Mitochondrial DNA sequencing reveals association of variants and haplogroup M33a2\u20323 with High altitude pulmonary edema susceptibility in Indian male lowlanders

Swati Sharma,Yamini Singh,Bhuvnesh Kumar,Lilly Ganju,Rajinder K Gupta,Shashi Bala Singh,Sayar Singh

doi:10.1038/s41598-019-47500-1

Abstract

High Altitude Pulmonary Edema (HAPE) is a threatening disorder caused due to acute exposure to high altitude above 3000 m. Apart from multiple factors involved, the genetic factors also play an important function in the pathogenesis of HAPE. This study aims to evaluate the role of mtDNA polymorphism and their association with haplogroup in understanding the etiology of HAPE. In this study, all the HAPE susceptible and acclimatized control subjects could be classified into nine haplogroups pertaining mostly to Macrohaplogroup M and U. The frequency of haplogroup M was significantly higher in HAPE susceptibles whereas the haplogroup M33a2′3 was found only in HAPE susceptibles. The variant G4491A and A4944G of MT-ND2, A14002G of MT-ND5, and C8562T of MT-ATP8, were definition site of haplogroup M33a2′3. The frequency of A10398G of MT-ND3, A8701G of MT-ATP6 and C14766T of MT-CYB genes were significantly higher in HAPE susceptibles. mtDNA copy number also plays a significant synergistic role in HAPE susceptibility. Our findings suggests that variants in MT-ND2 and MT-ND5 were predicted to confer decreased protein stability in HAPE susceptibles and in particular, highly conserved variants G4491A, A4944G and A14002G associated with haplogroup M33a2′3 may be the primary cause of susceptibility to HAPE in Indian male lowlanders.

Highlights

Mitochondria are semiautonomous cytoplasmic organelles of the eukaryotic system that imparts essential functions in energy metabolism, free radical production, calcium homeostasis and apoptosis[1,2,3]
On an average 97% processed data was aligned to the reference human genome and among the align reads 70% were aligned to mitochondrial genome with mapping quality ≥ Q29 and insert size ≥ 100 bp; an average of 17% of the passed reads were found to be duplicates
High Altitude Pulmonary Edema caused under hypoxic condition at high altitude have major impact in the energy generating oxidative phosphorylation (OXPHOS) system of mitochondria

Summary

Introduction

Mitochondria are semiautonomous cytoplasmic organelles of the eukaryotic system that imparts essential functions in energy metabolism, free radical production, calcium homeostasis and apoptosis[1,2,3]. Mitochondria may play an important role in high altitude adaptation/acclimatization, and the polymorphism in mtDNA might lead to susceptibility to HAPE. The mtDNA differs from nuclear genome in number of characteristics features, including frequent mutation, maternal inheritance, high copy number, and lack of recombination. All these features offer the potential for investigation of human evolution and origin[14]. We hypothesized that mtDNA haplogroup and polymorphism maybe an important factor in the susceptibility of HAPE To confirm this hypothesis whole mitochondrial genome sequencing of HAPE susceptible and acclimatized control individuals of Indian population has been done.

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