No abstract

Background: Malfunctioning or damaged mitochondria result in altered energy metabolism, redox equilibrium, and cellular dynamics and is a central point in the pathogenesis of neurological disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis. Therefore, it is of utmost importance to identify mitochondrial genetic susceptibility markers for neurodegenerative diseases. Potential markers include the respiratory chain enzymes Riboflavin kinase (RFK), Flavin adenine dinucleotide synthetase (FAD), Succinate dehydrogenase B subunit (SDHB), and Cytochrome C1 (CYC1). These enzymes are associated with neuroprotection and neurodegeneration. Objective: To test if variants in genes RFK, FAD, SDHB and CYC1 deviate from Hardy-Weinberg Equilibrium (HWE) in different human mitochondrial haplogroups. Methods: Sequence variants in genes RFK, FAD, SDHB and CYC1 of 2,504 non-affected individuals of the 1,000 genomes project were used for mitochondrial haplogroup assessment and HWE calculations in different mitochondrial haplogroups. Results: We show that RFK variants deviate from HWE in haplogroups G, H, L, V and W, variants of FAD in haplogroups B, J, L, U, and C, variants of SDHB in relation to the C, W, and A and CYC1 variants in B, L, U, D, and T. HWE deviation indicates action of selective pressures and genetic drift. Conclusions: HWE deviation of particular variants in relation to global populational HWE, could be, at least in part, associated with the differential susceptibility of specific populations and ethnicities to neurodegenerative diseases. Our data might contribute to the epidemiology and diagnostic/prognostic methods for neurodegenerative diseases.

peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/190363 doi: bioRxiv preprint first posted online Sep. 18, 2017; 3 Neandertal genetic contributions to the modern makeup of the human genome have been evidenced by comparative analyses of present day human genomes and paleogenomes (1-4). peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/190363 doi: bioRxiv preprint first posted online Sep. 18, 2017; 4 Single position cladograms of five representative polymorphic positions depict this pattern, which represents 10% of all polymorphic positions in the human mitochondrial genome.Here we show the pattern of position 2,706 (12S rRNA) (Fig. 1) (Table 1). It can be observed that the distribution of the clusters of modern human haplogroups with Neandertals vary among human haplogroups (Fig. 1).Haplogroup L3 is more related to Eurasian haplogroups than to the most divergent African clusters L1 and L2" (14). L3 is the haplogroup from which all modern humans outside of (16) It can be argued that the Neandertal signatures are in fact character states conserved since the last common ancestor of Neandertals and present day Homo sapiens (e.g. Homo erectus) but this would not be consistent with the absence of these signatures in ancient H. sapiens mitochondrial genomes (Fig. 1). Alternatively, the Neandertal signatures here described could be a consequence of random events. Because the random chance of the same nucleotide in a given position is 0.25 and there are 918 polymorphic positions in which 75 are Neandertal specific, it would roughly fit the 0.08 chance expectation. However, the chance that the 75 positions are simultaneously identical by chance alone would be roughly 0.25 75 which is far less than observed here.A back to Africa hypothesis has been proposed in which humans from Eurasia returned to Africa and impacted a wide range of sub-Saharan populations (19). Our data shows thatNeandertal signatures are present in all major African haplogroups thus confirming that the Back to Africa contribution to the modern mitochondrial African pool was extensive.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/190363 doi: bioRxiv preprint first posted online Sep. 18, 2017; 6 Our observations suggest that crosses between AMH males and Neandertal females left significantly less descendants than the reverse crosses (Neandertal males and AMH females), which seems to be the dominant pattern. Although it is generally accepted that recombination does not occur in the human mitochondrial genome there is a controversy over reported evidence on mitochondrial recombination (20,21). A scenario with complete absence of recombination presents a problem to expla...