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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
Background levels of mutation arise from normal cellular and environmental interactions. Mutation rates also reflect the fidelity of DNA replication and its proofreading and/or correction potential. Trinucleotide repeats are known to be particularly unstable and are associated with a range of genetic diseases including Huntington's chorea, myotonic dystrophy and fragile X syndrome. Disease severity is usually proportional to the increase in repeat length.
Cancer and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Tormod S. Nilsen, Pernille Hojman, Henning Wackerhage
The tissue-specific mutation rate can be increased further by exposure to environmental factors such as tobacco smoke or sunlight. Environmental factors (e.g. carcinogens and mutagens), inheritance or cell division, i.e. the doubling of DNA, can cause mutations that include cancer driver gene mutations. In a follow-up analysis, the same research group tried to quantify the contribution of environmental factors, inheritance and replication to mutations and cancer frequency. They concluded that mutations that occur during cell division account for two-thirds of the mutations in human cancer (12). Different mutations leave different mutational signatures, which are patterns of how the cancer-causing agent is changing the DNA (13). For example, the mutagens in tobacco smoke typically cause C-to-A mutations which are detectable in tissues exposed to tobacco smoke such as the lung.
Colon cancer: pathology and natural history
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
These traditional tumor suppressors are joined by an increasing number of susceptibility genes that indirectly suppress neoplasia. The prototypes for this class of genes encode DNA repair proteins that act as ‘caretakers’ of the genome (Figure 2). Inactivation of a caretaker gene results in a greatly increased mutation rate and is equivalent to a constant exposure to mutagens. These indirectly acting genes are not required for neoplasia. In fact, most non-hereditary (sporadic) tumors will evolve without them.
The human antibody sequence space and structural design of the V, J regions, and CDRH3 with Rosetta
Published in mAbs, 2022
Samuel Schmitz, Emily A. Schmitz, James E. Crowe, Jens Meiler
Rosetta restraints must be carefully balanced to not overshadow the scoring terms that evaluate the thermodynamic stability of the protein. To estimate the effect on the protein’s stability and the binding of the antibody to its antigen, Rosetta decoys created with HL restraints were compared to decoys without HL restraints (control). To ensure that the difference in the number of mutations between control and designs did not affect the results, decoys were also compared to control designs with a similar number of mutations. Each Rosetta HL design was assigned one control design that matched the V and J sequence identity the closest, and another control design that matched the sequence identity of the CDRH3 region the closest. We refer to this set of control sequences with matching sequence identity as “native group”. The native group is assigned to both, the CDRH3 and the combined V/J regions separately. We ensured that a control design with a similar number of mutations exists by limiting the number of mutations with a separate Rosetta design run using the FavorNativeResidue function, using the weights of 1.0, 1.5, 2.0, and 2.5. The native group is used as a reference to calculate the difference of HL between designs, and the next closest control design with a similar number of mutations. Supplementary Figure 1 demonstrates the close correlation of sequence identities between native, and human-like designs. Thus, for each Rosetta design, a control design that was generated by limiting the mutation rate can be found with a comparable mutation rate.
Recent advances in delivering RNA-based therapeutics to mitochondria
Published in Expert Opinion on Biological Therapy, 2022
Yuma Yamada, Sen Ishizuka, Manae Arai, Minako Maruyama, Hideyoshi Harashima
Through various investigations, we succeeded in preparing an rRNA-MITO-Porter encapsulating wild-type rRNA (12S) for use as a therapeutic RNA. The rRNA-MITO-Porter was added to A1555G mutant cells and the mutation rate of rRNA (12S) was quantified. The results showed that a significant reduction in the mutation rate was observed. We also observed the rRNA-MITO-Porter treatment resulted in an increase in mitochondrial respiratory capacity (Figure 3(b)) [56]. Single-dose treatment of rRNA-MITO-Porter resulted in a decrease in the rRNA mutation rate, which increased again at 72 hr post-treatment [56]. Therefore, multiple doses of rRNA-MITO-Porter were administered at 24 hr intervals up to 72 hr after the first dose and the mutation rates were then evaluated. As a result, the rRNA mutation rate decreased significantly and this decrease was proportional to the number of doses administered during the 72-hour period (Figure 3(c)), confirming that low mutation rates could be maintained by dosing at 24 hr intervals.
Mutational analysis of 16 STR markers in the Slovak population
Published in Annals of Human Biology, 2022
Zdenko Červenák, Filip Červenák, Marian Baldovič, Andrea Patlevičová, Soňa Masnicová
Moreover, several studies revealed that the mutation rate of a particular marker, as well as its individual alleles, varies from population to population (Sun et al. 2014; Shao et al. 2016). Therefore, we compared the mutation rates present in our study with mutation rates from seven other populations (Henke and Henke 2006; Hohoff et al. 2006; Martinez et al. 2017; Wang et al. 2017; Droździok et al. 2018; Qu et al. 2019; Xu et al. 2019). As a result, three significant differences were identified, two in comparison with Upper Silesia (vWA and D8S1179), and one in comparison with the Guangdong Han population (D8S1179). These differences are most likely due to different overall numbers of meiotic transfers collected, however different allelic structures of the markers may also play a role as the vWA STR marker encompasses alleles with identical physical length, but with a different number of the longest run of perfect repeats (LRPRs) (STRbase database, https://strbase.nist.gov). Therefore, it might be possible that different variants of the same allele are presented in geographically distant regions, thus leading to the different mutational rates of the same marker.