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In the beginning of the 20th century, the experiments conducted by Thomas Hunt Morgan set the foundation for the creation of a new field in biology, namely the field of genetics as we know it today. Correlating the process of transferring a chromosome with the process of transferring characters from parental generations to their progeny, led to the discovery of many important phenomena that occur during the stages of meiosis, the most important of which, is possibly the existence of recombination events between homologous pairs of chromosomes. In this paper, bioinformatic tools and recombination datasets from genetic maps were utilized, in order to estimate the average distance between a recombination hotspot and its subsequent, along the genome. The first purpose of this research, was the validation of T. H Morgan's theory of recombination, as it was developed in 1911, with contemporary methods that were unavailable at the time. By combining data sets, recombination events have collec ...
In the beginning of the 20th century, the experiments conducted by Thomas Hunt Morgan set the foundation for the creation of a new field in biology, namely the field of genetics as we know it today. Correlating the process of transferring a chromosome with the process of transferring characters from parental generations to their progeny, led to the discovery of many important phenomena that occur during the stages of meiosis, the most important of which, is possibly the existence of recombination events between homologous pairs of chromosomes. In this paper, bioinformatic tools and recombination datasets from genetic maps were utilized, in order to estimate the average distance between a recombination hotspot and its subsequent, along the genome. The first purpose of this research, was the validation of T. H Morgan's theory of recombination, as it was developed in 1911, with contemporary methods that were unavailable at the time. By combining data sets, recombination events have collected from meioses and sex-specific genetic maps have constructed. It was shown that, a substantial fraction of the genome shows some degree of sexually-specific variated recombination frequency. More specificaly the vast majority of male hotspots are clustered in small genetic distances as long as the female hotspots are disturbuted uniformly along the chromosomes. Recombination is occurred in Holliday junctions (HJs) that constitute important intermediate structures for many cell functions such as DNA recombination and DNA repair. The second stage of the research was conducted in order to characterize Holliday junctions that derive from a 10-nt degenerate iverted repeat sequence, with a 3-nt core motif. Inverted repeats are present in abundance in both prokaryotic and eukaryotic genomes and can form DNA secondary structures – hairpins and cruciforms that are involved in many important biological processes such as DNA replication, DNA transition and DNA methylation. In this study, the human genome was explored whether the IRs-HJ degenerate sequence associates with transposable elements (TEs) and mainly with those of the active and inactive ALU, LINE, SVA and HERV families. Six different forms of the IRs-HJs sequence motif were identified, and located the genomic coordinates of sequences containing both IRs-HJs and TEs. From 2982 total HJs, a significant number of 1319 TE-associated HJs were found, with a median distribution of 1 per 2.4 Mb. The HJs with higher GC content were observed more frequently at the genome. A high percentage of HJs were associated with all main TE families, with specificity for particular active or inactive elements: DNA elements and the retroelements ALUs, LINEs and HERVs up to 41.94%, 72.72%, 42.94% and 84.5%, respectively. Phylogenetic analysis revealed that HJs occur in both active and inactive TEs. Furthermore, the TE-associated HJs were almost exclusively found within a distance less than 1 Mb from human genes, while only 23 were not associated with any genes. This is the first report associating human HJs, with mobile elements. These data pinpoint that particular HJ forms show preference for specific active retrotransposon families of ALUs and LINEs, suggesting that retrotransposon-incorporated HJs may relocate or replicate in the genome through retrotransposition, contributing to recombination, genome plasticity and DNA repair. The third stage of this research was conducted in order to characterize sequences that promote genomic instability through particular Microdeletion and Microduplication Syndromes (MMS). MMS are rare recombinations, but cumulatively they represent a significant group of genetic abnormalities almost equal to aneuploidies. Some of them and in particular Di George Microdeletion can be found in frequencies second only to trisomy 21. Based on our database of MMS it was found that almost all MMS span in length less than 5Mbs which is the cut-off point of resolution in standard cytogenetics. Furthermore, a significant percentage of them are in length less than 0.5Mbs and all together, short and long MMS, have a high probability to harbor TE-associated and non-TE associated HJs-IRs. More importantly, gene proximity bioinformatics analysis revealed that a significantly high number of MMS associated IRs are proximal to regions of genes that control key developmental processes and transcription factors in humans. Collectively, it is proposed that IRs and other recombination primers such as TEs that exist in regions spanning MMS hotspots underlie a possible mechanism for their occurrence during gametogenesis. The final stage of the research was conducted in order to discover variations of PRDM9 sequence motif (CCNCCNTNNCCNC) which are responsible for the generation of breast invasive carcinoma (BRC), head and neck squamous cell carcinoma (HN) as well as for lung adenocarcinoma (LUAD). The final results showed a preference for specific PRDM9 sequences that reside within the boundaries of Double Strand Breaks and are responsible for the generation of specific types of cancer after proving by bioinformatics analysis the statistical significance of each PRDM9 sequence variation inside the BRC, HN and LUAD. For the first time, an immediate correlation between the PRDM9 sequence motif d(CCACCATCACCAC) and the emergence of breast invasive carcinoma (BRC), lung adenocarcinoma (LUAD) and head and neck squamous cell carcinoma (HN) is proved.
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