Background: Mitochondria,the important energy-producing organelles in eukaryotic cells,possess their own genomes(mitochondrial genome,mtDNA)that are capable of self-replication,transcription and encoding proteins.Parkinson’s disease(PD)is the second leading neurodegenerative disease worldwide.Several studies have shown that mitochondrial dysfunction as implicated as a key factor in PD pathogenesis.In recent years,many studies have used high-throughput sequencing technology to investigate the mitochondrial genome of specific population.However,these studies have mainly focused on the European population,and there is a lack of large sample sizes of Chinese populations.Methods: In present study,we employed whole-genome sequencing(WGS)in 3241 unrelated Chinese population,including 1962 patients with PD and 1279 normal controls.Then,the sequencing data have been analyzed using bioinformatic pipelines,including identification of mitochondrial variants using Sentieon,annotation of variants by ANNOVAR,assignment of mitochondrial haplogroups to which the samples belonged based on detected mitochondrial variants by Haplo Grep2,and calculation of mitochondrial copy number based on autosomal depth and mitochondrial depth.Finally,we constructed a MTCards database was constructed using programming languages such as Java.Result:(1)In total,we identified 3892 mtDNA variants.According to the population frequency of variants,3349(86%)were rare variants,426(11%)were low-frequency variants,and 117(3%)were common variants;according to the heterogeneity level of variants,3274(84%)were all homoplasmic state in the population,140(4%)were all heteroplasmic state in the population,and 478(12%)had both homoplasmic and heteroplasmic state.(2)We observed a trend toward extreme heterogeneity of mtDNA variants.Specifically,a vast majority of variant calls(90%)were identified in the homoplasmic state,and the remaining heteroplasmic variants was mainly concentrated in the high-or low-level interval.(3)We confirmed distinct purifying selection on mtDNA through multiple aspects,and inhibits the accumulation of harmful heteroplasmies at the individual level.(4)There was no statistically significant difference in the distribution of the overall mtDNA variant between patients with PD and control subjects.(5)We found that haplogroup M(20.27%)and D(20.15%)had the highest frequencies in the Chinese population,followed by B(18.51%)and F(16.45%).The number of variants per individual differed across haplogroup groups,with a higher number of homoplasmies for the M lineage.(6)The distribution frequencies of 11 common mitochondrial haplogroups in East Asian populations were not statistically different between the PD and normal control groups.No significant association has been found between mtDNA haplogroups and the risk of PD.(7)Our results indicated that mtDNA copy number was negatively correlated with age but positively correlated with the female sex.(8)We identified a significantly lower mtDNA copy number in the peripheral blood cells of PD patients in comparison with normal control,the gap between the two groups became smaller with increasing age.(9)Finally,we developed an MTCards database to facilitate the query of mtDNA variants in this study.Conclusions: In summary,to better understand the impact of mitochondrial dysfunction on human health and lifespan,and to further explore the genetic basis of mitochondrial-related diseases.We performed WGS and comprehensive analysis of genetic data form a large cohort of Chinese population,and systematically explored the characteristics of mtDNA variants,haplogroups and copy number,and also compare PD population with normal control population.In the end,we established MTCards database to provide a high-quality variant dataset for further identification of pathogenic variants in mitochondrial-related diseases. |