Molecular dating of species divergences has become an important means to add a temporal dimension to the Tree of Life. Increasingly larger datasets encompassing greater taxonomic diversity are becoming available to generate molecular timetrees by using sophisticated methods that model rate variation among lineages. However, the practical application of these methods is challenging because of the exorbitant calculation times required by current methods for contemporary data sizes, the difficulty in correctly modeling the rate heterogeneity in highly diverse taxonomic groups, and the lack of reliable clock calibrations and their uncertainty distributions for most groups of species. Here, we present a method that estimates relative times of divergences for all branching points (nodes) in very large phylogenetic trees without assuming a specific model for lineage rate variation or specifying any clock calibrations. The method (RelTime) performed better than existing methods when applied to very large computer simulated datasets where evolutionary rates were varied extensively among lineages by following autocorrelated and uncorrelated models. On average, RelTime completed calculations 1,000 times faster than the fastest Bayesian method, with even greater speed difference for larger number of sequences. This speed and accuracy will enable molecular dating analysis of very large datasets. Relative time estimates will be useful for determining the relative ordering and spacing of speciation events, identifying lineages with significantly slower or faster evolutionary rates, diagnosing the effect of selected calibrations on absolute divergence times, and estimating absolute times of divergence when highly reliable calibration points are available.bioinformatics | timescales | relaxed clocks T housands of research studies have reported the use of molecular dating techniques in establishing the timing of species divergences (e.g., refs. 1-5). With the availability of fast and cheap genome sequencing, molecular dating is being applied to increasingly larger datasets that span a much greater diversity of species and harbor extensive heterogeneity of evolutionary rates among lineages. This complexity poses many challenges that limit modern scientific investigations from truly leveraging the genome revolution. First, the application of the fastest molecular dating tools available already requires a very large amount of computational time for datasets containing only a few hundred sequences, which are modest for today's standards (6, 7). Second, current approaches require a priori selection of statistical distributions to model the heterogeneity of rates among branches in the evolutionary tree (e.g., autocorrelated versus uncorrelated rates, 8-12). Use of an incorrect statistical distribution is known to introduce significant bias in such analyses (10,(13)(14)(15). With increasingly larger datasets, it is unlikely that the same rate model will fit evolutionarily distant groups in the same large phylogeny, which exacerbates the...
We present a procedure to test the effect of calibration priors on estimated times, which applies a recently developed calibration-free approach (RelTime) method that produces relative divergence times for all nodes in the tree. We illustrate this protocol by applying it to a timetree of metazoan diversification (Erwin DH, Laflamme M, Tweedt SM, Sperling EA, Pisani D, Peterson KJ. 2011. The Cambrian conundrum: early divergence and later ecological success in the early history of animals. Science 334:1091-1097.), which placed the divergence of animal phyla close to the time of the Cambrian explosion inferred from the fossil record. These analyses revealed that the two maximum-only calibration priors in the pre-Cambrian are the primary determinants of the young divergence times among animal phyla in this study. In fact, these two maximum-only calibrations produce divergence times that severely violate minimum boundaries of almost all of the other 22 calibration constraints. The use of these 22 calibrations produces dates for metazoan divergences that are hundreds of millions of years earlier in the Proterozoic. Our results encourage the use of calibration-free approaches to identify most influential calibration constraints and to evaluate their impact in order to achieve biologically robust interpretations.
Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS). We present tailored analytical methods and software that facilitate X-wide association studies (XWAS), which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID). We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD). Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2) CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3) We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.
BackgroundMitochondrial dysfunction has been hypothesized to occur in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a disease characterized by fatigue, cognitive difficulties, pain, malaise, and exercise intolerance. We investigated whether haplogroup, single nucleotide polymorphisms (SNPs), or heteroplasmy of mitochondrial DNA (mtDNA) were associated with health status and/or symptoms.MethodsIllumina sequencing of PCR-amplified mtDNA was performed to analyze sequence and extent of heteroplasmy of mtDNAs of 193 cases and 196 age- and gender-matched controls from DNA samples collected by the Chronic Fatigue Initiative. Association testing was carried out to examine possible correlations of mitochondrial sequences with case/control status and symptom constellation and severity as reported by subjects on Short Form-36 and DePaul Symptom Questionnaires.ResultsNo ME/CFS subject exhibited known disease-causing mtDNA mutations. Extent of heteroplasmy was low in all subjects. Although no association between mtDNA SNPs and ME/CFS vs. healthy status was observed, haplogroups J, U and H as well as eight SNPs in ME/CFS cases were significantly associated with individual symptoms, symptom clusters, or symptom severity.ConclusionsAnalysis of mitochondrial genomes in ME/CFS cases indicates that individuals of a certain haplogroup or carrying specific SNPs are more likely to exhibit certain neurological, inflammatory, and/or gastrointestinal symptoms. No increase in susceptibility to ME/CFS of individuals carrying particular mitochondrial genomes or SNPs was observed.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0771-6) contains supplementary material, which is available to authorized users.
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