Investigating mitonuclear interactions in human admixed populations

Abstract

To function properly, mitochondria utilize products of 37 mitochondrial and >1,000 nuclear genes, which should be compatible with each other. Discordance between mitochondrial and nuclear genetic ancestry could contribute to phenotypic variation in admixed populations. Here, we explored potential mitonuclear incompatibility in six admixed human populations from the Americas: African Americans, African Caribbeans, Colombians, Mexicans, Peruvians and Puerto Ricans. By comparing nuclear versus mitochondrial ancestry in these populations, we first show that mitochondrial DNA (mtDNA) copy number decreases with increasing discordance between nuclear and mtDNA ancestry. The direction of this effect is consistent across mtDNA haplogroups of different geographic origins. This observation indicates suboptimal regulation of mtDNA replication when its components are encoded by nuclear and mtDNA genes with different ancestry. Second, while most populations analysed exhibit no such trend, in African Americans and Puerto Ricans, we find a significant enrichment of ancestry at nuclear-encoded mitochondrial genes towards the source populations contributing the most prevalent mtDNA haplogroups (African and Native American, respectively). This possibly reflects compensatory effects of selection in recovering mitonuclear interactions optimized in the source populations. Our results provide evidence of mitonuclear interactions in human admixed populations and we discuss their implications for human health and disease.

Figure 1.. Expected signatures of mito-nuclear incompatibility at the level of (a) individuals or (b) populations.

(a) The nuclear genome of admixed individuals might contain varying levels of ancestry from multiple ancestral populations, whereas mtDNA derives its ancestry from only one population. Increasing discordance (concordance) between mitochondrial and nuclear ancestry in individuals can lead to increasing (decreasing) levels of mito--nuclear incompatibility, which can have phenotypic consequences. (b) Sex--biased admixture can lead to varying levels of ancestry proportions on different chromosome types based on their modes of inheritance. In extreme cases, the mtDNA ancestry can be entirely from one population even though the nuclear ancestry is highly admixed. This discordance in ancestry between the nuclear and mitochondrial genomes might result in selective pressure for ‘matching’ ancestry at nuclear-encoded mitochondrial genes.

Figure 2.. Ternary plots showing the distribution of African, European, and Native American ancestry in the samples analyzed (samples sizes are shown in parentheses).

(a) ADMIXTURE components 1, 2, and 3 correspond to European (EUR), African (AFR), and Native American (NAT) ancestry, respectively. The grey points are the admixed samples from the 1,000 Genomes dataset and the colored points are samples serving as proxies for source populations. (b) The ancestry structure of admixed populations. (c) Distribution of mtDNA haplogroups among admixed individuals. (d) mtDNA haplogroups grouped by region where they are thought to have been most commonly found prior to admixture. ACB: African Caribbeans from Barbados; ASW: African Americans from South Western USA; CLM: Colombians from Colombia; MXL: Mexicans from Los Angeles, USA; PEL: Peruvians from Lima, Peru; PUR: Puerto Ricans from Puerto Rico.

Figure 3.. mtDNA copy number in (a) admixed and (b) non-admixed populations.

(a) mtDNA copy number is negatively correlated with the discordance between mitochondrial and nuclear DNA ancestry. Standardized beta coefficient, t-statistic, one-sided P-value, and correlation coefficient are shown. The discordance score is one minus the ancestry proportion from the same source population as for the mtDNA haplogroup. The red dashed line is the median mtDNA copy number calculated across the individuals from European (CEU) and African (YRI) source populations, plotted separately in (b).

Figure 4.. Expected vs. observed frequency of mtDNA haplogroups from each of the three source populations.

The colored boxes show the 95% bootstrap interval of the expected mtDNA haplogroup frequency based on the proportion of ancestral females estimated from the ancestry proportions on the X- chromosome and autosomes (Fig. 5). The black horizontal lines show the observed frequency of mtDNA haplogroup. While in most cases the observed mtDNA haplogroup frequency falls within range of expectations, in some cases (in CLM and PUR), the observed frequencies greatly deviate from expectation. ACB: African Caribbeans from Barbados; ASW: African Americans from South Western USA; CLM: Colombians from Colombia; MXL: Mexicans from Los Angeles, USA; PEL: Peruvians from Lima, Peru; PUR: Puerto Ricans from Puerto Rico.

Figure 5.. Systematic deviations in local ancestry for different functional categories of genes.

The y--axis shows local ancestry deviation and the x--axis lists the functional categories. ‘High-mt’ (167 genes) are nuclear genes that encode important subunits of mitochondrial replication, transcription and the OXPHOS complexes. ‘Low-mt’ (793 genes) are nuclear genes that were inferred to have mitochondrial function by Mitocarta 2.0 , but are not part of the ‘High-mt’ gene set. ‘Non-mt’ (17,456 genes) are genes that do not have known or inferred mitochondrial function based on Mitocarta 2.0 . A block bootstrap approach (see Methods) was used to generate the distributions. Briefly, we sampled 167 windows of 5 Mb spanning the genes, with replacement, within each category and calculated the mean local ancestry deviation across these windows. This was repeated for 1,000 bootstraps to generate the distributions. The horizontal bars indicate the empirical 95% confidence interval of the mean ancestry deviation. ACB: African Caribbeans from Barbados; ASW: African Americans from South Western USA; CLM: Colombians from Colombia; MXL: Mexicans from Los Angeles, USA; PEL: Peruvians from Lima, Peru; PUR: Puerto Ricans from Puerto Rico.