Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother–child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ∼30–35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10−8 (interquartile range from 4.2 × 10−9 to 4.1 × 10−8) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome

Toward a phylogenetic chronology of ancient Gaulish, Celtic, and Indo-European

Indo-European is the largest and best-documented language family in the world, yet the reconstruction of the Indo-European tree, first proposed in 1863, has remained controversial. Complications may include ascertainment bias when choosing the linguistic data, and disregard for the wave model of 1872 when attempting to reconstruct the tree. Essentially analogous problems were solved in evolutionary genetics by DNA sequencing and phylogenetic network methods, respectively. We now adapt these tools to linguistics, and analyze Indo-European language data, focusing on Celtic and in particular on the ancient Celtic language of Gaul (modern France), by using bilingual Gaulish–Latin inscriptions. Our phylogenetic network reveals an early split of Celtic within Indo-European. Interestingly, the next branching event separates Gaulish (Continental Celtic) from the British (Insular Celtic) languages, with Insular Celtic subsequently splitting into Brythonic (Welsh, Breton) and Goidelic (Irish and Scottish Gaelic). Taken together, the network thus suggests that the Celtic language arrived in the British Isles as a single wave (and then differentiated locally), rather than in the traditional two-wave scenario (“P-Celtic” to Britain and “Q-Celtic” to Ireland). The phylogenetic network furthermore permits the estimation of time in analogy to genetics, and we obtain tentative dates for Indo-European at 8100 BC ± 1,900 years, and for the arrival of Celtic in Britain at 3200 BC ± 1,500 years. The phylogenetic method is easily executed by hand and promises to be an informative approach for many problems in historical linguistics

Natural radioactivity and human mitochondrial DNA mutations

Radioactivity is known to induce tumors, chromosome lesions, and minisatellite length mutations, but its effects on the DNA sequence have not previously been studied. A coastal peninsula in Kerala (India) contains the world's highest level of natural radioactivity in a densely populated area, offering an opportunity to characterize radiation-associated DNA mutations. We sampled 248 pedigrees (988 individuals) in the high-radiation peninsula and in nearby low-radiation islands as a control population. We sequenced their mtDNA, and found that the pedigrees living in the high-radiation area have significantly (P < 0.01) increased germ-line point mutations between mothers and their offspring. In each mutation case, we confirmed maternity by autosomal profiling. Strikingly, the radioactive conditions accelerate mutations at nucleotide positions that have been evolutionary hot spots for at least 60,000 years