An asymptotically normal test for the selective neutrality hypothesis

An important parameter in the study of population evolution is $\theta=4N\nu$, where $N$ is the effective population size and $\nu$ is the rate of mutation per locus per generation. Therefore, $\theta$ represents the mean number of mutations per site per generation. There are many estimators of $\theta$, one of them being the mean number of pairwise nucleotide differences, which we call $\mathcal{T}_2$. Other estimators are $\mathcal{T}_1$, based on the number of segregating sites and $\mathcal{T}_3$, based on the number of singletons. The concept of selective neutrality can be interpreted as a differentiated nucleotide distribution for mutant sites when compared to the overall nucleotide distribution. Tajima (1989) has proposed the so-called Tajima's test of selective neutrality based on $\mathcal{T}_2-\mathcal{T}_1$. Its complex empirical behavior (Kiihl, 2005) motivates us to propose a test statistic solely based on $\mathcal{T}_2$. We are thus able to prove asymptotic normality under different assumptions on the number of sequences and number of sites via $U$-statistics theory.Comment: Published in at http://dx.doi.org/10.1214/193940307000000293 the IMS Collections (http://www.imstat.org/publications/imscollections.htm) by the Institute of Mathematical Statistics (http://www.imstat.org

Analise estatistica de polimorfismo molecular em sequencias de DNA utilizando informações filogeneticas

Orientador: Hildete Prisco PinheiroDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Matematica, Estatistica e Computação CientificaResumo: Variacao genetica no nivel de nucleotideo e uma fonte poderosa de informacao para o estudo da evolucao de uma populacao. Importantes aspectos da evolucao de populacoes naturais tem sido investigados utilizando sequencias de nucleotideos. A quantidade ? = 4N?, em que N e o tamanho efetivo da populacao e ? e a taxa de mutacao por sequencia (gene, locus) por geracao, e um parametro essencial porque determina o grau de polimorfismo em um locus. O sucesso da inferencia sobre a evolucao de uma populacao e medido pela acuracia da estimacao deste parametro. Esta dissertacao de mestrado apresenta diversos metodos de estimacao do parametro ?, bem como uma comparacao entre eles atraves de simulacoes e aplicacoes a dados reais. Utilizando informacoes filogeneticas de amostras de sequencias de DNA, constr'oi-se um modelo linear onde o coeficiente da variavel independente e a estimativa do parametro ?. Verificou-se que utilizando informacoes filogeneticas dos dados obtem-se estimadores bem mais eficientesAbstract: Genetic variation at the nucleotide level is a powerful source of information for studying the evolution of a population. Important aspects of the evolution of a population have been investigated by using nucleotide sequences. The quantity ? = 4N?, where N is the effective size of the population and ? is the mutation rate per sequence (gene, locus) per generation, is an essential parameter because it determines the degree of polymorphism at the locus. The degree of success in our inference about the evolution of a population is measured to some extent by the accuracy of estimation of this essential parameter. This work presents some methods of estimation of this parameter, comparisons between the different methods through computational simulations and applications to real data. The evolution of a species can be seen through a phylogenetic tree and a linear model can be constructed by using the phylogenetic information to estimate ?. It has been verified that the use of such information leads us to more accurate estimators of ?MestradoEstatisticaMestre em Estatístic

Manganese exposure induces microglia activation and dystrophy in the substantia nigra of non-human primates

Chronic manganese (Mn) exposure produces neurological deficits including a form of parkinsonism that is different from Parkinson's disease (PD). In chronic Mn exposure, dopamine neurons in the substantia nigra (SN) do not degenerate but they appear to be dysfunctional. Further, previous studies have suggested that the substantia nigra pars reticulata (SNr) is affected by Mn. In the present study, we investigated whether chronic Mn exposure induces microglia activation in the substantia nigra pars compacta (SNc) and SNr in Cynomolgus macaques. Animals were exposed to different weekly doses of Mn (3.3–5.0, 5.0-6.7, 8.3-10 mg Mn/kg body weight) and microglia were examined in the substantia nigra using LN3 immunohistochemistry. We observed that in control animals, LN3 labeled microglia were characterized by a resting phenotype. However, in Mn-treated animals, microglia increased in number and displayed reactive changes with increasing Mn exposure. This effect was more prominent in the SNr than in the SNc. In the SNr of animals administered the highest Mn dose, microglia activation was the most advanced and included dystrophic changes. Reactive microglia expressed increased iNOS, L-ferritin, and intracellular ferric iron which were particularly prominent in dystrophic compartments. Our observations indicate that moderate Mn exposure produces structural changes on microglia, which may have significant consequences on their function

MLML2R: an R package for maximum likelihood estimation of DNA methylation and hydroxymethylation proportions

Accurately measuring epigenetic marks such as 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) at the single-nucleotide level, requires combining data from DNA processing methods including traditional (BS), oxidative (oxBS) or Tet-Assisted (TAB) bisulfite conversion. We introduce the R package MLML2R, which provides maximum likelihood estimates (MLE) of 5-mC and 5-hmC proportions. While all other available R packages provide 5-mC and 5-hmC MLEs only for the oxBS+BS combination, MLML2R also provides MLE for TAB combinations. For combinations of any two of the methods, we derived the pool-adjacent-violators algorithm (PAVA) exact constrained MLE in analytical form. For the three methods combination, we implemented both the iterative method by Qu et al. [Qu, J., M. Zhou, Q. Song, E. E. Hong and A. D. Smith (2013): "Mlml: consistent simultaneous estimates of dna methylation and hydroxymethylation," Bioinformatics, 29, 2645-2646.], and also a novel non iterative approximation using Lagrange multipliers. The newly proposed non iterative solutions greatly decrease computational time, common bottlenecks when processing high-throughput data. The MLML2R package is flexible as it takes as input both, preprocessed intensities from Infinium Methylation arrays and counts from Next Generation Sequencing technologies. The MLML2R package is freely available at https://CRAN. R-project.org/package=MLML2R181FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2013/00506-1; 2014/03374-

Arsenic exposure and human blood DNA methylation and hydroxymethylation profiles in two diverse populations from Bangladesh and Spain

This work was supported by the Strategic Action for Research in Health sciences (PI15/00071) and CIBERCV, which are initiatives from Instituto de Salud Carlos III and the Spanish Ministry of Science and Innovation and co-funded with European Funds for Regional Development (FEDER) , and the United States National Institute of Health (grants R01 CA133595, P30 ES009089, T32 ES007322, P42 ES010349, and F31 ES029019) . MTP was supported by the Third AstraZeneca Award for Spanish Young Researchers. ADR received the support of a fellowship from "la Caixa" Foundation (ID 100010434, fellowship code "LCF/BQ/DR19/11740016") .Domingo-Relloso, A.; Bozack, A.; Kiihl, S.; Rodriguez-Hernandez, Z.; Rentero-Garrido, P.; Casasnovas, JA.; Leon-Latre, M.... (2022). Arsenic exposure and human blood DNA methylation and hydroxymethylation profiles in two diverse populations from Bangladesh and Spain. Environmental Research. 204:1-12. https://doi.org/10.1016/j.envres.2021.11202111220