The Strength and Timing of the Mitochondrial Bottleneck in Salmon Suggests a Conserved Mechanism in Vertebrates

Abstract

In most species mitochondrial DNA (mtDNA) is inherited maternally in an apparently clonal fashion, although how this is achieved remains uncertain. Population genetic studies show not only that individuals can harbor more than one type of mtDNA (heteroplasmy) but that heteroplasmy is common and widespread across a diversity of taxa. Females harboring a mixture of mtDNAs may transmit varying proportions of each mtDNA type (haplotype) to their offspring. However, mtDNA variants are also observed to segregate rapidly between generations despite the high mtDNA copy number in the oocyte, which suggests a genetic bottleneck acts during mtDNA transmission. Understanding the size and timing of this bottleneck is important for interpreting population genetic relationships and for predicting the inheritance of mtDNA based disease, but despite its importance the underlying mechanisms remain unclear. Empirical studies, restricted to mice, have shown that the mtDNA bottleneck could act either at embryogenesis, oogenesis or both. To investigate whether the size and timing of the mitochondrial bottleneck is conserved between distant vertebrates, we measured the genetic variance in mtDNA heteroplasmy at three developmental stages (female, ova and fry) in chinook salmon and applied a new mathematical model to estimate the number of segregating units (Ne) of the mitochondrial bottleneck between each stage. Using these data we estimate values for mtDNA Ne of 88.3 for oogenesis, and 80.3 for embryogenesis. Our results confirm the presence of a mitochondrial bottleneck in fish, and show that segregation of mtDNA variation is effectively complete by the end of oogenesis. Considering the extensive differences in reproductive physiology between fish and mammals, our results suggest the mechanism underlying the mtDNA bottleneck is conserved in these distant vertebrates both in terms of it magnitude and timing. This finding may lead to improvements in our understanding of mitochondrial disorders and population interpretations using mtDNA data.

Replication Errors Made During Oogenesis Lead to Detectable De Novo mtDNA Mutations in Zebrafish Oocytes with a Low mtDNA Copy Number

“…Most likely in humans, these pathogenic mutations are filtered out by mitophagy (Song et al 2014) or are at high levels not compatible with embryonic survival and remain unnoticed at low levels. Given the high sequence homology (72%; NCBI blast performed) between the mtDNA genome of zebrafish and humans and the high evolutionary conservation of the mtDNA bottleneck in animal species (Wolff et al 2011;Guo et al 2013;Otten and Smeets 2015;Otten et al 2016), our results indicate that the de novo risk might be similar among zebrafish and humans. Indeed, a study in 26 human oocytes (Jacobs et al 2007), seven oocytes (26.9%) were found to harbor de novo variants.…”

“…Furthermore, for all oocytes with one or more de novo mutation(s), we estimated the mtDNA copy number at which these mutations arose, based on their heteroplasmy levels. Given the high mtDNA sequence similarity between humans and zebrafish (Broughton et al 2001) and the conservation of the mtDNA bottleneck within the animal kingdom (Howell et al 1992;Cree et al 2008;Wolff et al 2011;Lee et al 2012), our findings have insinuations for the occurrence of de novo mtDNA disease in humans.…”

Paternal transmission of mitochondrial DNA as an integral part of mitochondrial inheritance in metapopulations of Drosophila simulans

“…We can only speculate why mechanisms to prevent paternal leakage fail in single pairs. If it was a purely stochastic phenomenon, then we would expect the distribution of affected individuals carrying paternal mtDNA to be even among all offspring and not pair specific (Bergstrom and Pritchard, 1998;Wolff et al, 2011). Pair specificity instead requires one or more mechanisms promoting maternal inheritance to fail in single pairs, allowing for the repeated occurrence among a pair's offspring.…”

Mitochondrial maintenance failure in aging and role of sexual dimorphism

“…Heteroplasmy has significant implications for aging, as studies in mouse show that the presence of more than one mitochondrial genotype can cause tissue-specific conflicts in metabolic regulation that result in deleterious phenotypes [98]. The female germ line has been confirmed to be acting as a selective sieve that reduces the transmission of non-optimal mitochondrial genomes in both Drosophila [108–110] and vertebrates, including mammals [11, 111, 112]. The data from Drosophila suggest that the mitochondria are being selected for their relative replication ability within the female germ line cells [108, 113].…”