Genomic profiling of mitochondrial DNA reveals novel complex gene mutations in familial type 2 diabetes mellitus individuals from Mizo ethnic population, Northeast India

Highlights

• The current work is the first approach related to mtDNA sequencing from a high risk tribal population.

• Mutations in the coding and noncoding regions of the mitochondria might have contribution towards the development of T2D.

• This study can be used as a diagnostic marker towards T2D.

Abstract

The variants reported for mitochondrial DNA (mtDNA) and type 2 diabetes (T2D) may not be accountable for the disease in certain other populations and the risk depends upon numerous factors which may include genetics, environment as well as ethnicity. This leads to a challenge in identifying, exploring and comparing the variants between diabetic cases and healthy controls in a remote unexplored tribal population. To study the possible contribution of mtDNA variants, we sequenced the entire mitochondrial genomes and the frequencies of mtSNPs, their association with familial T2D and the potential impact of non-synonymous substitutions on protein functions were determined. The mtSNP 8584 G > A (ATP6: A20T) was detected in 14.28% of the diabetic patients and none in the control groups. The mitochondrial ND3 variant 10398A > G was found to be significantly associated with the risk of T2D (OR = 9.489, 95% CI = 1.161–77.54, P value = 0.036). A novel Frame-shift substitution ND5: 81_81ins A at position 12,417 was observed in 53.57% of diabetic individuals. Majority of the variants lie in tRNA-Phe in the non-protein coding region of mtDNA for both diabetic cases and common cases. We concluded that mutations in the coding (synonymous or non-synonymous) and noncoding regions of the mitochondria might have contribution towards the development of T2D. Our study is the first to report the distinct mitochondrial variants which may be attributed to the susceptibility as well as development of type 2 diabetes in an ethnic tribe from northeast India.

Introduction

Type 2 diabetes is known to be characterized by mitochondrial dysfunction which may lead to oxidative stress. Since Mitochondria is the major site and source for production of ATP and reactive oxygen species, elevation in the glucose levels can disrupt the nature of the production (Rovira-Llopis et al., 2017, Szendroedi and Phielix, 2011). A number of impairment in the genes of mitochondria can play a critical role in the development of age-dependent insulin resistance and leads to type 2 diabetes (Petersen et al., 2003). There are many possible factors which play a role in the progression and evolution of type 2 diabetes; many individuals have more susceptibility in developing the disease. This is due to the fact that they inherited the susceptible genes from one of their parents or may be both. The only extra-chromosomal DNA in the Human cells lies in the mitochondrial genome and abnormalities in the mitochondrial DNA have been reported to cause diabetes (Ballinger et al., 1992).

Before the 1980′s, the genetic variants involved in the hereditary risk remained unclear, but with the advancement in genetic research and technologies several variants were discovered (Ali, 2013). From studies among different populations, the chances of heritability of an individual to type 2 diabetes may range from 20 to 80%; 40% chance for a person with single parent diagnosed with the disease and 70% chance, if both the parents are affected with the disease (Tillil and Köbberling, 1987, Meigs et al., 2000, Poulsen et al., 1999). In families with history of diabetes, mutations which may be either point or rearrangement have been identified (van den Ouweland et al., 1992). There are several mtDNA mutations recognized to consistently express a phenotype which includes diabetes (Choo-Kang et al., 2002). Although mtDNA point mutations have been described it has been observed to appear much rarer to be associated with diabetes (Lynn et al., 1998). Mitochondrial DNA deletions have been reported to cause diabetes in individuals with Chronic progressive external ophthalmoplegia (CPEO) and Kearns Sayre Syndrome (KSS) (Whittaker et al., 2007).

The risk of having the disease is higher with individuals having genetic alterations as compared to individuals having no alteration. At present, it has been reported that around 40 or more mutations in the mitochondria are known to be related with several mitochondrial disorders and type 2 diabetes. It has been reported by Lee et al. that even before the onset of type 2 diabetes, the copy number of mitochondrial DNA has decreased in the individuals with the disease (Lee et al., 1998). The mechanism involved in Oxidative phosphorylation in the mitochondria has also been found to be decreasing in the offspring of individuals having insulin resistant diabetic patients (Petersen et al., 2004).

Mizoram belongs to one of the eight sister states of the North-eastern region of India, bordered by Bangladesh and Myanmar and is the second least populous state in the country (NCERT, 2017). Mizoram has shown an increase in reports and cases of type 2 diabetes mellitus and it becomes a huge challenge to understand the impact of abnormalities in the mitochondria which may contribute to the development of type 2 diabetes. The study focuses on the possible contribution of mitochondrial variants in genetic predisposition to T2D as well as to find out whether mtDNA Coding and Control Region Variants contribute as a risk factor for the disease in Mizo population.