scholarly journals The population frequency of human mitochondrial DNA variants is highly dependent upon mutational bias

Biology Open ◽  
2021 ◽  
Author(s):  
Cory D. Dunn
Keyword(s):  
Mitochondrial Dna ◽  
Rare Variants ◽  
Mutational Bias ◽  
Low Frequencies ◽  
Synonymous Substitutions ◽  
Genomic Changes ◽  
Population Frequency ◽  
Variant Frequency ◽  
Mitochondrial Dna Variants

Next-generation sequencing can quickly reveal genetic variation potentially linked to heritable disease. As databases encompassing human variation continue to expand, rare variants have been of high interest, since the frequency of a variant is expected to be low if the genetic change leads to a loss of fitness or fecundity. However, the use of variant frequency when seeking genomic changes linked to disease remains very challenging. Here, we explore the role of selection in controlling human variant frequency using the HelixMT database, which encompasses hundreds of thousands of mitochondrial DNA (mtDNA) samples. We find that a substantial number of synonymous substitutions, which have no effect on protein sequence, were never encountered in this large study, while many other synonymous changes are found at very low frequencies. Further analyses of human and mammalian mtDNA datasets indicate that the population frequency of synonymous variants is predominantly determined by mutational biases rather than by strong selection acting upon nucleotide choice. Our work has important implications that extend to the interpretation of variant frequency for non-synonymous substitutions.

scholarly journals The population frequency of human mitochondrial DNA variants is highly dependent upon mutational bias

2021 ◽  
Author(s):  
Cory D. Dunn
Keyword(s):  
Mitochondrial Dna ◽  
Rare Variants ◽  
Association Studies ◽  
Mitochondrial Protein ◽  
Mutational Bias ◽  
Genome Wide Association Studies ◽  
Human Mitochondrial Dna ◽  
Genomic Changes ◽  
Common Genetic Variants ◽  
Variant Frequency

Genome-wide association studies (GWASs) typically seek common genetic variants that can influence disease likelihood. However, these analyses often fail to convincingly link specific genes and their variants with highly penetrant phenotypic effects. To solve the 'missing heritability problem' that characterizes GWASs, researchers have turned to rare variants revealed by next-generation sequencing when seeking genomic changes that may be pathogenic, as a reduction in variant frequency is an expected outcome of selection. While triage of rare variants has led to some success in illuminating genes linked to heritable disease, the interpretation and utilization of rare genomic changes remains very challenging. Human mitochondrial DNA (mtDNA) encodes proteins and RNAs required for the essential process of oxidative phosphorylation, and a number of metabolic diseases are linked to mitochondrial mutations. Recently, the mtDNAs of nearly 200,000 individuals were sequenced in order to produce the HelixMT database (HelixMTdb), a large catalog of human mtDNA variation. Here, we were surprised to find that many synonymous nucleotide substitutions were never detected within this quite substantial survey of human mtDNA. Subsequent study of more than 1000 mammalian mtDNAs suggested that selection on synonymous sites within mitochondrial protein-coding genes is minimal and unlikely to explain the rarity of most synonymous changes among humans. Rather, the mutational propensities of mtDNA are more likely to determine variant frequency. Our findings have general implications for the interpretation of variant frequencies when studying heritable disease.

scholarly journals Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jaakko Laaksonen ◽  
Pashupati P. Mishra ◽  
Ilkka Seppälä ◽  
Leo-Pekka Lyytikäinen ◽  
Emma Raitoharju ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mitochondrial Dna ◽  
Genome Wide Association Study ◽  
Rare Variants ◽  
Meta Analysis ◽  
Noncommunicable Diseases ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Mitochondrial Dna Variants

AbstractHigh blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.

scholarly journals Relationship between chromosomal and mitochondrial DNA variability of Drosophila subobscura population from the Lazar’s river canyon

Genetika ◽  
2012 ◽  
Vol 44 (2) ◽  
pp. 409-417 ◽  
Author(s):  
Mihailo Jelic ◽  
Bojan Kenig ◽  
Marija Tanaskovic ◽  
Marina Stamenkovic-Radak ◽  
Marko Andjelkovic
Keyword(s):  
Mitochondrial Dna ◽  
Restriction Site ◽  
Environmental Variability ◽  
Drosophila Subobscura ◽  
Frequent Pattern ◽  
Significant Linkage Disequilibrium ◽  
Low Frequencies ◽  
Mitochondrial Dna Variability ◽  
Significant Linkage

The genetic structure of Drosophila subobscura population from the Lazar?s River Canyon (Serbia) was studied with respect to restriction site polymorphism of mitochondrial DNA and chromosomal inversion polymorphism. The aim was to shed more light on the role of cytonuclear interactions in shaping mitochondrial DNA variability in this species. Similar to other populations of D. subobscura two main haplotypes (I and II) were found, as well as less common ones that appeared at very low frequencies. The frequency distribution of haplotypes did not depart from neutrality. We did not find statistically significant linkage disequilibrium between the haplotypes belonging to haplogroups I and II and any of the chromosomal arrangements. However, when we compared the data in hereby analyzed population and two previously analyzed populations we observed that haplotype I is more frequent in populations where standard inversion arrangements are less frequent. Pattern of the observed mitochondrial variability could be influenced either directly by environmental variability or through environmentally specific cytonuclear coadaptation.

scholarly journals Role of mitochondrial DNA variants and copy number in diabetic atherogenesis

2012 ◽  
Vol 11 (3) ◽  
pp. 3339-3348 ◽  
Author(s):  
M.C. Chien ◽  
W.T. Huang ◽  
P.W. Wang ◽  
C.W. Liou ◽  
T.K. Lin ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Copy Number ◽  
Dna Variants ◽  
Mitochondrial Dna Variants

Role of mitochondrial DNA variants in the development of fragile X-associated tremor/ataxia syndrome

Mitochondrion ◽  
2020 ◽  
Vol 52 ◽  
pp. 157-162
Author(s):  
Maria Isabel Alvarez-Mora ◽  
Cristina Santos ◽  
Lidia Carreño-Gago ◽  
Irene Madrigal ◽  
Maria Isabel Tejada ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Fragile X ◽  
Dna Variants ◽  
Ataxia Syndrome ◽  
Mitochondrial Dna Variants

The role of mitochondrial DNA in the cancerogenesis of cervix HPV positive women

2008 ◽  
Vol 21 (2) ◽  
pp. 85-89
Author(s):  
Alicja Warowicka ◽  
Joanna Pacholska-Bogalska ◽  
Anna Kwaśniewska ◽  
Anna Goździcka-Józefiak
Keyword(s):  
Mitochondrial Dna

scholarly journals The LEPR Gene Is Associated with Reproductive Seasonality Traits in Rasa Aragonesa Sheep

Animals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2448
Author(s):  
Kenza Lakhssassi ◽  
Malena Serrano ◽  
Belén Lahoz ◽  
María Pilar Sarto ◽  
Laura Pilar Iguácel ◽  
...  
Keyword(s):  
Amino Acid Change ◽  
Leptin Receptor ◽  
Extreme Values ◽  
Reproductive Traits ◽  
Reproductive Seasonality ◽  
Synonymous Substitutions ◽  
Lepr Gene ◽  
Exon 20 ◽  
First Time

The aim of this study was to characterize and identify causative polymorphisms in the leptin receptor (LEPR) gene responsible for the seasonal variation of reproductive traits in sheep. Three reproductive seasonality traits were studied: the total days of anoestrous (TDA), the progesterone cycling months (P4CM) and the oestrous cycling months (OCM). In total, 18 SNPs were detected in 33 ewes with extreme values for TDA and OCM. Six SNPs were non-synonymous substitutions and two of them were predicted in silico as deleterious: rs596133197 and rs403578195. These polymorphisms were then validated in 239 ewes. The SNP rs403578195, located in exon 8 and leading to a change of alanine to glycine (Ala284Gly) in the extracellular domain of the protein, was associated with the OCM trait, being the G allele associated with a decrease of 12 percent of the OCM trait. Haplotype analyses also suggested the involvement of other non-synonymous SNP located in exon 20 (rs405459906). This SNP also produces an amino acid change (Lys1069Glu) in the intracellular domain of the protein and segregates independently of rs403578195. These results confirm for the first time the role of the LEPR gene in sheep reproductive seasonality.

Role of Mitochondrial DNA in Inflammatory Airway Diseases

2021 ◽  
pp. 1485-1499
Author(s):  
Ryan J. Snyder ◽  
Steven R. Kleeberger
Keyword(s):  
Mitochondrial Dna ◽  
Airway Diseases

scholarly journals Cytosolic Ribosomal Mutations That Abolish Accumulation of Circular Intron in the Mitochondria Without Preventing Senescence of Podospora anserina

Genetics ◽  
1997 ◽  
Vol 145 (3) ◽  
pp. 697-705 ◽  
Author(s):  
Philippe Silar ◽  
France Koll ◽  
Michèle Rossignol
Keyword(s):  
Mitochondrial Dna ◽  
Ribosomal Proteins ◽  
Podospora Anserina ◽  
Cox1 Gene ◽  
Accuracy Control ◽  
Additional Function ◽  
Mutant Proteins ◽  
Double Stranded Dna ◽  
Dna Modifications

The filamentous fungus Podospora anserina presents a degeneration syndrome called Senescence associated with mitochondrial DNA modifications. We show that mutations affecting the two different and interacting cytosolic ribosomal proteins (S7 and S19) systematically and specifically prevent the accumulation of senDNAα (a circular double-stranded DNA plasmid derived from the first intron of the mitochondrial cox1 gene or intron α) without abolishing Senescence nor affecting the accumulation of other usually observed mitochondrial DNA rearrangements. One of the mutant proteins is homologous to the Escherichia coli S4 and Saccharomyces cerevisiae S13 ribosomal proteins, known to be involved in accuracy control of cytosolic translation. The lack of accumulation of senDNAα seems to result from a nontrivial ribosomal alteration unrelated to accuracy control, indicating that S7 and S19 proteins have an additional function. The results strongly suggest that modified expression of nucleus-encoded proteins contributes to Senescence in P. anserina. These data do not fit well with some current models, which propose that intron α plays the role of the cytoplasmic and infectious Determinant of Senescence that was defined in early studies.

scholarly journals The Role of Mitochondria in Carcinogenesis

2021 ◽  
Vol 22 (10) ◽  
pp. 5100
Author(s):  
Paulina Kozakiewicz ◽  
Ludmiła Grzybowska-Szatkowska ◽  
Marzanna Ciesielka ◽  
Jolanta Rzymowska
Keyword(s):  
Prostate Cancer ◽  
Mitochondrial Dna ◽  
Nuclear Dna ◽  
Dna Polymorphisms ◽  
Gene Encoding ◽  
Dna Mutations ◽  
Nadh Ubiquinone Oxidoreductase ◽  
Gene Coi ◽  
The Impact

The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension.

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