Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial dysfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS. The aim of this study was to determine whether mitogenome variants are associated with ALS. METHODS: We conducted a genome-wide association study (GWAS) in mitogenomes of 1965 ALS patients and 2547 controls. RESULTS: We identified 51 mitogenome variants with p values <10-7, of which 13 had odds ratios (ORs) >1, in genes RNR1, ND1, CO1, CO3, ND5, ND6, and CYB, while 38 variants had OR <1 in genes RNR1, RNA2, ND1, ND2, CO2, ATP8, ATP6, CO3, ND3, ND4, ND5, ND6, and CYB. The frequencies of haplogroups H, U, and L, the most frequent in our ALS data set, were the same in different onset sites (bulbar, limb, spinal, and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U. DISCUSSION: Our study shows that mitogenome single nucleotide variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy has the potential to serve as a basis for ALS treatment.

Convergent Mutations and Single Nucleotide Variants in Mitochondrial Genomes of Modern Humans and Neanderthals.

The genetic contributions of Neanderthals to the modern human genome have been evidenced by the comparison of present-day human genomes with paleogenomes. Neanderthal signatures in extant human genomes are attributed to intercrosses between Neanderthals and archaic anatomically modern humans (AMHs). Although Neanderthal signatures are well documented in the nuclear genome, it has been proposed that there is no contribution of Neanderthal mitochondrial DNA to contemporary human genomes. Here we show that modern human mitochondrial genomes contain 66 potential Neanderthal signatures, or Neanderthal single nucleotide variants (N-SNVs), of which 36 lie in coding regions and 7 result in nonsynonymous changes. Seven N-SNVs are associated with traits such as cycling vomiting syndrome, Alzheimer's disease and Parkinson's disease, and two N-SNVs are associated with intelligence quotient. Based on recombination tests, principal component analysis (PCA) and the complete absence of these N-SNVs in 41 archaic AMH mitogenomes, we conclude that convergent evolution, and not recombination, explains the presence of N-SNVs in present-day human mitogenomes.

Complete genome sequence and analysis of a Saccharomyces cerevisiae strain used for sugarcane spirit production.

Distillation of fermented sugarcane juice produces both rum and cachaça, significant sources of revenue in Brazil and elsewhere. In this study, we provide a genomic analysis of a Saccharomyces cerevisiae strain isolated from a cachaça distillery in Brazil. We determined the complete genome sequence of a strain with high flocculation capacity, high tolerance to ethanol, osmotic and heat shock stress and high fermentation rates and compared the sequence with that of the reference S288c genome as well as those of two other cachaça strains. Single-nucleotide polymorphism analysis identified alterations in genes involved in nitrogen and organic compound metabolism, integrity of organelles and ion homeostasis. The strain exhibited fragmentation of several flocculation genes relative to the reference genome, as well as loss of a stop codon in the FLO8 gene, which encodes a transcription factor required for FLO gene expression. The strain contained no genes not present in the reference genome strain but did lack several genes, including asparaginase genes, maltose utilization loci, and several genes from the tandem array of the DUP240 family. The three cachaça strains lacked different sets of genes, but the asparaginase genes and several of the DUP240 genes were common deficiencies. This study provides new insights regarding the selective pressure of sugarcane fermentation on the genome of yeast strains and offers additional genetic resources for modern synthetic biology and genome editing tools.

Genetically Modified Labeling Policies: Moving Forward or Backward?

One of the priorities to address food security is to increase the access of farmers to biotechnology, through the application of scientific advances, such as genetically modified organisms and food (GMF). However, the spread of (mis)information about their safety strengthens the clamor for mandatory GMF labeling. This paper provides an overview of food labeling policies, considering the principles suggested by the Codex Alimentarius Commission, and analyzes the consequences for the world food security of the Brazilian labeling policies compared to developed countries. We discuss the discriminatory application of GMF mandatory labeling in the absence of any scientific evidence as it has the potential of causing social harm and jeopardizes research, production, and distribution of food and consumers' right to information.

A Possible Role for Platelet-Activating Factor Receptor in Amyotrophic Lateral Sclerosis Treatment.

Amyotrophic lateral sclerosis (ALS) is the third most prevalent neurodegenerative disease affecting upper and lower motor neurons. An important pathway that may lead to motor neuron degeneration is neuroinflammation. Cerebrospinal Fluids of ALS patients have increased levels of the inflammatory cytokine IL-18. Because IL-18 is produced by dendritic cells stimulated by the platelet-activating factor (PAF), a major neuroinflammatory mediator, it is expected that PAF is involved in ALS. Here we show pilot experimental data on amplification of PAF receptor (PAFR) mRNA by RT-PCR. PAFR is overexpressed, as compared to age matched controls, in the spinal cords of transgenic ALS SOD1-G93A mice, suggesting PAF mediation. Although anti-inflammatory drugs have been tested for ALS before, no clinical trial has been conducted using PAFR specific inhibitors. Therefore, we hypothesize that administration of PAFR inhibitors, such as Ginkgolide B, PCA 4248 and WEB 2086, have potential to function as a novel therapy for ALS, particularly in SOD1 familial ALS forms. Because currently there are only two approved drugs with modest effectiveness for ALS therapy, a search for novel drugs and targets is essential.

High hydrostatic pressure activates gene expression that leads to ethanol production enhancement in a Saccharomyces cerevisiae distillery strain.

High hydrostatic pressure (HHP) is a stress that exerts broad effects on microorganisms with characteristics similar to those of common environmental stresses. In this study, we aimed to identify genetic mechanisms that can enhance alcoholic fermentation of wild Saccharomyces cerevisiae isolated from Brazilian spirit fermentation vats. Accordingly, we performed a time course microarray analysis on a S. cerevisiae strain submitted to mild sublethal pressure treatment of 50 MPa for 30 min at room temperature, followed by incubation for 5, 10 and 15 min without pressure treatment. The obtained transcriptional profiles demonstrate the importance of post-pressurisation period on the activation of several genes related to cell recovery and stress tolerance. Based on these results, we over-expressed genes strongly induced by HHP in the same wild yeast strain and identified genes, particularly SYM1, whose over-expression results in enhanced ethanol production and stress tolerance upon fermentation. The present study validates the use of HHP as a biotechnological tool for the fermentative industries.

High hydrostatic pressure activates transcription factors involved in Saccharomyces cerevisiae stress tolerance.

A number of transcriptional control elements are activated when Saccharomyces cerevisiae cells are submitted to various stress conditions, including high hydrostatic pressure (HHP). Exposure of Saccharomyces cerevisiae cells to HHP results in global transcriptional reprogramming, similar to that observed under other industrial stresses, such as temperature, ethanol and oxidative stresses. Moreover, treatment with a mild hydrostatic pressure renders yeast cells multistress tolerant. In order to identify transcriptional factors involved in coordinating response to high hydrostatic pressure, we performed a time series microarray expression analysis on a wild S. cerevisiae strain exposed to 50 MPa for 30 min followed by recovery at atmospheric pressure (0.1 MPa) for 5, 10 and 15 min. We identified transcription factors and corresponding DNA and RNA motifs targeted in response to hydrostatic pressure. Moreover, we observed that different motif elements are present in the promoters of induced or repressed genes during HHP treatment. Overall, as we have already published, mild HHP treatment to wild yeast cells provides multiple protection mechanisms, and this study suggests that the TFs and motifs identified as responding to HHP may be informative for a wide range of other biotechnological and industrial applications, such as fermentation, that may utilize HHP treatment.