Investigating mitonuclear interactions in human admixed populations.
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ABSTRACT:
SUBMITTER: Zaidi AA
PROVIDER: S-EPMC6925600 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
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Project description:Cold climates represent one of the major environmental challenges that anatomically modern humans faced during their dispersal out of Africa. The related adaptive traits have been achieved by modulation of thermogenesis and thermoregulation processes where nuclear (nuc) and mitochondrial (mt) genes play a major role. In human populations, mitonuclear genetic interactions are the result of both the peculiar genetic history of each human group and the different environments they have long occupied. This study aims to investigate mitonuclear genetic interactions by considering all the mitochondrial genes and 28 nuclear genes involved in brown adipose tissue metabolism, which have been previously hypothesized to be crucial for cold adaptation. For this purpose, we focused on three human populations (i.e., Finnish, British, and Central Italian people) of European ancestry from different biogeographical and climatic areas, and we used a machine learning approach to identify relevant nucDNA-mtDNA interactions that characterized each population. The obtained results are twofold: (i) at the methodological level, we demonstrated that a machine learning approach is able to detect patterns of genetic structure among human groups from different latitudes both at single genes and by considering combinations of mtDNA and nucDNA loci; (ii) at the biological level, the analysis identified population-specific nuclear genes and variants that likely play a relevant biological role in association with a mitochondrial gene (such as the "obesity gene" FTO in Finnish people). Further studies are needed to fully elucidate the evolutionary dynamics (e.g., migration, admixture, and/or local adaptation) that shaped these nucDNA-mtDNA interactions and their functional role.
| S-EPMC7686538 | biostudies-literature
Project description:There is extensive evidence from model systems that disrupting associations between co-adapted mitochondrial and nuclear genotypes can lead to deleterious and even lethal consequences. While it is tempting to extrapolate from these observations and make inferences about the human-health effects of altering mitonuclear associations, the importance of such associations may vary greatly among species, depending on population genetics, demographic history and other factors. Remarkably, despite the extensive study of human population genetics, the statistical associations between nuclear and mitochondrial alleles remain largely uninvestigated. We analysed published population genomic data to test for signatures of historical selection to maintain mitonuclear associations, particularly those involving nuclear genes that encode mitochondrial-localized proteins (N-mt genes). We found that significant mitonuclear linkage disequilibrium (LD) exists throughout the human genome, but these associations were generally weak, which is consistent with the paucity of population genetic structure in humans. Although mitonuclear LD varied among genomic regions (with especially high levels on the X chromosome), N-mt genes were statistically indistinguishable from background levels, suggesting that selection on mitonuclear epistasis has not preferentially maintained associations involving this set of loci at a species-wide level. We discuss these findings in the context of the ongoing debate over mitochondrial replacement therapy.
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Project description:Metazoans exist only with a continuous and rich supply of chemical energy from oxidative phosphorylation in mitochondria. The oxidative phosphorylation machinery that mediates energy conservation is encoded by both mitochondrial and nuclear genes, and hence the products of these two genomes must interact closely to achieve coordinated function of core respiratory processes. It follows that selection for efficient respiration will lead to selection for compatible combinations of mitochondrial and nuclear genotypes, and this should facilitate coadaptation between mitochondrial and nuclear genomes (mitonuclear coadaptation). Herein, we outline the modes by which mitochondrial and nuclear genomes may coevolve within natural populations, and we discuss the implications of mitonuclear coadaptation for diverse fields of study in the biological sciences. We identify five themes in the study of mitonuclear interactions that provide a roadmap for both ecological and biomedical studies seeking to measure the contribution of intergenomic coadaptation to the evolution of natural populations. We also explore the wider implications of the fitness consequences of mitonuclear interactions, focusing on central debates within the fields of ecology and biomedicine.
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Project description:In nature, organisms are faced with constant nutritional options which fuel key life-history traits. Studies have shown that species can actively make nutritional decisions based on internal and external cues. Metabolism itself is underpinned by complex genomic interactions involving components from both nuclear and mitochondrial genomes. Products from these two genomes must coordinate how nutrients are extracted, used and recycled. Given the complicated nature of metabolism, it is not well understood how nutritional choices are affected by mitonuclear interactions. This is under the rationale that changes in genomic interactions will affect metabolic flux and change physiological requirements. To this end we used a large Drosophila mitonuclear genetic panel, comprising nine isogenic nuclear genomes coupled to nine mitochondrial haplotypes, giving a total of 81 different mitonuclear genotypes. We use a capillary-based feeding assay to screen this panel for dietary preference between carbohydrate and protein. We find significant mitonuclear interactions modulating nutritional choices, with these epistatic interactions also being dependent on sex. Our findings support the notion that complex genomic interactions can place a constraint on metabolic flux. This work gives us deeper insights into how key metabolic interactions can have broad implications on behaviour.
| S-EPMC10698477 | biostudies-literature
Project description:Admixture has been a pervasive phenomenon in human history, extensively shaping the patterns of population genetic diversity. There is increasing evidence to suggest that admixture can also facilitate genetic adaptation to local environments, i.e., admixed populations acquire beneficial mutations from source populations, a process that we refer to as "adaptive admixture." However, the role of adaptive admixture in human evolution and the power to detect it remain poorly characterized. Here, we use extensive computer simulations to evaluate the power of several neutrality statistics to detect natural selection in the admixed population, assuming multiple admixture scenarios. We show that statistics based on admixture proportions, Fadm and LAD, show high power to detect mutations that are beneficial in the admixed population, whereas other statistics, including iHS and FST, falsely detect neutral mutations that have been selected in the source populations only. By combining Fadm and LAD into a single, powerful statistic, we scanned the genomes of 15 worldwide, admixed populations for signatures of adaptive admixture. We confirm that lactase persistence and resistance to malaria have been under adaptive admixture in West Africans and in Malagasy, North Africans, and South Asians, respectively. Our approach also uncovers other cases of adaptive admixture, including APOL1 in Fulani nomads and PKN2 in East Indonesians, involved in resistance to infection and metabolism, respectively. Collectively, our study provides evidence that adaptive admixture has occurred in human populations whose genetic history is characterized by periods of isolation and spatial expansions resulting in increased gene flow.
| S-EPMC9069077 | biostudies-literature
Project description:BackgroundAfrica is an important watershed in the genetic history of domestic cattle, as two lineages of modern cattle, Bos taurus and B. indicus, form distinct admixed cattle populations. Despite the predominant B. indicus nuclear ancestry of African admixed cattle, B. indicus mitochondria have not been found on the continent. This discrepancy between the mitochondrial and nuclear genomes has been previously hypothesized to be driven by male-biased introgression of Asian B. indicus into ancestral African B. taurus. Given that this hypothesis mandates extreme demographic assumptions relying on random genetic drift, we propose a novel hypothesis of selection induced by mitonuclear incompatibility and assess these hypotheses with regard to the current genomic status of African admixed cattle.ResultsBy analyzing 494 mitochondrial and 235 nuclear genome sequences, we first confirmed the genotype discrepancy between mitochondrial and nuclear genome in African admixed cattle: the absence of B. indicus mitochondria and the predominant B. indicus autosomal ancestry. We applied approximate Bayesian computation (ABC) to assess the posterior probabilities of two selection hypotheses given this observation. The results of ABC indicated that the model assuming both male-biased B. indicus introgression and selection induced by mitonuclear incompatibility explains the current genomic discrepancy most accurately. Subsequently, we identified selection signatures at autosomal loci interacting with mitochondria that are responsible for integrity of the cellular respiration system. By contrast with B. indicus-enriched genome ancestry of African admixed cattle, local ancestries at these selection signatures were enriched with B. taurus alleles, concurring with the key expectation of selection induced by mitonuclear incompatibility.ConclusionsOur findings support the current genome status of African admixed cattle as a potential outcome of male-biased B. indicus introgression, where mitonuclear incompatibility exerted selection pressure against B. indicus mitochondria. This study provides a novel perspective on African cattle demography and supports the role of mitonuclear incompatibility in the hybridization of mammalian species.
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Project description:We examined the associations between mitochondrial DNA haplogroups (MT-hgs; mitochondrial haplotype groups defined by a specific combination of single nucleotide polymorphisms labeled as letters running from A to Z) and their interactions with a polygenic risk score composed of nuclear-encoded mitochondrial genes (nMT-PRS) with risk of dementia and age of onset (AOO) of dementia. MT-hg K (Odds ratio [OR]: 2.03 [95% CI: 1.04, 3.97]) and a 1 SD larger nMT-PRS (OR: 2.2 [95% CI: 1.68, 2.86]) were associated with elevated odds of dementia. Significant antagonistic interactions between the nMT-PRS and MT-hg K (OR: 0.45 [95% CI: 0.22, 0.9]) and MT-hg T (OR: 0.22 [95% CI: 0.1, 0.49]) were observed. Individual MT-hgs were not associated with AOO; however, a significant antagonistic interactions was observed between the nMT-PRS and MT-hg T (Hazard ratio: 0.62 [95% CI: 0.42, 0.91]) and a synergistic interaction between the nMT-PRS and MT-hg V (Hazard ratio: 2.28 [95% CI: 1.19, 4.35]). These results suggest that MT-hgs influence dementia risk and that variants in the nuclear and mitochondrial genome interact to influence the AOO of dementia.
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Project description:Genome-wide association studies (GWASs) are commonly used for the mapping of genetic loci that influence complex traits. A problem that is often encountered in both population-based and family-based GWASs is that of identifying cryptic relatedness and population stratification because it is well known that failure to appropriately account for both pedigree and population structure can lead to spurious association. A number of methods have been proposed for identifying relatives in samples from homogeneous populations. A strong assumption of population homogeneity, however, is often untenable, and many GWASs include samples from structured populations. Here, we consider the problem of estimating relatedness in structured populations with admixed ancestry. We propose a method, REAP (relatedness estimation in admixed populations), for robust estimation of identity by descent (IBD)-sharing probabilities and kinship coefficients in admixed populations. REAP appropriately accounts for population structure and ancestry-related assortative mating by using individual-specific allele frequencies at SNPs that are calculated on the basis of ancestry derived from whole-genome analysis. In simulation studies with related individuals and admixture from highly divergent populations, we demonstrate that REAP gives accurate IBD-sharing probabilities and kinship coefficients. We apply REAP to the Mexican Americans in Los Angeles, California (MXL) population sample of release 3 of phase III of the International Haplotype Map Project; in this sample, we identify third- and fourth-degree relatives who have not previously been reported. We also apply REAP to the African American and Hispanic samples from the Women's Health Initiative SNP Health Association Resource (WHI-SHARe) study, in which hundreds of pairs of cryptically related individuals have been identified.
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Project description:Critical mitochondrial functions, including cellular respiration, rely on frequently interacting components expressed from both the mitochondrial and nuclear genomes. The fitness of eukaryotic organisms depends on a tight collaboration between both genomes. In the face of an elevated rate of evolution in mtDNA, current models predict that the maintenance of mitonuclear compatibility relies on compensatory evolution of the nuclear genome. Mitonuclear interactions would therefore exert an influence on evolutionary trajectories. One prediction from this model is that the same nuclear genome evolving with different mitochondrial haplotypes would follow distinct molecular paths toward higher fitness. To test this prediction, we submitted 1,344 populations derived from 7 mitonuclear genotypes of Saccharomyces cerevisiae to >300 generations of experimental evolution in conditions that either select for a mitochondrial function or do not strictly require respiration for survival. Performing high-throughput phenotyping and whole-genome sequencing on independently evolved individuals, we identified numerous examples of gene-level evolutionary convergence among populations with the same mitonuclear background. Phenotypic and genotypic data on strains derived from this evolution experiment identify the nuclear genome and the environment as the main determinants of evolutionary divergence, but also show a modulating role for the mitochondrial genome exerted both directly and via interactions with the two other components. We finally recapitulated a subset of prominent loss-of-function alleles in the ancestral backgrounds and confirmed a generalized pattern of mitonuclear-specific and highly epistatic fitness effects. Together, these results demonstrate how mitonuclear interactions can dictate evolutionary divergence of populations with identical starting nuclear genotypes.
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Project description: Not available
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