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Register a new userLMM-Lasso: A Lasso Multi-Marker Mixed Model for Association Mapping with Population Structure Correction
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Exploring the genetic basis of heritable traits remains one of the central challenges in biomedical research. In simple cases, single polymorphic loci explain a significant fraction of the phenotype variability. However, many traits of interest appear to be subject to multifactorial control by groups of genetic loci instead. Accurate detection of such multivariate associations is nontrivial and often hindered by limited power. At the same time, confounding influences such as population structure cause spurious association signals that result in false positive findings if they are not accounted for in the model. Here, we propose LMM-Lasso, a mixed model that allows for both, multi-locus mapping and correction for confounding effects. Our approach is simple and free of tuning parameters, effectively controls for population structure and scales to genome-wide datasets. We show practical use in genome-wide association studies and linkage mapping through retrospective analyses. In data from Arabidopsis thaliana and mouse, our method is able to find a genetic cause for significantly greater fractions of phenotype variation in 91% of the phenotypes considered. At the same time, our model dissects this variability into components that result from individual SNP effects and population structure. In addition to this increase of genetic heritability, enrichment of known candidate genes suggests that the associations retrieved by LMM-Lasso are more likely to be genuine.
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Despite numerous mass extinctions in the Phanerozoic eon, the overall trend in biodiversity evolution was not blocked and the life has never been wiped out. Almost all possible catastrophic events (large igneous province, asteroid impact, climate change, regression and transgression, anoxia, acidification, sudden release of methane clathrate, multi-cause etc.) have been proposed to explain the mass extinctions. However, we should, above all, clarify at what timescale and at what possible levels should we explain the mass extinction? Even though the mass extinctions occurred at short-timescale and at the species level, we reveal that their cause should be explained in a broader context at tectonic timescale and at both the molecular level and the species level. The main result in this paper is that the Phanerozoic biodiversity evolution has been explained by reconstructing the Sepkoski curve based on climatic, eustatic and genomic data. Consequently, we point out that the P-Tr extinction was caused by the tectonically originated climate instability. We also clarify that the overall trend of biodiversification originated from the underlying genome size evolution, and that the fluctuation of biodiversity originated from the interactions among the earths spheres. The evolution at molecular level had played a significant role for the survival of life from environmental disasters.
One of the outstanding challenges in comparative genomics is to interpret the evolutionary importance of regulatory variation between species. Rigorous molecular evolution-based methods to infer evidence for natural selection from expression data are at a premium in the field, and to date, phylogenetic approaches have not been well-suited to address the question in the small sets of taxa profiled in standard surveys of gene expression. We have developed a strategy to infer evolutionary histories from expression profiles by analyzing suites of genes of common function. In a manner conceptually similar to molecular evolution models in which the evolutionary rates of DNA sequence at multiple loci follow a gamma distribution, we modeled expression of the genes of an emph{a priori}-defined pathway with rates drawn from an inverse gamma distribution. We then developed a fitting strategy to infer the parameters of this distribution from expression measurements, and to identify gene groups whose expression patterns were consistent with evolutionary constraint or rapid evolution in particular species. Simulations confirmed the power and accuracy of our inference method. As an experimental testbed for our approach, we generated and analyzed transcriptional profiles of four emph{Saccharomyces} yeasts. The results revealed pathways with signatures of constrained and accelerated regulatory evolution in individual yeasts and across the phylogeny, highlighting the prevalence of pathway-level expression change during the divergence of yeast species. We anticipate that our pathway-based phylogenetic approach will be of broad utility in the search to understand the evolutionary relevance of regulatory change.
Least squares trees, multi-dimensional scaling and Neighbor Nets are all different and popular ways of visualizing multi-dimensional data. The method of flexi-Weighted Least Squares (fWLS) is a powerful method of fitting phylogenetic trees, when the exact form of errors is unknown. Here, both polynomial and exponential weights are used to model errors. The exact same models are implemented for multi-dimensional scaling to yield flexi-Weighted MDS, including as special cases methods such as the Sammon Stress function. Here we apply all these methods to population genetic data looking at the relationships of Abrahams Children encompassing Arabs and now widely dispersed populations of Jews, in relation to an African outgroup and a variety of European populations. Trees, MDS and Neighbor Nets of this data are compared within a common likelihood framework and the strengths and weaknesses of each method are explored. Because the errors in this type of data can be complex, for example, due to unexpected genetic transfer, we use a residual resampling method to assess the robustness of trees and the Neighbor Net. Despite the Neighbor Net fitting best by all criteria except BIC, its structure is ill defined following residual resampling. In contrast, fWLS trees are favored by BIC and retain considerable strong internal structure following residual resampling. This structure clearly separates various European and Middle Eastern populations, yet it is clear all of the models have errors much larger than expected by sampling variance alone.
Tissue heterogeneity is a major confounding factor in studying individual populations that cannot be resolved directly by global profiling. Experimental solutions to mitigate tissue heterogeneity are expensive, time consuming, inapplicable to existing data, and may alter the original gene expression patterns. Here we ask whether it is possible to deconvolute two-source mixed expressions (estimating both proportions and cell-specific profiles) from two or more heterogeneous samples without requiring any prior knowledge. Supported by a well-grounded mathematical framework, we argue that both constituent proportions and cell-specific expressions can be estimated in a completely unsupervised mode when cell-specific marker genes exist, which do not have to be known a priori, for each of constituent cell types. We demonstrate the performance of unsupervised deconvolution on both simulation and real gene expression data, together with perspective discussions.
Phylogenetic tree inference using deep DNA sequencing is reshaping our understanding of rapidly evolving systems, such as the within-host battle between viruses and the immune system. Densely sampled phylogenetic trees can contain special features, including sampled ancestors in which we sequence a genotype along with its direct descendants, and polytomies in which multiple descendants arise simultaneously. These features are apparent after identifying zero-length branches in the tree. However, current maximum-likelihood based approaches are not capable of revealing such zero-length branches. In this paper, we find these zero-length branches by introducing adaptive-LASSO-type regularization estimators to phylogenetics, deriving their properties, and showing regularization to be a practically useful approach for phylogenetics.
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