African mtDNA Haplogroups Research Articles

Extracellular vesicle mitochondrial DNA levels are associated with race and mitochondrial DNA haplogroup

Circulating cell-free mitochondrial DNA (ccf-mtDNA) acts as a damage-associated molecular pattern molecule and may be cargo within extracellular vesicles (EVs). ccf-mtDNA and select mitochondrial DNA (mtDNA) haplogroups are associated with cardiovascular disease. We hypothesized that ccf-mtDNA and plasma EV mtDNA would be associated with hypertension, sex, self-identified race, and mtDNA haplogroup ancestry. Participants were normotensive (n= 107) and hypertensive (n= 108) African American and White adults from the Healthy Aging in Neighborhoods of Diversity across the Life Span study. ccf-mtDNA levels were higher in African American participants compared with White participants in both plasma and EVs, but ccf-mtDNA levels were not related to hypertension. EV mtDNA levels were highest in African American participants with African mtDNA haplogroup. Circulating inflammatory protein levels were altered with mtDNA haplogroup, race, and EV mtDNA. Our findings highlight that race is a social construct and that ancestry is crucial when examining health and biomarker differences between groups.

African mitochondrial haplogroup L7: a 100,000-year-old maternal human lineage discovered through reassessment and new sequencing

Archaeological and genomic evidence suggest that modern Homo sapiens have roamed the planet for some 300–500 thousand years. In contrast, global human mitochondrial (mtDNA) diversity coalesces to one African female ancestor (“Mitochondrial Eve”) some 145 thousand years ago, owing to the ¼ gene pool size of our matrilineally inherited haploid genome. Therefore, most of human prehistory was spent in Africa where early ancestors of Southern African Khoisan and Central African rainforest hunter-gatherers (RFHGs) segregated into smaller groups. Their subdivisions followed climatic oscillations, new modes of subsistence, local adaptations, and cultural-linguistic differences, all prior to their exodus out of Africa. Seven African mtDNA haplogroups (L0–L6) traditionally captured this ancient structure—these L haplogroups have formed the backbone of the mtDNA tree for nearly two decades. Here we describe L7, an eighth haplogroup that we estimate to be ~ 100 thousand years old and which has been previously misclassified in the literature. In addition, L7 has a phylogenetic sublineage L7a*, the oldest singleton branch in the human mtDNA tree (~ 80 thousand years). We found that L7 and its sister group L5 are both low-frequency relics centered around East Africa, but in different populations (L7: Sandawe; L5: Mbuti). Although three small subclades of African foragers hint at the population origins of L5'7, the majority of subclades are divided into Afro-Asiatic and eastern Bantu groups, indicative of more recent admixture. A regular re-estimation of the entire mtDNA haplotype tree is needed to ensure correct cladistic placement of new samples in the future.

Increased blood-derived mitochondrial DNA copy number in African ancestry individuals with Parkinson's disease

IntroductionAltered levels of mitochondrial DNA copy number (mtDNA-CN) have been proposed as a proxy for mitochondrial dysfunction. Following reports of mtDNA depletion in the blood and substantia nigra of Parkinson's disease (PD) cases, mtDNA-CN was also suggested as a possible biomarker for PD. Therefore, this study aimed to investigate whether blood mtDNA-CN levels of African ancestry PD cases would be altered compared to controls, as previously reported in individuals of Asian and European ancestry. MethodsDroplet digital polymerase chain reaction (ddPCR) was performed to quantify blood-derived mtDNA-CN levels as a ratio of a mitochondrial gene (MT-TL1) to a nuclear gene (B2M) in 72 PD cases and 79 controls of African ancestry (i.e. individuals with African mtDNA haplogroups) from South Africa. mtDNA-CN per cell was calculated by the formula 2 × MT-TL1/B2M. ResultsAccepting study limitations, we report significantly higher mtDNA-CN in whole blood of our PD cases compared to controls (median difference = 81 copies/cell), independent of age (95% CI [64, 98]; P < 0.001]). These findings contradict previous reports of mtDNA depletion in PD cases. ConclusionsWe caution that the observed differences in mtDNA-CN between the present and past studies may be a result of unaccounted-for factors and variability in study designs. Consequently, larger well-designed investigations may help determine whether mtDNA-CN is consistently altered in the blood of PD cases across different ancestries and whether it can serve as a viable biomarker for PD.

T Cell Activation Markers and African Mitochondrial DNA Haplogroups among Non-Hispanic Black Participants in AIDS Clinical Trials Group Study 384

IntroductionMitochondrial function influences T cell dynamics and is affected by mitochondrial DNA (mtDNA) variation. We previously reported an association between African mtDNA haplogroup L2 and less robust CD4 cell recovery on antiretroviral therapy (ART) in non-Hispanic black ACTG 384 subjects. We explored whether additional T cell parameters in this cohort differed by mtDNA haplogroup.MethodsACTG 384 randomized ART-naïve subjects to two different nucleoside regimens with efavirenz, nelfinavir, or both. CD4 and CD8 memory and activation markers were available at baseline and week 48 on most subjects. mtDNA sequencing was performed on whole blood DNA, and haplogroups were determined. We studied non-Hispanic black subjects with HIV RNA <400 copies/mL at week 48. Analyses included Wilcoxon ranksum test and linear regression.ResultsData from 104 subjects were included. Major African mtDNA haplogroups included L1 (N = 25), L2 (N = 31), and L3 (N = 32). Baseline age, HIV RNA, and CD4 cells did not differ between L2 and non-L2 haplogroups. Compared to non-L2 haplogroups, L2 subjects had lower baseline activated CD4 cells (median 12% vs. 17%; p = 0.03) and tended toward lower activated CD8 cells (41% vs. 47%; p = 0.06). At 48 weeks of ART, L2 subjects had smaller decreases in activated CD4 cells (−4% vs. −11%; p = 0.01), and smaller CD4 cell increases (+95 vs. +178; p = 0.002). In models adjusting for baseline age, CD4 cells, HIV RNA, and naïve-to-memory CD4 cell ratio, haplogroup L2 was associated with lower baseline (p = 0.04) and 48-week change in (p = 0.01) activated CD4 cells.ConclusionsAmong ART-naïve non-Hispanic blacks, mtDNA haplogroup L2 was associated with baseline and 48-week change in T cell activation, and poorer CD4 cell recovery. These data suggest mtDNA variation may influence CD4 T cell dynamics by modulating T cell activation. Further study is needed to replicate these associations and identify mechanisms.

Mitochondrial Genomics and CD4 T-Cell Count Recovery After Antiretroviral Therapy Initiation in AIDS Clinical Trials Group Study 384

Mitochondrial DNA (mtDNA) variation has been associated with time to progression to AIDS and adverse effects from antiretroviral therapy (ART). In this study, full mitochondrial DNA (mtDNA) sequence data from US-based adult participants in the AIDS Clinical Trials Group study 384 was used to assess associations between mtDNA variants and CD4 T-cell recovery with ART. Full mtDNA sequence was determined using chip-based array sequencing. Sequence and CD4 cell count data was available at baseline and after ART initiation for 423 subjects with HIV RNA levels <400 copies per milliliter plasma. The primary outcome was change in CD4 count of ≥100 cells per cubic millimeter from baseline. Analyses were adjusted for baseline age, CD4 cell count, HIV RNA, and naive:memory CD4 cell ratio. Race-stratified analysis of mtDNA variants with a minor allele frequency >1% revealed multiple mtDNA variants marginally associated (P < 0.05 before Bonferroni correction) with CD4 cell recovery. The most significant single nucleotide polymorphism associations were those tagging the African L2 haplogroup, which was associated with a decreased likelihood of ≥100 cells per cubic millimeter CD4 count increase at week 48 in non-Hispanic blacks (adjusted odds ratio = 0.17; 95% confidence interval = 0.06 to 0.53; P = 0.002). An African mtDNA haplogroup was associated with CD4 cell recovery after ART in this clinical trial population. These initial findings warrant replication and further investigation to confirm the role of mtDNA variation in CD4 cell recovery during ART.

Mitochondrial control region data of 3 ethnic groups from angola

Samples of 70 individuals from 3 ethnic groups from Angola (Bakongos, Kimbundu and Ovimbundu) were studied analysing the polymorphisms of the entire mitochondrial control region in order to verify the genetic diversity. A total of 68 different haplotypes were identified, 66 being unique. Sequence diversity was estimated to be 1.0000 ± 0.0113 and nucleotide diversity for Bakongo, Kimbundu and Ovimbundu ethnic groups were 0.015556 ± 0.007970, 0.016772 ± 0.008517 and 0.016020 ± 0.008411, respectively. It was possible to include the majority of the mtDNA haplotypes into a specific African mtDNA haplogroup.

Ancient Local Evolution of African mtDNA Haplogroups in Tunisian Berber Populations

Our objective is to highlight the age of sub-Saharan gene flows in North Africa and particularly in Tunisia. Therefore we analyzed in a broad phylogeographic context sub-Saharan mtDNA haplogroups of Tunisian Berber populations considered representative of ancient settlement. More than 2,000 sequences were collected from the literature, and networks were constructed. The results show that the most ancient haplogroup is L3*, which would have been introduced to North Africa from eastern sub-Saharan populations around 20,000 years ago. Our results also point to a less ancient western sub-Saharan gene flow to Tunisia, including haplogroups L2a and L3b. This conclusion points to an ancient African gene flow to Tunisia before 20,000 BP. These findings parallel the more recent findings of both archaeology and linguistics on the prehistory of Africa. The present work suggests that sub-Saharan contributions to North Africa have experienced several complex population processes after the occupation of the region by anatomically modern humans. Our results reveal that Berber speakers have a foundational biogeographic root in Africa and that deep African lineages have continued to evolve in supra-Saharan Africa.

Ancient Local Evolution of African mtDNA Haplogroups in Tunisian Berber Populations

Our objective is to highlight the age of sub-Saharan gene flows in North Africa and particularly in Tunisia. Therefore we analyzed in a broad phylogeographic context sub-Saharan mtDNA haplogroups of Tunisian Berber populations considered representative of ancient settlement. More than 2,000 sequences were collected from the literature, and networks were constructed. The results show that the most ancient haplogroup is L3*, which would have been introduced to North Africa from eastern sub-Saharan populations around 20,000 years ago. Our results also point to a less ancient western sub-Saharan gene flow to Tunisia, including haplogroups L2a and L3b. This conclusion points to an ancient African gene flow to Tunisia before 20,000 BP. These findings parallel the more recent findings of both archaeology and linguistics on the prehistory of Africa. The present work suggests that sub-Saharan contributions to North Africa have experienced several complex population processes after the occupation of the region by anatomically modern humans. Our results reveal that Berber speakers have a foundational biogeographic root in Africa and that deep African lineages have continued to evolve in supra-Saharan Africa.

Genetic signatures of parental contribution in black and white populations in Brazil

Two hundred and three individuals classified as white were tested for 11 single nucleotide polymorphisms plus two insertion/deletions in their Y-chromosomes. A subset of these individuals (n = 172) was also screened for sequences in the first hypervariable segment of their mitochondrial DNA (mtDNA). In addition, complementary studies were done for 11 of the 13 markers indicated above in 54 of 107 black subjects previously investigated in this southern Brazilian population. The prevalence of Y-chromosome haplogroups among whites was similar to that found in the Azores (Portugal) or Spain, but not to that of other European countries. About half of the European or African mtDNA haplogroups of these individuals were related to their places of origin, but not their Amerindian counterparts. Persons classified in these two categories of skin color and related morphological traits showed distinct genomic ancestries through the country. These findings emphasize the need to consider in Brazil, despite some general trends, a notable heterogeneity in the pattern of admixture dynamics within and between populations/groups.

Bayesian coalescent inference of major human mitochondrial DNA haplogroup expansions in Africa

Past population size can be estimated from modern genetic diversity using coalescent theory. Estimates of ancestral human population dynamics in sub-Saharan Africa can tell us about the timing and nature of our first steps towards colonizing the globe. Here, we combine Bayesian coalescent inference with a dataset of 224 complete human mitochondrial DNA (mtDNA) sequences to estimate effective population size through time for each of the four major African mtDNA haplogroups (L0-L3). We find evidence of three distinct demographic histories underlying the four haplogroups. Haplogroups L0 and L1 both show slow, steady exponential growth from 156 to 213kyr ago. By contrast, haplogroups L2 and L3 show evidence of substantial growth beginning 12-20 and 61-86kyr ago, respectively. These later expansions may be associated with contemporaneous environmental and/or cultural changes. The timing of the L3 expansion--8-12kyr prior to the emergence of the first non-African mtDNA lineages--together with high L3 diversity in eastern Africa, strongly supports the proposal that the human exodus from Africa and subsequent colonization of the globe was prefaced by a major expansion within Africa, perhaps driven by some form of cultural innovation.

MtDNA Haplogroup Analysis of Black Brazilian and Sub-Saharan Populations: Implications for the Atlantic Slave Trade

Seventy individuals from two African and four black Brazilian populations were studied for the first hypervariable segment of mtDNA. To delineate a more complete phylogeographic scenario of the African mtDNA haplogroups in Brazil and to provide additional information on the nature of the Atlantic slave trade, we analyzed our data together with previously published data. The results indicate different sources of African slaves for the four major Brazilian regions. In addition, the data revealed patterns that differ from those expected on the basis of historical registers, thus suggesting the role of ethnic sex differences in the slave trade.

Biochemical features of mtDNA 14484 (ND6/m64V) point mutation associated with Leber's hereditary optic neuropathy

We report the effect on complex I function of the 14484 Leber's hereditary optic neuropathy (LHON) mutation affecting the ND6 subunit gene. The same gene was also reported to carry another mutation, at position 14459, associated with the LHON/dystonia phenotype that induces a reduction of complex I–specific activity and increases the sensitivity to the product decylubiquinol. Given the proximity of both mutations in the ND6 gene, we tested the specific activity of complex I and its sensitivity to myxothiazol and nonylbenzoquinol, both inhibitors at the ubiquinol product site, in platelet submitochondrial particles from nine 14484 homoplasmic individuals, 8 Italians with Caucasian mtDNA haplogroup J (adjunctive 4216 and 13708 mutations), and 1 Tunisian with an African mtDNA haplogroup. The specific activity of complex I was not affected by the 14484 mutation, but the sensitivity to both inhibitors was significantly increased compared with control subjects regardless of the presence of haplogroup J polymorphisms. Analysis of 70 different amino acid sequences of the ND6 subunit indicated that the 14484 mutation affects an amino acid belonging to its most conserved region, which shows local similarities with cytochrome b regions interacting with ubiquinone or ubiquinol in complex III. Our results suggest that both 14484 and 14459 mutations may affect amino acids forming the interaction site of ubiquinol product, and the 14484 mutation produces a biochemical defect resembling in part that already reported for the common 11778/ND4 LHON mutation. Ann Neurol 1999;45:320–328

Biochemical features of mtDNA 14484 (ND6/m64V) point mutation associated with Leber's hereditary optic neuropathy

We report the effect on complex I function of the 14484 Leber's hereditary optic neuropathy (LHON) mutation affecting the ND6 subunit gene. The same gene was also reported to carry another mutation, at position 14459, associated with the LHON/dystonia phenotype that induces a reduction of complex I-specific activity and increases the sensitivity to the product decylubiquinol. Given the proximity of both mutations in the ND6 gene, we tested the specific activity of complex I and its sensitivity to myxothiazol and nonylbenzoquinol, both inhibitors at the ubiquinol product site, in platelet submitochondrial particles from nine 14484 homoplasmic individuals, 8 Italians with Caucasian mtDNA haplogroup J (adjunctive 4216 and 13708 mutations), and 1 Tunisian with an African mtDNA haplogroup. The specific activity of complex I was not affected by the 14484 mutation, but the sensitivity to both inhibitors was significantly increased compared with control subjects regardless of the presence of haplogroup J polymorphisms. Analysis of 70 different amino acid sequences of the ND6 subunit indicated that the 14484 mutation affects an amino acid belonging to its most conserved region, which shows local similarities with cytochrome b regions interacting with ubiquinone or ubiquinol in complex III. Our results suggest that both 14484 and 14459 mutations may affect amino acids forming the interaction site of ubiquinol product, and the 14484 mutation produces a biochemical defect resembling in part that already reported for the common 11778/ND4 LHON mutation.