dense relationships. This is enough to make the first of them more vulnerable for expansion of mictosatellite repeats. Stability of bulge increases in the follow- ing direction: GTC < CAG < GAC < CTG, on the contrary, the frequency of formation of new repeats decreases in the similar direction: GTC > CAG > GAC > CTG. Calculations of thermodynamic characteristics of replicable sequences allow developing number of model sys- tems, evaluating the ability of mictosatellite sequences to influence the DNA modifications, forming various sec- ondary structures, related to phenomenon of expansion of mictosatellite repeats. Types of markers, obtained as a result of PCR, are divided into two groups on the basis of primers’ design: the first group is known as STSs (sequence-tagged sites) with primers, constructed from known sequences, and the second one is based on the random primers. The most informative or polymorphic STS-marker emerges during amplification of DNA-area, containing sequences of mictosatellite repeats. This marker is based on STS, and is marked as simple-sequence length polymorphism (SSLP) or sequence-tagged microsatellite site (STMS). Each STMS-marker detects inherited Mendelian codominant alleles in single locus in genome.
mictosatellite sequences, mictosatellite expansions, replication errors, mictosatellite instability, PCR-based markers
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Publication of the article:
«Bulletin of problems biology and medicine» Issue 3 part 3 (112), 2014 year, 11-16 pages, index UDK 616 – 006. 6 : 577. 2