Existing methods for identifying structural variants (SVs) from short read datasets are inaccurate. This complicates disease-gene identification and efforts to understand the consequences of genetic ...variation. In response, we have created Wham (Whole-genome Alignment Metrics) to provide a single, integrated framework for both structural variant calling and association testing, thereby bypassing many of the difficulties that currently frustrate attempts to employ SVs in association testing. Here we describe Wham, benchmark it against three other widely used SV identification tools-Lumpy, Delly and SoftSearch-and demonstrate Wham's ability to identify and associate SVs with phenotypes using data from humans, domestic pigeons, and vaccinia virus. Wham and all associated software are covered under the MIT License and can be freely downloaded from github (https://github.com/zeeev/wham), with documentation on a wiki (http://zeeev.github.io/wham/). For community support please post questions to https://www.biostars.org/.
The mammalian foregut gives rise to the dorsally located esophagus and stomach and the ventrally located trachea and lung. Proper patterning and morphogenesis of the common foregut tube and its ...derived organs is essential for viability of the organism at birth. Here, we show that conditional inactivation of BMP type I receptor genes Bmpr1a and Bmpr1b (Bmpr1a;b) in the ventral endoderm leads to tracheal agenesis and ectopic primary bronchi. Molecular analyses of these mutants reveal a reduction of ventral endoderm marker NKX2-1 and an expansion of dorsal markers SOX2 and P63 into the prospective trachea and primary bronchi. Subsequent genetic experiments show that activation of canonical WNT signaling, previously shown to induce ectopic respiratory fate in otherwise wild-type mice, is incapable of promoting respiratory fate in the absence of Bmpr1a;b. Furthermore, we find that inactivation of Sox2 in Bmpr1a;b mutants does not suppress ectopic lung budding but does rescue trachea formation and NKX2-1 expression. Together, our data suggest that signaling through BMPR1A;B performs at least two roles in early respiratory development: first, it promotes tracheal formation through repression of Sox2; and second, it restricts the site of lung bud initiation.
Intensive artificial selection over thousands of years has produced hundreds of varieties of domestic pigeon. As Charles Darwin observed, the morphological differences among breeds can rise to the ...magnitude of variation typically observed among different species. Nevertheless, different pigeon varieties are interfertile, thereby enabling forward genetic and genomic approaches to identify genes that underlie derived traits. Building on classical genetic studies of pigeon variation, recent molecular investigations find a spectrum of coding and regulatory alleles controlling derived traits, including plumage color, feather growth polarity, and limb identity. Developmental and genetic analyses of pigeons are revealing the molecular basis of variation in a classic example of extreme intraspecific diversity, and have the potential to nominate genes that control variation among other birds and vertebrates in general.
•Domestic rock pigeons display dramatic variation within a single species.•Pigeons are amenable to genetic, genomic, and developmental studies of diversity.•The molecular basis for several classic traits is now known.•Variation in pigeons is relevant to other evolutionary and biomedical phenotypes.•Pigeons can reveal general mechanisms of avian and vertebrate diversity.
The mammalian respiratory system, consisting of both trachea and lung, initiates from the foregut endoderm. The molecular program that instructs endodermal cells to adopt the respiratory fate is not ...fully understood. Here we show that conditional inactivation of β-Catenin (also termed Ctnnb1) in foregut endoderm leads to absence of both the trachea and lung due to a failure in maintaining the respiratory fate. In converse, conditional expression of an activated form of β-Catenin leads to expansion of Nkx2.1, an early marker for the trachea and lung, into adjacent endoderm including the stomach epithelium. Analyses of these mutants show that the loss or gain of trachea/lung progenitor identity is accompanied by an expansion or contraction of esophagus/stomach progenitor identity, respectively. Our findings reveal an early role for β-Catenin in the establishment of respiratory progenitors in mouse foregut endoderm.
The geographic origins of breeds and the genetic basis of variation within the widely distributed and phenotypically diverse domestic rock pigeon (Columba livia) remain largely unknown. We generated ...a rock pigeon reference genome and additional genome sequences representing domestic and feral populations. We found evidence for the origins of major breed groups in the Middle East and contributions from a racing breed to North American feral populations. We identified the gene EphB2 as a strong candidate for the derived head crest phenotype shared by numerous breeds, an important trait in mate selection in many avian species. We also found evidence that this trait evolved just once and spread throughout the species, and that the crest originates early in development by the localized molecular reversal of feather bud polarity.
Understanding the molecular basis of phenotypic diversity is a critical challenge in biology, yet we know little about the mechanistic effects of different mutations and epistatic relationships among ...loci that contribute to complex traits. Pigmentation genetics offers a powerful model for identifying mutations underlying diversity and for determining how additional complexity emerges from interactions among loci. Centuries of artificial selection in domestic rock pigeons (Columba livia) have cultivated tremendous variation in plumage pigmentation through the combined effects of dozens of loci. The dominance and epistatic hierarchies of key loci governing this diversity are known through classical genetic studies 1–6, but their molecular identities and the mechanisms of their genetic interactions remain unknown. Here we identify protein-coding and cis-regulatory mutations in Tyrp1, Sox10, and Slc45a2 that underlie classical color phenotypes of pigeons and present a mechanistic explanation of their dominance and epistatic relationships. We also find unanticipated allelic heterogeneity at Tyrp1 and Sox10, indicating that color variants evolved repeatedly though mutations in the same genes. These results demonstrate how a spectrum of coding and regulatory mutations in a small number of genes can interact to generate substantial phenotypic diversity in a classic Darwinian model of evolution 7.
•Interactions among three genes control multiple color phenotypes in pigeons•Pigmentation genes incur a spectrum of coding and regulatory mutations•Some color variants evolved repeatedly though mutations in the same genes
Domyan et al. find that interactions among the genes Tyrp1, Sox10, and Slc45a2 control a wide range of color phenotypes in pigeons. These genes incur a spectrum of coding and regulatory mutations, and some color variants in pigeons evolved repeatedly though mutations in the same genes.
For species to adapt to their environment, evolution must act upon genetic variation that is present in the population. Elucidating the molecular mechanisms that give rise to this variation is thus ...of crucial importance for understanding how organisms evolve. In addition to variation caused by point mutations, structural variation (deletions, duplications, inversions, translocations) is also an important source of variety. Mechanisms involving recombination, transposition and retrotransposition, and replication have been proposed for generating structural variation, and each are capable of explaining certain rearrangements. In this study, we conduct a detailed analysis of two partially overlapping rearrangements (
and
allele) in domestic rock pigeon (
which are both associated with the
phenotype. We find that a replicative mechanism is best able to explain the complex architecture of the
allele, and is also compatible with the simpler architecture of the
allele as well.
The domestic rock pigeon (
) is among the most widely distributed and phenotypically diverse avian species.
is broadly studied in ecology, genetics, physiology, behavior, and evolutionary biology, ...and has recently emerged as a model for understanding the molecular basis of anatomical diversity, the magnetic sense, and other key aspects of avian biology. Here we report an update to the
genome reference assembly and gene annotation dataset. Greatly increased scaffold lengths in the updated reference assembly, along with an updated annotation set, provide improved tools for evolutionary and functional genetic studies of the pigeon, and for comparative avian genomics in general.
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