Selection Increases Mitonuclear DNA Discordance but Reconciles Incompatibility in African Cattle

Abstract

Mitochondrial function relies on the coordinated interactions between genes in the mitochondrial DNA and nuclear genomes. Imperfect interactions following mitonuclear incompatibility may lead to reduced fitness. Mitochondrial DNA introgressions across species and populations are common and well documented. Various strategies may be expected to reconcile mitonuclear incompatibility in hybrids or admixed individuals. African admixed cattle (Bos taurus × B. indicus) show sex-biased admixture, with taurine (B. taurus) mitochondrial DNA and a nuclear genome predominantly of humped zebu (B. indicus). Here, we leveraged local ancestry inference approaches to identify the ancestry and distribution patterns of nuclear functional genes associated with the mitochondrial oxidative phosphorylation process in the genomes of African admixed cattle. We show that most of the nuclear genes involved in mitonuclear interactions are under selection and of humped zebu ancestry. Variations in mitochondrial DNA copy number may have contributed to the recovery of optimal mitochondrial function following admixture with the regulation of gene expression, alleviating or nullifying mitochondrial dysfunction. Interestingly, some nuclear mitochondrial genes with enrichment in taurine ancestry may have originated from ancient African aurochs (B. primigenius africanus) introgression. They may have contributed to the local adaptation of African cattle to pathogen burdens. Our study provides further support and new evidence showing that the successful settlement of cattle across the continent was a complex mechanism involving adaptive introgression, mitochondrial DNA copy number variation, regulation of gene expression, and selection of ancestral mitochondria-related genes.

Keywords: African cattle; admixture; mitonuclear DNA discordance; mitonuclear interactions; mtDNA copy numbers; purifying selection.

Fig. 1.

Identifying potential donor populations of African admixed cattle. a) Phylogeny, population admixture analysis. b) PCA. After pruning for linkage disequilibrium, a total of 1,482,502 SNPs from 258 samples were analyzed. K indicates the number of ancestry components assumed in the ADMIXTURE analysis. The cross-validation error was substantially reduced at K = 4.

Fig. 2.

Human-mediated admixture shaped the interactions between heterologous mtDNA and nuclear genomes of African admixed cattle. a) The brief history of admixture and the pattern of mitonuclear interactions in African admixed cattle. African cattle represent an excellent model for studying the genomic mechanisms mitigating the effect of mitonuclear DNA discordance as well as for understanding the genome interplay under suboptimal mitonuclear combination. b) Deviations of nucleotide diversity (π) between four gene sets involved in mitonuclear interactions in African admixed cattle. c) Deviations of genetic differentiation for four gene sets involved in mitonuclear interactions between Asian zebu and African taurine. The mitonuclear DNA discordance may be triggered by admixture of Asian zebu and African taurine due to unique mitonuclear coevolution. Box plots of π in a 50 kb genomic window with a sliding window of 10 kb. Significance was evaluated by two-sided t-tests (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; and ns means no statistical significance).

Fig. 3.

Deviations of ancestry for genes involved in mitonuclear interactions in African admixed cattle. a) Deviations in African admixed cattle local ancestry across genes involved in mitonuclear interactions. The values of F_ST, F_dM, and Loter were calculated using a 50 kb window size and a 10 kb step size. (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; and ns means no statistical significance). b) Density plots of estimates of Tajima's D for gene sets of mitonuclear (n = 1,064), high-mito (n = 144), OXPHOS (n = 149), and selective genes (n = 21) in African admixed cattle. Significance was evaluated by two-sided t-tests.

Fig. 4.

Correlation between mtDNA-CN and the ratio of taurine ancestry in African cattle. a) The ratio of taurine ancestry and mtDNA-CN in cattle. The black solid lines represent the medians of each boxplot and serve as links. The dashed line indicates 25% level of genome-wide taurine ancestry (Additional file 2: supplementary fig. S1, Supplementary Material online). b) The mtDNA-CN was negatively correlated (R = −0.21, P = 0.025) with African taurine ancestry in the populations (n = 116, highlighted in red in figure a) with <25% genome-wide ancestry.

Fig. 5.

Genetic correlation for mtDNA-CN variation in African admixed cattle. a) GWAS was performed with GEMMA for mtDNA-CN variation in African admixed cattle taken as a quantitative trait that follows a normal distribution (see Additional file 2: supplementary fig. S13b, Supplementary Material online). The blood mtDNA-CN was highly heritable as indicated by the heritability of 96.7% based on the genomic relationship matrix. The dashed line indicates the significance threshold of 1 × 10⁻⁷. Among the 71 coding genes associated with mtDNA-CN, 14 candidate genes playing roles in mtDNA-CN regulation, mitochondrial protein synthesis, ATP generation, and mitochondrial function are indicated in the Manhattan plot. b) Deviations in taurine ancestry for the 71 coding genes associated with mtDNA-CN compared with the genome-wide or four subsets of mitonuclear genes. c) Deviations in taurine ancestry across 14 candidate genes involving in mitochondrial function, metabolism, assembly, and mtDNA-CN. Statistical significance was calculated by two-sided t-tests (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; and ns means no significance).

Fig. 6.

Nuclear compensation reconciles mitonuclear incompatibility in African cattle. The sex-biased crossbreeding is postulated to explain the discrepancy between mitochondrial (B. taurus: 100%) and nuclear (B. indicus: 75%) ancestries of present-day African humped cattle. Ever-increasing mitonuclear DNA discordance is inevitable in African humped cattle resulting in mitonuclear incompatibilities. Accordingly, we hypothesized three scenarios: (i) The enrichment of taurine ancestry (i.e. the source of mtDNA) under selection reduces mitonuclear DNA discordance, known as the mitonuclear coevolution mechanism; (ii) Mitonuclear genes are highly conserved between taurine and zebu, and their admixture may not trigger mitonuclear incompatibility; and (iii) Evolution of nuclear genes may help reverse or alleviate mitonuclear incompatibility, known as nuclear compensation. Our results indicate that most functional genes involved in mitonuclear interactions exhibited significant enrichment in African taurine ancestry under strong selection, failing to support the mitonuclear coevolution. While enriched zebu ancestry increases mitonuclear DNA discordance, it facilitates the evolution of nuclear compensation. Regulations in gene expression ascribed to different activities of regulatory elements from parental genomes mainly generate lower levels of reactive oxygen species, decrease oxidative stress, alleviate mitochondrial damage, increase ATP generation, and maintain mtDNA-CN, and maintain mitonuclear interactions.

Fig. 7.

Selective sweeps and phylogeny for genes with enrichment of taurine ancestry. a) Selective sweeps for the 21 genes in the African taurine breeds Muturu and N’Dama. The dashed line indicates the top 1% of all the likelihood ratio values. Only loci with likelihood values >500 are displayed. b) Archaic adaptive introgression in African cattle was indicated by ML tree in the genomic region of chr2: 87,864,908 to 90,470,906. c) Shared homozygous loci with African aurochs Th7 in the genomic region of chr2: 87,864,908 to 90,470,906. Orange and blue dots, along with connecting lines, represent African taurine and Eurasian taurine ancestry, respectively. Green dots and lines indicate loci shared with Th7.