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The mild hypothermia response (MHR) maintains organismal homeostasis during cold exposure and is thought to be critical for the neuroprotection documented with therapeutic hypothermia. To date, little is known about the transcriptional regulation of the MHR. We utilize a forward CRISPR-Cas9 mutagenesis screen to identify the histone lysine methyltransferase SMYD5 as a regulator of the MHR. SMYD5 represses the key MHR gene SP1 at euthermia. This repression correlates with temperature-dependent levels of histone H3 lysine 26 trimethylation (H3K36me3) at the SP1 locus and globally, indicating that the mammalian MHR is regulated at the level of histone modifications. We have identified 37 additional SMYD5-regulated temperature-dependent genes, suggesting a broader MHR-related role for SMYD5. Our study provides an example of how histone modifications integrate environmental cues into the genetic circuitry of mammalian cells and provides insights that may yield therapeutic avenues for neuroprotection after catastrophic events.

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Highly fecund natural populations characterized by high early mortality abound, yet our knowledge about their recruitment dynamics is somewhat rudimentary. This knowledge gap has implications for our understanding of genetic variation, population connectivity, local adaptation, and the resilience of highly fecund populations. The concept of sweepstakes reproductive success, which posits a considerable variance and skew in individual reproductive output, is key to understanding the distribution of individual reproductive success. However, it still needs to be determined whether highly fecund organisms reproduce through sweepstakes and, if they do, the relative roles of neutral and selective sweepstakes. Here, we use coalescent-based statistical analysis of population genomic data to show that selective sweepstakes likely explain recruitment dynamics in the highly fecund Atlantic cod. We show that the Kingman coalescent (modelling no sweepstakes) and the Xi-Beta coalescent (modelling random sweepstakes), including complex demography and background selection, do not provide an adequate fit for the data. The Durrett-Schweinsberg coalescent, in which selective sweepstakes result from recurrent and pervasive selective sweeps of new mutations, offers greater explanatory power. Our results show that models of sweepstakes reproduction and multiple-merger coalescents are relevant and necessary for understanding genetic diversity in highly fecund natural populations. These findings have fundamental implications for understanding the recruitment variation of fish stocks and general evolutionary genomics of high-fecundity organisms.

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Detailed modeling of a species' history is of prime importance for understanding how natural selection operates over time. Most methods designed to detect positive selection along sequenced genomes, however, use simplified representations of past histories as null models of genetic drift. Here, we present the first method that can detect signatures of strong local adaptation across the genome using arbitrarily complex admixture graphs, which are typically used to describe the history of past divergence and admixture events among any number of populations. The method-called graph-aware retrieval of selective sweeps (GRoSS)-has good power to detect loci in the genome with strong evidence for past selective sweeps and can also identify which branch of the graph was most affected by the sweep. As evidence of its utility, we apply the method to bovine, codfish, and human population genomic data containing panels of multiple populations related in complex ways. We find new candidate genes for important adaptive functions, including immunity and metabolism in understudied human populations, as well as muscle mass, milk production, and tameness in specific bovine breeds. We are also able to pinpoint the emergence of large regions of differentiation owing to inversions in the history of Atlantic codfish.

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Introgressive hybridization creates networks of genetic relationships across species. Among marine fish of the Gadidae family, Pacific cod and walleye pollock are separate invasions of an Atlantic cod ancestor into the Pacific. Cods are ecological success stories, and their ecologies allow them to support the largest fisheries of the world. The enigmatic walleye pollock differs morphologically, behaviorally, and ecologically from its relatives, representing a niche shift. Here, we apply whole-genome sequencing to Pacific, Arctic, and Atlantic gadids and reveal extensive introgression among them with the ABBA-BABA test and pseudolikelihood phylogenetic network analysis. We propose that walleye pollock resulted from extensive adaptive introgression or homoploid hybrid speciation. The path of evolution of these taxa is more web than a tree. Their ability to invade and expand into new habitats and become ecologically successful may depend on genes acquired through adaptive introgression or hybrid speciation.

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Very few animal taxa are known to reside permanently in glacier ice/snow. Here we report the widespread colonization of Icelandic glaciers and ice fields by species of bdelloid Rotifera. Specimens were collected within the accumulation zones of Langjökull and Vatnajökull ice caps, among the largest European ice masses. Rotifers reached densities up to ∼100 individuals per liter-equivalent of glacier ice/snow, and were freeze-tolerant. Phylogenetic analyses indicate that glacier rotifers are polyphyletic, with independent ancestries occurring within the Pleistocene. Collectively, these data identify a previously undescribed environmental niche for bdelloid rotifers and suggest their presence in comparable habitats worldwide.

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Natural selection, the most important force in evolution, comes in three forms. Negative purifying selection removes deleterious variation and maintains adaptations. Positive directional selection fixes beneficial variants, producing new adaptations. Balancing selection maintains variation in a population. Important mechanisms of balancing selection include heterozygote advantage, frequency-dependent advantage of rarity, and local and fluctuating episodic selection. A rare pathogen gains an advantage because host defenses are predominantly effective against prevalent types. Similarly, a rare immune variant gives its host an advantage because the prevalent pathogens cannot escape the host's apostatic defense. Due to the stochastic nature of evolution, neutral variation may accumulate on genealogical branches, but trans-species polymorphisms are rare under neutrality and are strong evidence for balancing selection. Balanced polymorphism maintains diversity at the major histocompatibility complex (MHC) in vertebrates. The Atlantic cod is missing genes for both MHC-II and CD4, vital parts of the adaptive immune system. Nevertheless, cod are healthy in their ecological niche, maintaining large populations that support major commercial fisheries. Innate immunity is of interest from an evolutionary perspective, particularly in taxa lacking adaptive immunity. Here, we analyze extensive amino acid and nucleotide polymorphisms of the cathelicidin gene family in Atlantic cod and closely related taxa. There are three major clusters, Cath1, Cath2, and Cath3, that we consider to be paralogous genes. There is extensive nucleotide and amino acid allelic variation between and within clusters. The major feature of the results is that the variation clusters by alleles and not by species in phylogenetic trees and discriminant analysis of principal components. Variation within the three groups shows trans-species polymorphism that is older than speciation and that is suggestive of balancing selection maintaining the variation. Using Bayesian and likelihood methods positive and negative selection is evident at sites in the conserved part of the genes and, to a larger extent, in the active part which also shows episodic diversifying selection, further supporting the argument for balancing selection.

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High-fecundity organisms, such as Atlantic cod, can withstand substantial natural selection and the entailing genetic load of replacing alleles at a number of loci due to their excess reproductive capacity. High-fecundity organisms may reproduce by sweepstakes leading to highly skewed heavy-tailed offspring distribution. Under such reproduction the Kingman coalescent of binary mergers breaks down and models of multiple merger coalescent are more appropriate. Here we study nucleotide variation at the Ckma (Creatine Kinase Muscle type A) gene in Atlantic cod. The gene shows extreme differentiation between the North (Canada, Greenland, Iceland, Norway, Barents Sea) and the South (Faroe Islands, North-, Baltic-, Celtic-, and Irish Seas) with FST > 0.8 between regions whereas neutral loci show no differentiation. This is evidence of natural selection. The protein sequence is conserved by purifying selection whereas silent and non-coding sites show extreme differentiation. The unfolded site-frequency spectrum has three modes, a mode at singleton sites and two high frequency modes at opposite frequencies representing divergent branches of the gene genealogy that is evidence for balancing selection. Analysis with multiple-merger coalescent models can account for the high frequency of singleton sites and indicate reproductive sweepstakes. Coalescent time scales vary with population size and with the inverse of variance in offspring number. Parameter estimates using multiple-merger coalescent models show that times scales are faster than under the Kingman coalescent.

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Developmental globin gene expression and gene switching in vertebrates have been extensively studied. Globin gene regions have been characterized in some fish species and show linked α and ß loci. Understanding coordinated expression between α and ß globin genes in fish is of importance for further insights into globin gene regulation in teleosts and higher vertebrates. We characterize linked ß and α globin genes in Atlantic cod, pulled from the Atlantic cod genome with a PCR research strategy, by screening a genomic λ library and primer walking. The genes are oriented tail-to-head (5'-3'), differing from the head-to-head orientation in transcriptional polarity characteristic of teleostean globin genes. Four tandem repeats are found in an intergenic region of 1500 base pairs. One microsatellite, which consists primarily of atg tandem repeats, has an open reading frame. The globin genes and open reading frame have a CCAAT promoter element and TATA boxes. The promoters of the open reading frame and the ß gene share an 89-bp block (with 100% identity) that probably regulates transcription.

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Allozyme variation in Atlantic cod hemoglobins shows various signs of natural selection. We report a genomic exploration of globin genes in this non-model organism. Applying a PCR based strategy with a strict criterion of phylogenetically informative sites we estimate the number of linked ß and α globin genes. We estimate PCR error rate by PCR of cloned DNA and recloning and by analysis of singleton variable sites among clones. Based on the error rate we exclude variable sites so that the remaining variation meets successively stricter criteria of doubleton and triplet variable site. Applying these criteria we find ten clusters of linked ß/α globin genes in the genome of Atlantic cod. Six variable amino acid changes in both genes were found in linkage disequilibrium with silent nucleotide substitutions. A phylogenetic tree, based on our strictly phylogenetically informative sites among 57 clones from 19 individuals, is split into two major branches by an amino acid change in a ß gene. This change is supported by extensive linkage disequilibrium between the amino acid change and numerous other phylogenetically informative silent nucleotide sites. The different gene sets in the genome may represent different loci encoding different globins and/or allelic variation at some loci.