Prioritizing psychological factors in young consumers' coffee brand preferences through a novel behavioral leadership fuzzy decision-making modelling.

Mitochondrial DNA (mtDNA) heteroplasmy arises when a cell or tissue contains a mixture of two or more different mtDNA alleles. Heteroplasmy dynamics tend to be complex, varying across generations, during development, in disease and with ageing. Historically, most studies of mtDNA heteroplasmy in humans have focused on rare, maternally transmitted disorders, which are typically driven by loss-of-function mtDNA mutations at high levels of heteroplasmy. However, there is growing evidence that low levels of mtDNA heteroplasmic variants are found in nearly all humans. Using biobank-scale genomics, we previously reported that nearly everyone harbours two different classes of such variants in blood. ‘Length heteroplasmies’ (insertion/deletion (indel) mutations within polypyrimidine tracts) do not accumulate with age, tend to be maternally transmitted and, once inherited, exhibit levels of heteroplasmy under nuclear genetic control. The associated nuclear DNA (nucDNA) loci tend to implicate mitochondria-localized proteins with established roles in mtDNA replication and maintenance. By contrast, heteroplasmic mtSNVs tend not to be inherited but rather seem to be somatic in origin and accumulate with age. The mechanism of this age-related accrual of heteroplasmic mtSNVs in blood is unknown. Classically, oxidative damage to mtDNA from reactive oxygen species has been invoked as a part of a ‘vicious cycle’ in which mtDNA mutations lead to further generation of reactive oxygen species and more mutations. More recent studies of ageing brains and tumour samples have questioned the role of oxidative damage in mutation generation. Once individual mutations arise, it is unclear how they become abundant enough to detect. Here we investigated why mtSNVs accumulate with age in blood. We report an analysis of mtDNA using a callset of approximately 750,000 individuals across the UK Biobank (UKB) and All of Us (AoU). We resolved the mutational spectrum of age-accumulating blood mtDNA and then performed a genome-wide association study (GWAS) for the burden of mtSNVs to identify mechanisms of control by rare and common germline nuclear genetic variants. Unexpectedly, the loci we identified were related not to mitochondrial homeostasis but rather to CH. Our analyses support a model in which individual blood cells randomly accumulate low levels of neutral mtDNA variation (that is, cryptic mutations), probably owing to replication-related errors, that are not detectable in bulk. However, with age-related expansion of individual cellular clones (by means of CH), these low-level cryptic variants become detectable and give rise to the observed accumulation with age.