Analysis of human mitochondrial genome co-occurrence networks of Asian population at varying altitudes

Rahul K Verma,Sarika Jalan,Pramod Shinde,Mikhail Ivanchenko,Alena Kalyakulina,Ajay Deep Kachhvah,Cristina Giuliani

doi:10.1038/s41598-020-80271-8

Abstract

Networks have been established as an extremely powerful framework to understand and predict the behavior of many large-scale complex systems. We studied network motifs, the basic structural elements of networks, to describe the possible role of co-occurrence of genomic variations behind high altitude adaptation in the Asian human population. Mitochondrial DNA (mtDNA) variations have been acclaimed as one of the key players in understanding the biological mechanisms behind adaptation to extreme conditions. To explore the cumulative effects of variations in the mitochondrial genome with the variation in the altitude, we investigated human mt-DNA sequences from the NCBI database at different altitudes under the co-occurrence motifs framework. Analysis of the co-occurrence motifs using similarity clustering revealed a clear distinction between lower and higher altitude regions. In addition, the previously known high altitude markers 3394 and 7697 (which are definitive sites of haplogroup M9a1a1c1b) were found to co-occur within their own gene complexes indicating the impact of intra-genic constraint on co-evolution of nucleotides. Furthermore, an ancestral ‘RSRS50’ variant 10,398 was found to co-occur only at higher altitudes supporting the fact that a separate route of colonization at these altitudes might have taken place. Overall, our analysis revealed the presence of co-occurrence interactions specific to high altitude at a whole mitochondrial genome level. This study, combined with the classical haplogroups analysis is useful in understanding the role of co-occurrence of mitochondrial variations in high altitude adaptation.

Highlights

Networks have been established as an extremely powerful framework to understand and predict the behavior of many large-scale complex systems
The factors contributing to these variations are, (i) proteins from Mitochondrial DNA (mtDNA) interact with each other and with those imported from the cytoplasm, and form four of the five complexes of the oxidative phosphorylation (OXPHOS); and (ii) the presumption of total absence of crossing over in mtDNA, i.e., each genome has a set hierarchical history which is shared by all the genes
Here we have considered the simplest motifs of order two only for the further analysis. Among these variable sites, ∼ 65% sites were found to be located in protein-coding regions with the rest lying in non-coding regions (Table 1)

Summary

Introduction

Networks have been established as an extremely powerful framework to understand and predict the behavior of many large-scale complex systems. This study, combined with the classical haplogroups analysis is useful in understanding the role of co-occurrence of mitochondrial variations in high altitude adaptation. Mitochondria are the energy centers in eukaryotic cells and recent studies showed that the diversity of the mitochondrial genome may have a role in the adaptation to hypoxia in T ibetans[20]. Mitochondria have their own DNA of 16,569 bp encoding 13 proteins and 24 RNAs (2 ribosomal RNAs and 22 transfer RNAs) and are inherited solely through the maternal line (uniparental inheritance). It was suggested that a site undergoing evolutionary pressure might have affected the genealogy of the whole mitochondrial g enome[25]

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