Genetic Variation, Not Cell Type of Origin, Underlies Regulatory Differences in iPSCs

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Genetic Variation, Not Cell Type of Origin, Underlies Regulatory Differences in iPSCs
Courtney L Kagan, Nicholas E Banovich, Bryan J Pavlovic, Kristen Patterson, Irene Gallego Romero, Jonathan K Pritchard, Yoav Gilad
doi: http://dx.doi.org/10.1101/013888

The advent of induced pluripotent stem cells (iPSCs) revolutionized Human Genetics by allowing us to generate pluripotent cells from easily accessible somatic tissues. This technology can have immense implications for regenerative medicine, but iPSCs also represent a paradigm shift in the study of complex human phenotypes, including gene regulation and disease. Yet, an unresolved caveat of the iPSC model system is the extent to which reprogrammed iPSCs retain residual phenotypes from their precursor somatic cells. To directly address this issue, we used an effective study design to compare regulatory phenotypes between iPSCs derived from two types of commonly used somatic precursor cells. We show that the cell type of origin only minimally affects gene expression levels and DNA methylation in iPSCs. Instead, genetic variation is the main driver of regulatory differences between iPSCs of different donors.

Rates of karyotypic evolution in Estrildid finches differ between island and continental clades

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Rates of karyotypic evolution in Estrildid finches differ between island and continental clades
Daniel M Hooper, Trevor D Price
doi: http://dx.doi.org/10.1101/013987

Reasons why chromosomal rearrangements spread to fixation and frequently distinguish related taxa remain poorly understood. We used cytological descriptions of karyotype to identify large pericentric inversions between species of Estrildid finches (family Estrildidae) and a time-dated phylogeny to assess the genomic, geographic, and phylogenetic context of karyotype evolution in this group. Inversions between finch species fixed at an average rate of one every 2.26 My. Inversions were twice as likely to fix on the sex chromosomes compared to the autosomes, possibly a result of their repeat density, and inversion fixation rate for all chromosomes scales with range size. Alternative mutagenic input explanations are not supported, as the number of inversions on a chromosome does not correlate with its length or map size. Inversions have fixed 3.3× faster in three continental clades than in two island chain clades, and fixation rate correlates with both range size and the number of sympatric species pairs. These results point to adaptation as the dominant mechanism driving fixation and suggest a role for gene flow in karyotype divergence. A review shows that the rapid karyotype evolution observed in the Estrildid finches appears to be more general across birds, and by implication other understudied taxa.

MultiMeta: an R package for meta-analysing multi-phenotype genome-wide association studies

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MultiMeta: an R package for meta-analysing multi-phenotype genome-wide association studies
Dragana Vuckovic, Paolo Gasparini, Nicole Soranzo, Valentina Iotchkova
doi: http://dx.doi.org/10.1101/013920

Summary: As new methods for multivariate analysis of Genome Wide Association Studies (GWAS) become available, it is important to be able to combine results from different cohorts in a meta-analysis. The R package MultiMeta provides an implementation of the inverse-variance based method for meta-analysis, generalized to an n-dimensional setting. Availability: The R package MultiMeta can be downloaded from CRAN Contact: dragana.vuckovic@burlo.trieste.it

RNA-guided gene drives can efficiently bias inheritance in wild yeast

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RNA-guided gene drives can efficiently bias inheritance in wild yeast
James E DiCarlo, Alejandro Chavez, Sven L Dietz, Kevin M Esvelt, George M Church
doi: http://dx.doi.org/10.1101/013896

Inheritance-biasing elements known as “gene drives” may be capable of spreading genomic alterations made in laboratory organisms through wild populations. We previously considered the potential for RNA-guided gene drives based on the versatile CRISPR/Cas9 genome editing system to serve as a general method of altering populations. Here we report molecularly contained gene drive constructs in the yeast Saccharomyces cerevisiae that are typically copied at rates above 99% when mated to wild yeast. We successfully targeted both non-essential and essential genes and showed that the inheritance of an unrelated “cargo” gene could be biased by an adjacent drive. Our results demonstrate that RNA-guided gene drives are capable of efficiently biasing inheritance when mated to wild-type organisms over successive generations.

Digit evolution in gymnophthalmid lizards

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Digit evolution in gymnophthalmid lizards
Juliana Roscito, Pedro M. S. Nunes, Miguel T Rodrigues
doi: http://dx.doi.org/10.1101/013953

Background The tetrapod limb is a highly diverse structure, and reduction of the limbs accounts for much of the phenotypes observed within species. Squamate reptiles represent one of the many lineages in which the limbs have been greatly modified from the pentadactyl generalized pattern; within the group, limb-reduced morphologies can vary from minor reductions in size of elements to complete limblessness, with several intermediate forms in between. Even though limb reduction is widespread, it is not clear what are the evolutionary and developmental mechanisms involved in the formation of reduced limb morphologies. Methods In this study, we present an overview of limb morphology within the microteiid lizard group Gymnophthalmidae, focusing on digit number. Results We show that there are two major groups of limb-reduced gymnophthalmids. The first group is formed by lizard-like – and frequently pentadactyl – species, in which minor reductions (such as the loss of 1-2 phalanges mainly in digits I and V) are the rule; these morphologies generally correspond to those seen in other squamates. The second group is formed by species showing more drastic losses, which can include the absence of an externally distinct limb in adults. We also show the expression patterns of Sonic Hedgehog (Shh) in the greatly reduced fore and hindlimb of a serpentiform gymnophthalmid. Conclusions Our discussion focus on identifying shared patterns of limb reduction among tetrapods, and explaining these patterns and the morphological variation within the gymnophthalmids based on the current knowledge of the molecular signaling pathways that coordinate limb development.

Dissecting phylogenetic signal and accounting for bias in whole-genome data sets: a case study of the Metazoa

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Dissecting phylogenetic signal and accounting for bias in whole-genome data sets: a case study of the Metazoa
Marek L Borowiec, Ernest K Lee, Joanna C Chiu, David C Plachetzki
doi: http://dx.doi.org/10.1101/013946

Transcriptome-enabled phylogenetic analyses have dramatically improved our understanding of metazoan phylogeny in recent years, although several important questions remain. The branching order near the base of the tree is one such outstanding issue. To address this question we assemble a novel data set comprised of 1,080 orthologous loci derived from 36 publicly available genomes and dissect the phylogenetic signal present in each individual partition. The size of this data set allows for a closer look at the potential biases and sources of non-phylogenetic signal. We assessed a range of measures for each data partition including information content, saturation, rate of evolution, long-branch score, and taxon occupancy and explored how each of these characteristics impacts phylogeny estimation. We then used these data to prepare a reduced set of partitions that fit an optimal set of criteria and are amenable to the most appropriate and computationally intensive analyses using site-heterogeneous models of sequence evolution. We also employed several strategies to examine the potential for long-branch attraction to bias our inferences. All of our analyses support Ctenophora as the sister lineage to other Metazoa, although support for this relationship varies among analyses. We find no support for the traditional view uniting the ctenophores and Cnidaria (jellies, anemones, corals, and kin). We also examine phylogenetic placement of myriapods (centipedes and millipedes) and find it more sensitive to the type of analysis and data used. Our study provides a workflow for minimizing systematic bias in whole genome-based phylogenetic analyses.

Ecological patterns of genome size variation in salamanders

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Ecological patterns of genome size variation in salamanders
Bianca Sclavi, John Herrick
Comments: 19 Pages, 4 figures, 1 supplementary figure
Subjects: Genomics (q-bio.GN); Populations and Evolution (q-bio.PE)

Salamanders (urodela) have among the largest vertebrate genomes, ranging in size from 10 to over 80 pg. The urodela are divided into ten extant families each with a characteristic range in genome size. Although changes in genome size often occur randomly and in the absence of selection pressure, non-random patterns of genome size variation are evident among specific vertebrate lineages. Here we report that genome size in salamander families varies inversely with species richness and other ecological factors: clades that began radiating earlier (older crown age) tend to have smaller genomes, higher levels of diversity and larger geographical ranges. These observations support the hypothesis that urodel families with larger genomes either have a lower propensity to diversify or are more vulnerable to extinction than families with smaller genomes.

Rise and fall of asexual mutators in adapted populations

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Rise and fall of asexual mutators in adapted populations
Ananthu James, Kavita Jain
Subjects: Populations and Evolution (q-bio.PE)

In an adapted population in which most mutations are deleterious, the mutation rates are expected to be low. Indeed, in recent experiments on adapted populations of asexual mutators, beneficial mutations that lower the mutation rates have been observed to get fixed. Using a multitype branching process and a deterministic argument, we calculate the time to fix the wildtype mutation rate in an asexual population of mutators, and find it to be a ${\tt U}$-shaped function of the population size. In contrast, the fixation time for mutators is known to increase with population size. On comparing these two time scales, we find that a critical population size exists below which the mutators prevail, while the mutation rate remains low in larger populations. We also discuss how our analytical results compare with the experiments.

Estimating phylogenetic trees from genome-scale data

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Estimating phylogenetic trees from genome-scale data
Liang Liu, Zhenxiang Xi, Shaoyuan Wu, Charles Davis, Scott V. Edwards
Comments: 39 pages, 3 figures
Subjects: Populations and Evolution (q-bio.PE)

As researchers collect increasingly large molecular data sets to reconstruct the Tree of Life, the heterogeneity of signals in the genomes of diverse organisms poses challenges for traditional phylogenetic analysis. A class of phylogenetic methods known as “species tree methods” have been proposed to directly address one important source of gene tree heterogeneity, namely the incomplete lineage sorting or deep coalescence that occurs when evolving lineages radiate rapidly, resulting in a diversity of gene trees from a single underlying species tree. Although such methods are gaining in popularity, they are being adopted with caution in some quarters, in part because of an increasing number of examples of strong phylogenetic conflict between concatenation or supermatrix methods and species tree methods. Here we review theory and empirical examples that help clarify these conflicts. Thinking of concatenation as a special case of the more general model provided by the multispecies coalescent can help explain a number of differences in the behavior of the two methods on phylogenomic data sets. Recent work suggests that species tree methods are more robust than concatenation approaches to some of the classic challenges of phylogenetic analysis, including rapidly evolving sites in DNA sequences, base compositional heterogeneity and long branch attraction. We show that approaches such as binning, designed to augment the signal in species tree analyses, can distort the distribution of gene trees and are inconsistent. Computationally efficient species tree methods that incorporate biological realism are a key to phylogenetic analysis of whole genome data.

The SMC’ is a highly accurate approximation to the ancestral recombination graph

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The SMC’ is a highly accurate approximation to the ancestral recombination graph

Peter R. Wilton, Shai Carmi, Asger Hobolth
(Submitted on 12 Jan 2015)

Two sequentially Markov coalescent models (SMC and SMC’) are available as tractable approximations to the ancestral recombination graph (ARG). We present a model of coalescence at two fixed points along a pair of sequences evolving under the SMC’. Using our model, we derive a number of new quantities related to the pairwise SMC’, thereby analytically quantifying for the first time the similarity between the SMC’ and ARG. We use our model to show that the joint distribution of pairwise coalescence times at recombination sites under the SMC’ is the same as it is marginally under the ARG, demonstrating that the SMC’ is the canonical first-order sequentially Markov approximation to the pairwise ARG. Finally, we use these results to show that population size estimates under the pairwise SMC are asymptotically biased, while under the pairwise SMC’ they are approximately asymptotically unbiased.