Exploring the impact of mitonuclear discordance on disease in Latin American admixed populations
The coevolution of nuclear and mitochondrial genomes has guaranteed mitochondrial function for millions of years. The introduction of European (EUR) and African (AFR) genomes into the Ameridian continent during the Columbus exchange in Latin America created an opportunity to naturally test different combinations of nuclear and mitochondrial genomes. However, the impact of potential "mitonuclear discordance" (MND, differences in ancestries) has not been evaluated in Latin American admixed individuals (AMR) affected with developmental disorders, even though MND alters mitochondrial function and reduces viability in other organisms. To characterize MND in healthy and affected AMR individuals, we used AMR genotype data from the 1000 Genomes Project (n=385), two cohorts of 22q.11 deletion syndrome patients 22qDS-ARG (n=26) and 22qDS-CHL (n=58), and a cohort of patients with multiple congenital anomalies and/or neurodevelopmental disorders (DECIPHERD, n=172). Based on their importance to mitochondrial function, genes were divided into all mitonuclear genes (n=1035), high-mt (n=167), low-mt (n=793), or OXPHOS (n=169). We calculated local ancestry using FLARE, and estimated MND as the fraction of nuclear mitochondrial genes ancestry not matching the mtDNA ancestry, and {Delta}MND as (MNDoffspring - MNDmother)/MNDmother. Generally, MND showed population and haplogroup distinctive distributions (ANOVA p<0.05), with haplogroup D showing the lowest MND 0.49{+/-}0.17 (mean {+/-} s.d.). MND was significantly lower in 22qDS-ARG patients 0.43{+/-}0.24 and DECIPHERD patients 0.56{+/-}0.12 compared to healthy individuals 0.60{+/-}0.09 (ANOVA p<0.05). OXPHOS and high-mt showed the same trend, but with greater differences between healthy and affected individuals. MND seems to inform population history, and constraint among affected individuals, especially for OXPHOS and high-mt genes. Author summaryWe investigated the role of mitonuclear discordance (MND) in disease among Latin American admixed populations, describing how mismatches between nuclear and mitochondrial ancestries could impact mitochondrial function and disease phenotypes. Utilizing datasets from the 1000 Genomes Project and cohorts with rare genetic disorders, we demonstrated population- and haplogroup-specific patterns of MND, with haplogroup A showing the highest MND values. Affected individuals exhibited significantly lower MND than healthy controls, particularly in genes related to oxidative phosphorylation, suggesting potential links between MND and disease. Intergenerational analyses also revealed constraints on MND, pointing to selective pressures in disease contexts. These findings underscore the importance of mitonuclear interactions in shaping disease phenotypes and highlight the need for further research into their functional and clinical implications, particularly in underrepresented populations.