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Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing.

ABSTRACT: The role that mtDNA heteroplasmy plays in healthy aging, familial longevity and the heritability patterns of low levels heteroplasmy in the elderly are largely unknown. We analyzed the low levels of mtDNA heteroplasmy in blood in a cohort of centenarians, their offspring and a group of offspring of non long?lived parents, characterized by a less favorable health phenotype. The aims of this study are to: (i) investigate the transmission of low level heteroplasmies in the elderly; (ii) explore the association of heteroplasmy with age and longevity and (iii) investigate heteroplasmy patterns in these three groups. We sequenced a 853 bp mtDNA fragment in 88 individuals to an average coverage of 49334?fold, using quality control filtering and triplicate PCR analysis to reduce any methodological bias, and we detected 119 heteroplasmic positions with a minor allele frequency?0.2%. The results indicate that low?level heteroplasmies are transmitted and maintained within families until extreme age. We did not find any heteroplasmic variant associated with longevity and healthy aging but we identified an unique heteroplasmy profile for each family, based on total level and positions. This familial profile suggests that heteroplasmy may contribute to familial longevity.

SUBMITTER: Giuliani C

PROVIDER: S-EPMC4100808 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing.

Giuliani Cristina C Barbieri Chiara C Li Mingkun M Bucci Laura L Monti Daniela D Passarino Giuseppe G Luiselli Donata D Franceschi Claudio C Stoneking Mark M Garagnani Paolo P

Aging 20140601 6

The role that mtDNA heteroplasmy plays in healthy aging, familial longevity and the heritability patterns of low levels heteroplasmy in the elderly are largely unknown. We analyzed the low levels of mtDNA heteroplasmy in blood in a cohort of centenarians, their offspring and a group of offspring of non long‐lived parents, characterized by a less favorable health phenotype. The aims of this study are to: (i) investigate the transmission of low level heteroplasmies in the elderly; (ii) explore the ...[more]

PMID: 25013208

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Project description:We used ultra-deep sequencing to obtain tens of thousands of HIV-1 sequences from regions targeted by CD8+ T lymphocytes from longitudinal samples from three acutely infected subjects, and modeled viral evolution during the critical first weeks of infection. Previous studies suggested that a single virus established productive infection, but these conclusions were tempered because of limited sampling; now, we have greatly increased our confidence in this observation through modeling the observed earliest sample diversity based on vastly more extensive sampling. Conventional sequencing of HIV-1 from acute/early infection has shown different patterns of escape at different epitopes; we investigated the earliest escapes in exquisite detail. Over 3-6 weeks, ultradeep sequencing revealed that the virus explored an extraordinary array of potential escape routes in the process of evading the earliest CD8 T-lymphocyte responses--using 454 sequencing, we identified over 50 variant forms of each targeted epitope during early immune escape, while only 2-7 variants were detected in the same samples via conventional sequencing. In contrast to the diversity seen within epitopes, non-epitope regions, including the Envelope V3 region, which was sequenced as a control in each subject, displayed very low levels of variation. In early infection, in the regions sequenced, the consensus forms did not have a fitness advantage large enough to trigger reversion to consensus amino acids in the absence of immune pressure. In one subject, a genetic bottleneck was observed, with extensive diversity at the second time point narrowing to two dominant escape forms by the third time point, all within two months of infection. Traces of immune escape were observed in the earliest samples, suggesting that immune pressure is present and effective earlier than previously reported; quantifying the loss rate of the founder virus suggests a direct role for CD8 T-lymphocyte responses in viral containment after peak viremia. Dramatic shifts in the frequencies of epitope variants during the first weeks of infection revealed a complex interplay between viral fitness and immune escape.

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Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing.

Publications

Transmission from centenarians to their offspring of mtDNA heteroplasmy revealed by ultra-deep sequencing.

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