Pedigree derived mutation rate across the entire mitochondrial genome of the Norfolk Island population

Abstract

Estimates of mutation rates for various regions of the human mitochondrial genome (mtGenome) vary widely, depending on whether they are inferred using a phylogenetic approach or obtained directly from pedigrees. Traditionally, only the control region, or small portions of the coding region have been targeted for analysis due to the cost and effort required to produce whole mtGenome Sanger profiles. Here, we report one of the first pedigree derived mutation rates for the entire human mtGenome. The entire mtGenome from 225 individuals originating from Norfolk Island was analysed to estimate the pedigree derived mutation rate and compared against published mutation rates. These individuals were from 45 maternal lineages spanning 345 generational events. Mutation rates for various portions of the mtGenome were calculated. Nine mutations (including two transitions and seven cases of heteroplasmy) were observed, resulting in a rate of 0.058 mutations/site/million years (95% CI 0.031–0.108). These mutation rates are approximately 16 times higher than estimates derived from phylogenetic analysis with heteroplasmy detected in 13 samples (n = 225, 5.8% individuals). Providing one of the first pedigree derived estimates for the entire mtGenome, this study provides a better understanding of human mtGenome evolution and has relevance to many research fields, including medicine, anthropology and forensics.

New Canary Islands Roman mediated settlement hypothesis deduced from coalescence ages of curated maternal indigenous lineages

“…For shallow phylogenetic trees that concur with the time frame studied here, an alternative evolutionary rate of one mutation every 1400 years was proposed 14 which have been used in the present study. Notably, this predicted fast evolutionary rate for recent times has been empirically corroborated recently by an extended pedigree analysis, using the entire mtDNA genome, obtaining a mutation rate of 5.8 × 10 −8 (95% CI 3.10–10.8 × 10 –8 ) mutation/site/year that nicely overlaps with the one used here of 4.33 × 10 –8 (95% CI 3.90–4.82 × 10 –8 ) mutation/site/year 39 . Applying this evolutionary rate to the phylogenetic trees (Figs.…”

Evaluating the suitability of current mitochondrial DNA interpretation guidelines for multigenerational whole mitochondrial genome comparisons

“…Additional samples were unavailable for this research with a conservative minor allele frequency (MAF) of >20% utilized to reduce incorrect heteroplasmy calls. Heteroplasmy was determined as described in Connell et al [28], using the MAF, the peak height in electropherograms, and the reproducibility of peaks.…”

“…Base differences and heteroplasmy (excluding hypervariable region C‐stretches) observed between maternal pairs were confirmed using SS via the BigDye Terminator v3.1 Cycle Sequencing Kit on the 3500 Genetic Analyzer (Thermo fisher Scientific). Methods and primers used for SS were described previously [28]. Sanger sequencing primers are outlined in Table S1.…”

“…The sample information for this research was described previously [28]. Individuals chosen for this research were included in the NI Health Study and the associated NI core pedigree for research investigations at Queensland University of Technology.…”

“…Using the NI core pedigree, individual maternal pedigrees were constructed by establishing a list of founding mothers and tracing their maternal line. Pedigree construction and analysis has been described previously [28]. In total, 45 pedigrees (families) were chosen (Figure S1B).…”