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The mutations fall in clusters.

Out of the 14 analysed mutations, 10 involves charged residues and of these charged mutations all the HCM type mutations fall in section 2 (Fig. 5) and all DCM mutations fall in section 1 of the Tm quasi-repeat.

Overall, KRS mutations appear to affect structural stability of the enzyme leading to CMT and therefore these mutations fall in category (b) and (d).

For each pair, two positions each with a mixture of two or more mutations were excluded from the covariation analysis, since it is impossible to discriminate whether these mutations fall in the same viral genome.

Overall, the results of this analysis showed that even if all the mutations fall in ESE sites predicted from either ESEfinder, or RescueESE or PESX, less than half of them led to splicing alterations.

The splicing analysis we have performed suggests that the ESEs predicted by these algorithms are likely to act as real enhancer when mutations fall in short loosely defined exons that are more frequently expected to contain sequences promoting exon inclusion in the mature transcript.

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Subsequently, we searched for groups of singleton mutations falling in specific mtDNA regions that may increase the susceptibility to AD.

We verified the significance of this finding by comparing the number of the tRNA+rRNA mutations with the number of mutations falling in the remaining of coding region (43 in AD patients and 37 in controls).

In particular we focused on singleton mutations falling in tRNA and rRNA genes, considering that previous studies have shown that mutations in these genes, including the transition at np 4336 (tRNAGln) and the G3196A mutation (16S rRNA), may be associated with AD [24], [42].

Using the same restriction analysis strategy as described above for the brain subparts, we observed that the duodenum mucosal layer is highly susceptible to no-change mutation accumulation (Figure 7A) with only a small fraction of the mutations falling in the size-change class.

All the mutations falling in positions within the sr1, sr2, sr3, and srX domains have been represented in Supp.

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