Biology subjects

Repetto, G. M.

Publications and source records attributed to Repetto, G. M..

3 recordsLinked to original sources

bioRxiv2025

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.

genomics↗

bioRxiv2022

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS and sporadic congenital heart disease

BackgroundCongenital heart disease (CHD) affecting the conotruncal region of the heart, occur in half of patients with 22q11.2 deletion syndrome. This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, mapped to the 22q11.2 region, encoding a T-box transcription factor, is one of the main genes for the etiology of the syndrome. We suggest that genetic modifiers of CHD in patients with 22q11.2 deletion syndrome may be in the TBX1 gene network. MethodsTo identify genetic modifiers of 22q11.2 deletion syndrome, we analyzed whole genome sequence of subjects with 22q11.2DS, of which 456 were cases with conotruncal heart defects and 537 were controls with normal cardiac structures. We retained the most damaging rare coding variants and examined 19 functional gene sets for association that were weighted upon expression of genes in cardiac progenitor cells in mouse embryos identified by RNA-sequencing. ResultsWe identified rare damaging coding variants in chromatin regulatory genes as modifiers of conotruncal heart defects in 22q11.2DS. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2 deletion syndrome cases. Many of these genes were identified as risk factors for sporadic CHD in the general population increasing the likelihood that these genes are medically important contributors for CHD. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. Some of the genes identified, such as KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models, providing mechanistic validation of these genes found. ConclusionsOur findings indicate that disturbance of chromatin regulatory genes impact a TBX1 gene network serving as genetic modifiers of 22q11.2 deletion syndrome. Since some of these chromatin regulatory genes were found in individuals with sporadic CHD, we suggest that there are shared mechanisms involving the TBX1 gene network in the etiology of CHD.

genetics↗

bioRxiv2018

Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior

Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts and mouse brains carrying a 22q11.2-like defect, Df(16)A+/-. Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the Drosophila SLC25A4 orthologue, dSLC25A4-sesB, affected synapse function and impaired sleep patterns in a neuronal-specific manner. These results identify a novel synaptic role of mitochondrial inner membrane solute transporters. We propose that mitochondria are among key organelles affected by genetic defects that increase the risk of neurodevelopmental disorders.

neuroscience↗