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Results for “Evolutionary Biology”

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bioRxiv2015

Phylogenomic Reconstruction Supports Supercontinent Origins for Leishmania

Leishmania, a genus of parasites transmitted to human hosts and mammalian/reptilian reservoirs by an insect vector, is the causative agent of the human disease complex leishmaniasis. The evolutionary relationships within the genus Leishmania and its origins are the source of ongoing debate, reflected in conflicting phylogenetic and biogeographic reconstructions. This study employs a recently described bioinformatics method, SISRS, to identify over 200,000 informative sites across the genome from newly sequenced and publicly available Leishmania data. This dataset is used to reconstruct the evolutionary relationships of this genus. Additionally, we constructed a large multi-gene dataset; we used this dataset to reconstruct the phylogeny and estimate divergence dates for species. We conclude that the genus Leishmania evolved at least 90-100 million years ago. Our results support the hypothesis that Leishmania clades separated prior to, and during, the breakup of Gondwana. Additionally, we confirm that reptile-infecting Leishmania are derived from mammalian forms, and that the species that infect porcupines and sloths form a clade long separated from other species. We also firmly place the guinea-pig infecting species, L. enrietti, the globally dispersed L. siamensis, and the newly identified Australia species from kangaroos as sibling species whose distribution arises from the ancient connection between Australia, Antarctica, and South America.

Evolutionary Biology↗

bioRxiv2015

Gene Regulatory Evolution During Speciation in a Songbird

Over the last decade tremendous progress has been made towards a comparative understanding of gene regulatory evolution. However, we know little about how gene regulation evolves in birds, and how divergent genomes interact in their hybrids. Because of unique features of birds - female heterogamety, a highly conserved karyotype, and the slow evolution of reproductive incompatibilities - an understanding of regulatory evolution in birds is critical to a comprehensive understanding of regulatory evolution and its implications for speciation. Using a novel complement of analyses of replicated RNA-seq libraries, we demonstrate abundant divergence in gene expression between subspecies of zebra finches Taeniopygia guttata. By comparing parental populations and their F1 hybrids, we also show that gene misexpression is relatively rare, a pattern that may partially explain the slow buildup of postzygotic reproductive isolation observed in birds relative to other taxa. Although we expected that the action of genetic drift on the island-dwelling zebra finch subspecies would be manifested in a high rate of trans regulatory divergence, we found that most divergence was in cis regulation, following a pattern commonly observed in other taxa. Thus our study highlights both unique and shared features of avian regulatory evolution.

Evolutionary Biology↗

bioRxiv2015

Sex and Ageing: The Role of Sexual Recombination in Longevity

1I use a set of machines based on the concept of nested rule systems built on the a modified version of the Wolfram elemental cellular automata to investigate the role of recombination in providing resistance to ageing. Class III and class IV machines are observed to respond differently to recombination. Class IV machines show recombinational centring in their neutral networks whereas class III machines respond negatively to recombination. Rule 110 shows a unusual response to recombination. Recombination selects for resistance to recombination, the population moves to regions of genome space with high redundancy, this results in organisms with highly robust genomes, more likely to complete development and to be long lived. The increase in longevity may be sufficient to compensate for the costs of sex, including the two fold cost of sex, through increased reproductive potential in long lived organisms requiring long maturation times. Large complex species should therefore be resistant to invasion by asexual mutants whereas small simple organisms with early maturation should be vulnerable to invasion by asexual forms.

Evolutionary Biology↗

bioRxiv2015

Dissecting the genetic basis of a complex cis-regulatory adaptation

Although single genes underlying several evolutionary adaptations have been identified, the genetic basis of complex, polygenic adaptations has been far more challenging to pinpoint. Here we report that the budding yeast Saccharomyces paradoxus has recently evolved resistance to citrinin, a naturally occurring mycotoxin. Applying a genome-wide test for selection on cis-regulation, we identified five genes involved in the citrinin response that are constitutively up-regulated in S. paradoxus. Four of these genes are necessary for resistance, and are also sufficient to increase the resistance of a sensitive strain when over-expressed. Moreover, cis-regulatory divergence in the promoters of these genes contributes to resistance, while exacting a cost in the absence of citrinin. Our results demonstrate how the subtle effects of individual regulatory elements can be combined, via natural selection, into a complex adaptation. Our approach can be applied to dissect the genetic basis of polygenic adaptations in a wide range of species.\n\nAuthor SummaryAdaptation via natural selection has been a subject of great interest for well over a century, yet we still have little understanding of its molecular basis. What are the genetic changes that are actually being selected? While single genes underlying several adaptations have been identified, the genetic basis of complex, polygenic adaptations has been far more challenging to pinpoint. The complex trait that we study here is the resistance of Saccharomyces yeast to a mycotoxin called citrinin, which is produced by many other species of fungi, and is a common food contaminant for both humans and livestock. We found that sequence changes in the promoters of at least three genes have contributed to citrinin resistance, by up-regulating their transcription even in the absence of citrinin. Higher expression of these genes confers a fitness advantage in the presence of citrinin, while exacting a cost in its absence-- a fitness tradeoff. Our results provide a detailed view of a complex adaptation, and our approach can be applied to polygenic adaptations in a wide range of species.

Evolutionary Biology↗

bioRxiv2015

Disruption of endosperm development is a major cause of hybrid seed inviability between Mimulus guttatus and M. nudatus

O_LIDivergence of developmental mechanisms within populations may lead to hybrid developmental failure, and may be a factor driving speciation in angiosperms.\nC_LIO_LIWe investigate patterns of endosperm and embryo development in Mimulus guttatus and the closely related, serpentine endemic M. nudatus, and compare them to those of reciprocal hybrid seed. We address whether disruption in hybrid seed development is the primary source of reproductive isolation between these sympatric taxa.\nC_LIO_LIM. guttatus and M. nudatus differ in the pattern and timing of endosperm and embryo development. Some hybrid seed exhibit early disruption of endosperm development and are completely inviable, while others develop relatively normally at first, but later exhibit impaired endosperm proliferation and low germination success. These developmental patterns are reflected in mature hybrid seed, which are either small and flat (indicating little to no endosperm), or shriveled (indicating reduced endosperm volume). Hybrid seed inviability forms a potent reproductive barrier between M. guttatus and M. nudatus.\nC_LIO_LIWe shed light on the extent of developmental variation between closely related species within the M. guttatus species complex, an important ecological model system, and provide a partial mechanism for the hybrid barrier between M. guttatus and M. nudatus.\nC_LI

Evolutionary Biology↗

bioRxiv2015

Evolution of increased larval competitive ability in Drosophila melanogaster without increased larval feeding rate

Multiple experimental evolution studies on D. melanogaster in the 1980s and 1990s indicated that enhanced competitive ability evolved primarily through increased larval tolerance to nitrogenous wastes and increased larval feeding and foraging rate, at the cost of efficiency of food conversion to biomass, and this became the widely accepted view of how adaptation to larval crowding evolves in fruitflies. We recently showed that populations of D. ananassae and D. n. nasuta subjected to extreme larval crowding evolved greater competitive ability without evolving higher feeding rates, primarily through a combination of reduced larval duration, faster attainment of minimum critical size for pupation, greater efficiency of food conversion to biomass, increased pupation height and, perhaps, greater urea/ammonia tolerance. This was a very different suite of traits than that seen to evolve under similar selection in D. melanogaster and was closer to the expectations from the theory of K-selection. At that time, we suggested two possible reasons for the differences in the phenotypic correlates of greater competitive ability seen in the studies with D. melanogaster and the other two species. First, that D. ananassae and D. n. nasuta had a very different genetic architecture of traits affecting competitive ability compared to the long-term, laboratory populations of D. melanogaster used in the earlier studies, either because the populations of the former two species were relatively recently wild-caught, or by virtue of being different species. Second, that the different evolutionary trajectories in D. ananassae and D. n. nasuta versus D. melanogaster were a reflection of differences in the manner in which larval crowding was imposed in the two sets of selection experiments. The D. melanogaster studies used a higher absolute density of eggs per unit volume of food, and a substantially larger total volume of food, than the studies on D. ananassae and D. n. nasuta. Here, we show that long-term laboratory populations of D. melanogaster, descended from some of the populations used in the earlier studies, evolve essentially the same set of traits as the D. ananassae and D. n. nasuta crowding-adapted populations when subjected to a similar larval density at low absolute volumes of food. As in the case of D. ananassae and D. n. nasuta, and in stark contrast to earlier studies with D. melanogaster, these crowding-adapted populations of D. melanogaster did not evolve greater larval feeding rates as a correlate of increased competitive ability. The present results clearly suggest that the suite of phenotypes through which the evolution of greater competitive ability is achieved in fruitflies depends critically not just on larval density per unit volume of food, but also on the total amount of food available in the culture vials. We discuss these results in the context of an hypothesis about how larval density and the height of the food column in culture vials might interact to alter the fitness costs and benefits of increased larval feeding rates, thus resulting in different routes to the evolution of greater competitive ability, depending on the details of exactly how the larval crowding was implemented.

Evolutionary Biology↗

bioRxiv2015

Viruses are a dominant driver of protein adaptation in mammals

Viruses interact with hundreds to thousands of proteins in mammals, yet adaptation against viruses has only been studied in a few proteins specialized in antiviral defense. Whether adaptation to viruses typically involves only specialized antiviral proteins or affects a broad array of proteins is unknown. Here, we analyze adaptation in ~1,300 virus-interacting proteins manually curated from a set of 9,900 proteins conserved across mammals. We show that viruses (i) use the more evolutionarily constrained proteins from the cellular functions they hijack and that (ii) despite this high constraint, virus-interacting proteins account for a high proportion of all protein adaptation in humans and other mammals. Adaptation is elevated in virus-interacting proteins across all functional categories, including both immune and non-immune functions. Our results demonstrate that viruses are one of the most dominant drivers of evolutionary change across mammalian and human proteomes.

Evolutionary Biology↗

bioRxiv2015

Enhancement of larval immune system traits as a correlated response to selection for rapid development in Drosophila melanogaster

We have shown earlier that the evolution of rapid development is accompanied by a correlated decrease in larval feeding rate and competitive ability in laboratory populations of Drosophila melanogaster (Prasad et al. 2001; Shakarad et al. 2005). Here, we show that our faster developing populations have evolved higher hemocyte density and phenol oxidase activity in the larval hemolymph. The increased hemocyte density could be responsible for the evolution of decreased feeding rate as hemocytes and the cephalopharyngeal musculature share common embryonic precursor cells (Kraajiveld et al. 2001). We also show that the bacterial load in larval food vials of the faster developing populations is substantially higher than in controls. Our results suggest that the evolution of reduced competitive ability in the faster developing populations is probably due to larval feeding rate trading off with enhanced larval immune system function. Enhanced larval immune function, in turn, is most likely selected for due to the role of hemocytes (Lanot et al. 2001, Wood and Jacinto 2007) and phenol oxidase (Pentz et al. 1986) in development, and perhaps also due to inadvertent selection on immune performance resulting from the higher bacterial load faced by larvae in the faster developing populations.

Evolutionary Biology↗

bioRxiv2015

Modes of migration and multilevel selection in evolutionary multiplayer games

The evolution of cooperation in group-structured populations has received much attention, but little is known about the effects of different modes of migration of individuals between groups. Here, we have incorporated four different modes of migration that differ in the degree of coordination among the individuals. For each mode of migration, we identify the set of multiplayer games in which the cooperative strategy has higher fixation probability than defection. The comparison shows that the set of games under which cooperation may evolve generally expands depending upon the degree of coordination among the migrating individuals. Weak altruism can evolve under all modes of individual migration, provided that the benefit to cost ratio is high enough. Strong altruism, however, evolves only if the mode of migration involves coordination of individual actions. Depending upon the migration frequency and degree of coordination among individuals, conditions that allow selection to work at the level of groups can be established.

Evolutionary Biology↗

bioRxiv2015

Inferring the correlated fitness effects of nonsynonymous mutations at the same site using triallelic population genomics

The distribution of mutation fitness effects is central to evolutionary genetics. Typical univariate distributions, however, cannot model the effects of multiple mutations at the same site, so we introduce a model in which mutations at the same site have correlated fitness effects. To infer the strength of that correlation, we developed a diffusion approximation to the triallelic frequency spectrum, which we applied to data from D. melanogaster. We found a moderate correlation between the fitness effects of nonsynonymous mutations at the same codon, suggesting that both mutation identity and location are important for determining fitness effects in proteins. We validated our approach by comparing with biochemical mutational scanning experiments, finding strong quantitative agreement, even between different organisms. We also found that the correlation of mutation fitness effects was not affected by protein solvent exposure or structural disorder. Together, our results suggest that the correlation of fitness effects at the same site is a previously overlooked yet fundamental property of protein evolution.

Evolutionary Biology↗

bioRxiv2015

Variation in linked selection and recombination drive genomic divergence during allopatric speciation of European and American aspens

Despite the global economic and ecological importance of forest trees, the genomic basis of differential adaptation and speciation in tree species is still poorly understood. Populus tremula and P. tremuloides are two of the most widespread tree species in the Northern Hemisphere. Using whole-genome re-sequencing data of 24 P. tremula and 22 P. tremuloides individuals, we find that the two species diverged [~]2.2-3.1 million years ago, coinciding with the severing of the Bering land bridge and the onset of dramatic climatic oscillations during the Pleistocene. Both species have experienced substantial population expansions following long-term declines after species divergence. We detect widespread and heterogeneous genomic differentiation between species, and in accordance with the expectation of allopatric speciation, coalescent simulations suggest that neutral evolutionary processes can account for most of the observed patterns of genomic differentiation. However, there is an excess of regions exhibiting extreme differentiation relative to those expected under demographic simulations, which is indicative of the action of natural selection. Overall genetic differentiation is negatively associated with recombination rate in both species, providing strong support for a role of linked selection in generating the heterogeneous genomic landscape of differentiation between species. Finally, we identify a number of candidate regions and genes that may have been subject to positive and/or balancing selection during the speciation process.

Evolutionary Biology↗

bioRxiv2016

Expression of segment polarity genes in brachiopods supports a non-segmental ancestral role of engrailed for bilaterians

The diverse and complex developmental mechanisms of segmentation have been more thoroughly studied in arthropods, vertebrates and annelids--distantly related animals considered to be segmented. Far less is known about the role of \"segmentation genes\" in organisms that lack a segmented body. Here we investigate the expression of the arthropod segment polarity genes engrailed, wnt1 and hedgehog in the development of brachiopods--marine invertebrates without a subdivided trunk but closely related to the segmented annelids. We found that a stripe of engrailed expression demarcates the ectodermal boundary that delimits the anterior region of Terebratalia transversa and Novocrania anomala embryos. In T. transversa, this engrailed domain is abutted by a stripe of wnt1 expression in a pattern similar to the parasegment boundaries of insects--except for the expression of hedgehog, which is restricted to endodermal tissues of the brachiopod embryos. We found that pax6 and pax2/5/8, putative regulators of engrailed, also demarcate the anterior boundary in the two species, indicating these genes might be involved in the anterior patterning of brachiopod larvae. In a comparative phylogenetic context, these findings suggest that bilaterians might share an ancestral, non-segmental domain of engrailed expression during early embryogenesis.

Evolutionary Biology↗

bioRxiv2015

Adaptation to heavy-metal contaminated environments proceeds via selection on pre-existing genetic variation

Anthropogenic environmental changes create evolutionary pressures on populations to adapt to novel stresses. It is as yet unclear, when populations respond to these selective pressures, the extent to which this results in convergent genetic evolution and whether convergence is due to independent mutations or shared ancestral variation. We address these questions using a classic example of adaptation by natural selection by investigating the rapid colonization of the plant species Mimulus guttatus to copper contaminated soils. We use field-based reciprocal transplant experiments to demonstrate that mine alleles at a major copper tolerance locus, Tol1, are strongly selected in the mine environment. We assemble the genome of a mine adapted genotype and identify regions of this genome in tight genetic linkage to Tol1. We discover a set of a multicopper oxidase genes that are genetically linked to Tol1 and exhibit large differences in expression between tolerant and non-tolerant genotypes. We overexpressed this gene in M. guttatus and A. thaliana and found the introduced gene contributes to enhanced copper tolerance. We identify convergent adaptation loci that are additional to Tol1 by measuring genome-wide differences in allele frequency between pairs of mine and off-mine populations and narrow these regions to specific candidate genes using differences in protein sequence and gene expression. Furthermore, patterns of genetic variation at the two most differentiated candidate loci are consistent with selection acting upon alleles that predates the existence of the copper mine habitat. These results suggest that adaptation to the mine habitat occurred via selection on ancestral variation, rather than independent de novo mutations or migration between populations.

Evolutionary Biology↗

bioRxiv2015

Apoptosis in snowflake yeast: novel trait, or side effect of toxic waste?

Recent experiments evolving de novo multicellularity in yeast have found that large-cluster forming genotypes also exhibit higher rates of programmed cell death (apoptosis). This was previously interpreted as the evolution of a simple form of cellular division of labor: apoptosis results in the scission of cell-cell connections, allowing snowflake yeast to produce proportionally smaller, faster-growing propagules. Through spatial simulations, Duran-Nebreda and Sole (2015) develop the novel null hypothesis that apoptosis is not an adaptation, per se, but is instead caused by the accumulation of toxic metabolites in large clusters. Here we test this hypothesis by synthetically creating unicellular derivatives of snowflake yeast through functional complementation with the ancestral ACE2 allele. We find that multicellular snowflake yeast with elevated apoptosis exhibit a similar rate of apoptosis when cultured as single cells. We also show that larger snowflake yeast clusters tend to contain a greater fraction of older, senescent cells, which may explain why larger clusters of a given genotype are more apoptotic. Our results show that apoptosis is not caused by side effects of spatial structure, such as starvation or waste product accumulation, and are consistent with the hypothesis that elevated apoptosis is a trait which co-evolves with large cluster size.

Evolutionary Biology↗

bioRxiv2015

Elevation of linkage disequilibrium above neutral expectations in ancestral and derived populations of Drosophila melanogaster

The extent to which selection and demography impact patterns of genetic diversity in natural populations of Drosophila melanogaster is yet to be fully understood. We previously observed that the pattern of LD at scales of ~10 kb in the Drosophila Genetic Reference Panel (DGRP), consisting of 145 inbred strains from Raleigh, North Carolina, measured both between pairs of sites and as haplotype homozygosity, is elevated above neutral demographic expectations. Further, we demonstrated that signatures of strong and recent soft sweeps are abundant. However, the extent to which this pattern is specific to this derived and admixed population is unknown. Neither is it clear whether such a pattern may have arisen as a consequence of the extensive inbreeding performed to generate the DGRP data. Here we analyze > 100 fully sequenced strains from Zambia, an ancestral population to the Raleigh population, that has experienced little to no admixture and was generated by sequencing haploid embryos rather than inbred strains. This data set allows us to determine whether patterns of elevated LD and signatures of abundant soft sweeps are generic to multiple populations of D. melanogaster or whether they are generated either by inbreeding, bottlenecks or admixture in the DGRP dataset. We find an elevation in long-range LD and haplotype homozygosity in the Zambian dataset, confirming the result from the DGRP data set. This elevation in LD and haplotype structure remains even after controlling for many sources of LD in the data including genomic inversions, admixture, population substructure, close relatedness of individual strains, and recombination rate variation. Furthermore, signatures of partial soft sweeps similar to those found in the DGRP are common in Zambia. These results suggest that while the selective forces and sources of adaptive mutations may differ in Zambia and Raleigh, elevated long-range LD and signatures of soft sweeps are generic in D. melanogaster.

Evolutionary Biology↗

bioRxiv2015

Para-allopatry in hybridizing fire-bellied toads (Bombina bombina and B. variegata): inference from transcriptome-wide coalescence analyses

Ancient origins, profound ecological divergence and extensive hybridization make the fire-bellied toads Bombina bombina and B. variegata (Anura: Bombinatoridae) an intriguing test case of ecological speciation. Narrow Bombina hybrid zones erect barriers to neutral introgression whose strength has been estimated previously. We test this prediction by inferring the rate of gene exchange between pure populations on either side of the intensively studied Krakow transect. We developed a software pipeline to extract high confidence sets of orthologous genes from de novo transcriptome assemblies, fitted a range of divergence models to these data and assessed their relative support with analytic likelihoods calculations. There was clear evidence for post-divergence gene flow, but, as expected, no perceptible signal of recent introgression via the nearby hybrid zone. The analysis of two additional Bombina taxa (B. v. scabra and B. orientalis) validated our parameter estimates against a larger set of prior expectations. Despite substantial cumulative introgression over millions of years, adaptive divergence of the hybridizing taxa is essentially unaffected by their lack of reproductive isolation. Extended distribution ranges also buffer them against small-scale environmental perturbations that have been shown to reverse the speciation process in other, more recent ecotypes.

Evolutionary Biology↗

bioRxiv2015

The Strength of Selection Against Neanderthal Introgression

Hybridization between humans and Neanderthals has resulted in a low level of Neanderthal ancestry scattered across the genomes of many modern-day humans. After hybridization, on average, selection appears to have removed Neanderthal alleles from the human population. Quantifying the strength and causes of this selection against Neanderthal ancestry is key to understanding our relationship to Neanderthals and, more broadly, how populations remain distinct after secondary contact. Here, we develop a novel method for estimating the genome-wide average strength of selection and the density of selected sites using estimates of Neanderthal allele frequency along the genomes of modern-day humans. We confirm that East Asians had somewhat higher initial levels of Neanderthal ancestry than Europeans even after accounting for selection. We find that the bulk of purifying selection against Neanderthal ancestry is best understood as acting on many weakly deleterious alleles. We propose that the majority of these alleles were effectively neutral--and segregating at high frequency--in Neanderthals, but became selected against after entering human populations of much larger effective size. While individually of small effect, these alleles potentially imposed a heavy genetic load on the early-generation human-Neanderthal hybrids. This work suggests that differences in effective population size may play a far more important role in shaping levels of introgression than previously thought.\n\nAuthor SummaryA small percentage of Neanderthal DNA is present in the genomes of many contemporary human populations due to hybridization tens of thousands of years ago. Much of this Neanderthal DNA appears to be deleterious in humans, and natural selection is acting to remove it. One hypothesis is that the underlying alleles were not deleterious in Neanderthals, but rather represent genetic incompatibilities that became deleterious only once they were introduced to the human population. If so, reproductive barriers must have evolved rapidly between Neanderthals and humans after their split. Here, we show that oberved patterns of Neanderthal ancestry in modern humans can be explained simply as a consequence of the difference in effective population size between Neanderthals and humans. Specifically, we find that on average, selection against individual Neanderthal alleles is very weak. This is consistent with the idea that Neanderthals over time accumulated many weakly deleterious alleles that in their small population were effectively neutral. However, after introgressing into larger human populations, those alleles became exposed to purifying selection. Thus, rather than being the result of hybrid incompatibilities, differences between human and Neanderthal effective population sizes appear to have played a key role in shaping our present-day shared ancestry.

Evolutionary Biology↗

bioRxiv2015

Age-related and heteroplasmy-related variation in human mtDNA copy number

The mitochondrial (mt) genome is present in many copies in human cells, and intra-individual variation in mtDNA sequences is known as heteroplasmy. Recent studies found that heteroplasmies are highly tissue-specific, site-specific, and allele-specific, however the functional implications have not been explored. This study investigates variation in mtDNA copy numbers (mtCN) in 12 different tissues obtained at autopsy from 152 individuals (ranging in age from 3 days to 96 years). Three different methods to estimate mtCN were compared: shotgun sequencing (in 4 tissues), capture-enriched sequencing (in 12 tissues) and droplet digital PCR (ddPCR, in 2 tissues). The highest precision in mtCN estimation was achieved using shotgun sequencing data. However, capture-enrichment data provide reliable estimates of relative (albeit not absolute) mtCNs. Comparisons of mtCN from different tissues of the same individual revealed that mtCNs in different tissues are, with few exceptions, uncorrelated. Hence, each tissue of an individual seems to regulate mtCN in a tissue-related rather than an individual-dependent manner. Skeletal muscle (SM) samples showed an age-related decrease in mtCN that was especially pronounced in males, while there was an age-related increase in mtCN for liver (LIV) samples. MtCN in SM samples was significantly negatively correlated with both the total number of heteroplasmic sites and with minor allele frequency (MAF) at two heteroplasmic sites, 408 and 16327. Heteroplasmies at both sites are highly specific for SM, accumulate with aging and are part of functional elements that regulate mtDNA replication. These data support the hypothesis that selection acting on these heteroplasmic sites is reducing mtCN in SM of older individuals.\n\nAuthor SummaryThe total number of mitochondrial genomes in a human cell differs between individuals and between the tissues of a single individual; however the factors that influence this variation remain unknown. We estimated mtDNA copy number (mtCN) in 12 different tissues of 152 individuals applying three different methods, and found age-related variation for two tissues: mtCN in skeletal muscle is negatively correlated with age (especially in males) while mtCN in liver is positively correlated with age. Overall, mtCNs of different tissues within an individual are mainly independent of each other, indicating that tissue-specific rather than individual-specific processes largely influence mtCN.\n\nHeteroplasmy refers to intra-individual differences in the sequence of the mtDNA genome and heteroplasmic mutations accumulate during aging. Linear and partial regression analyses of mtCN with heteroplasmy (determined in a previous study of these same samples) revealed that the decrease of mtCN in skeletal muscle is mainly correlated with an increasing total number of heteroplasmic sites, and with increasing minor allele frequency at two sites (408 and 16327), that are heteroplasmic almost exclusively in skeletal muscle. As both sites are part of functional elements required for regulation of mtDNA replication, we suggest that selection may be acting via increasing heteroplasmy to reduce mtCN during aging.

Evolutionary Biology↗