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Consequently, the comparisons between diametrically different mutational loads in humans and mice have meaningful biologic rationale.

The mechanisms underpinning these associations remain unclear, but could include additional mutational loads in the germ line of older fathers [33], [34], [35] and/or epigenetic changes in the sperm of older fathers [36], [37].

In prokaryotes, Hsp60 (GroEL) is essential to organismal fitness under high mutational loads in Escherichia coli (Fares et al. 2002; Maisnier-Patin et al. 2005) and in Buchnera aphidicola (Moran 1996).

The quantification of the m.3890G>A/MT-ND1 mutation load by ARMS qPCR in different tissues showed that it was almost homoplasmic in the skeletal muscle and heteroplasmic, with different mutational loads, in blood cells and urinary epithelium (Fig. 3A).

We evaluated the clonal IGHV segments between functionally defined regions of the IGHV genes: the highly conserved framework regions (FR1-3) which flank the hypermutated complementarity determining regions (CDR1-2) [ 37] for four FL specimens that express varying levels of mutational loads in their total IGHV sequence (10.3 to 17.9% variation).

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Redfield [ 19] modelled the effect of elevated male mutation rates on the mutational load in infinite sexual populations and compared the results with those from infinite diploid asexual populations.

Furthermore, examination of the mutational load in this strain, which was generated as part of the Million Mutation Project (Thompson et al. 2013), revealed no obvious strong loss-of-function mutations in genes known to influence aging or RNAi (Table S19).

The higher mutational load in MSI-H CRC can elicit an endogenous immune anti-tumor response, counterbalanced by the expression of immune inhibitory signals, such as PD-1 or PD-L1, that resist tumor elimination.

Although it has been evidenced that genome editing techniques have minimal impacts on genomic mutational load in human pluripotent stem cells using whole-genome sequencing (Smith et al., 2014; Suzuki et al., 2014; Veres et al., 2014; Yang et al., 2014), the safety issue of gene editing in germ line cells still deserves extreme cautions as such changes are permanent and heritable.

Therefore programmed cell death in N. vectensis gametes may act as a safeguard mechanism against too high mutational load in the germ line.

There seems to be an upper boundary for the mutational load in cancer.

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