Hardy-Weinberg Equilibrium in different mitochondrial haplogroups of four genes associated with neuroprotection and neurodegeneration.

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.

Hardy-Weinberg Equilibrium in different mitochondrial haplogroups of four genes associated with neuroprotection and neurodegeneration / Equilíbrio de Hardy-Weinberg em diferentes haplogrupos mitocondriais de quatro genes associados à neuroproteção e neurodegeneração

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.

RESUMO Introdução: Mitocôndrias defeituosas ou danificadas resultam em alterações do metabolismo energético, equilíbrio redox e dinâmica celular e são, portanto, identificadas como o ponto central da patogênese em muitos distúrbios neurológicos, como a doença de Alzheimer, a doença de Parkinson, a doença de Huntington e a Esclerose Lateral Amiotrófica. Portanto, é de fundamental importância identificar marcadores de susceptibilidade genética mitocondrial para doenças neurodegenerativas. Entre os potenciais marcadores relevantes estão as enzimas da cadeia respiratória riboflavina quinase (RFK), flavina adenina dinucleotídeo sintetase (FAD), succinato desidrogenase subunidade B (SDHB) e citocromo C1 (CYC1). Estas enzimas estão associadas à neuroproteção e à neurodegeneração. Objetivo: Testar se variantes nas sequências dos genes RFK, FAD, SDHB e CYC1 desviam do Equilíbrio de Hardy-Weinberg (HWE) em diferentes haplogrupos mitocondriais humanos. Métodos: Neste trabalho utilizamos os variantes nos genes RFK, FAD, SDHB e CYC1 de sequências de 2.504 indivíduos não afetados do projeto de 1.000 genomas para o cálculo dos valores de HWE em diferentes haplogrupos mitocondriais. Resultados: As variantes de RFK desviam de HWE nos haplogrupos G, H, L, V e W, variantes de FAD nos haplogrupos B, J, L, U e C, variantes de SDHB em relação às variantes C, W e A e CYC1 em B, L, U, D e T. O desvio de HWE indica a ação de pressões seletivas e desvio genético. Conclusões: O desvio do HWE de variantes particulares em relação ao HWE populacional global poderia estar, pelo menos em parte, associado à suscetibilidade diferencial de populações e etnias específicas a doenças neurodegenerativas. Nossos dados podem contribuir para a epidemiologia e métodos diagnósticos/prognósticos para doenças neurodegenerativas.