Browsing by Subject "Evolutionary genetics"

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1,000 ancient genomes uncover 10,000 years of natural selection in Europe
(2023-04-17) Le, Megan Khiet; Press, William H.; Narasimhan, Vagheesh M.
Ancient DNA has revolutionized our understanding of human history. However, its potential for revealing how cultural evolution to adapt new lifestyles may have driven biological adaptation has not been met. We assembled genome-wide data from 1,291 individuals from Europe over 10,000 years, allowing us to resolve the timing of selection into the Neolithic, Bronze Age, and Historical periods, and to identify 25 loci with evidence of rapid changes in allele frequency during these periods. All 10 candidate loci in the Historical period were detected in previous scans, with many associated with vitamin D metabolism. Strikingly, 17 out of 19 of the candidates from the Neolithic and Bronze Age periods were not previously detected, highlighting the unique power of ancient DNA to reveal selective events not uncoverable in modern samples due to subsequent drift or admixture. In the Neolithic period, we found evidence for human pathogen co-evolution: we detected selection at a locus that confers resistance to Salmonella infection at a time when ancient Salmonella have been shown to adapt to human hosts. Neolithic period candidates are also related to body weight and insulin secretion, suggesting adaptation to a primarily starch-based diet; in contrast, major shifts of allele frequencies in the Bronze Age tended to occur more in variants affecting pigmentation. We also tested for selection on complex traits, leveraging strategies to address confounders that have impeded such analyses in recent years. In the Neolithic period, we detected selection favoring alleles that today decrease body weight, perhaps reflecting genomic adaptation to changes in food availability. In the Historical Period, we detected selection favoring variants that today increase risk for autoimmune disease and cardiovascular disease, plausibly due to a selective pressure for more active inflammatory response in facing the increased exposure to infectious disease. These changes resulted in higher risk for diseases that cause pervasive morbidity in today’s aging populations
Ancient and Recent Adaptive Evolution of Primate Non-Homologous End Joining Genes
(Public Library of Science, 2010-10-21) Demogines, Ann; East, Alysia M.; Lee, Ji-Hoon; Grossman, Sharon R.; Sabeti, Pardis C.; Paull, Tanya T.; Sawyer, Sara L.
In human cells, DNA double-strand breaks are repaired primarily by the non-homologous end joining (NHEJ) pathway. Given their critical nature, we expected NHEJ proteins to be evolutionarily conserved, with relatively little sequence change over time. Here, we report that while critical domains of these proteins are conserved as expected, the sequence of NHEJ proteins has also been shaped by recurrent positive selection, leading to rapid sequence evolution in other protein domains. In order to characterize the molecular evolution of the human NHEJ pathway, we generated large simian primate sequence datasets for NHEJ genes. Codon-based models of gene evolution yielded statistical support for the recurrent positive selection of five NHEJ genes during primate evolution: XRCC4, NBS1, Artemis, POLλ, and CtIP. Analysis of human polymorphism data using the composite of multiple signals (CMS) test revealed that XRCC4 has also been subjected to positive selection in modern humans. Crystal structures are available for XRCC4, Nbs1, and Polλ; and residues under positive selection fall exclusively on the surfaces of these proteins. Despite the positive selection of such residues, biochemical experiments with variants of one positively selected site in Nbs1 confirm that functions necessary for DNA repair and checkpoint signaling have been conserved. However, many viruses interact with the proteins of the NHEJ pathway as part of their infectious lifecycle. We propose that an ongoing evolutionary arms race between viruses and NHEJ genes may be driving the surprisingly rapid evolution of these critical genes.
Bringing Molecules Back into Molecular Evolution
(Public Library of Science, 2012-06-28) Wilke, Claus O.
Much molecular-evolution research is concerned with sequence analysis. Yet these sequences represent real, three-dimensional molecules with complex structure and function. Here I highlight a growing trend in the field to incorporate molecular structure and function into computational molecular-evolution work. I consider three focus areas: reconstruction and analysis of past evolutionary events, such as phylogenetic inference or methods to infer selection pressures; development of toy models and simulations to identify fundamental principles of molecular evolution; and atom-level, highly realistic computational modeling of molecular structure and function aimed at making predictions about possible future evolutionary events.
Characterising and Predicting Haploinsufficiency in the Human Genome
(Public Library of Science, 2010-10-14) Huang, Ni; Lee, Insuk; Marcotte, Edward M.; Hurles, Matthew E.
Haploinsufficiency, wherein a single functional copy of a gene is insufficient to maintain normal function, is a major cause of dominant disease. Human disease studies have identified several hundred haploinsufficient (HI) genes. We have compiled a map of 1,079 haplosufficient (HS) genes by systematic identification of genes unambiguously and repeatedly compromised by copy number variation among 8,458 apparently healthy individuals and contrasted the genomic, evolutionary, functional, and network properties between these HS genes and known HI genes. We found that HI genes are typically longer and have more conserved coding sequences and promoters than HS genes. HI genes exhibit higher levels of expression during early development and greater tissue specificity. Moreover, within a probabilistic human functional interaction network HI genes have more interaction partners and greater network proximity to other known HI genes. We built a predictive model on the basis of these differences and annotated 12,443 genes with their predicted probability of being haploinsufficient. We validated these predictions of haploinsufficiency by demonstrating that genes with a high predicted probability of exhibiting haploinsufficiency are enriched among genes implicated in human dominant diseases and among genes causing abnormal phenotypes in heterozygous knockout mice. We have transformed these gene-based haploinsufficiency predictions into haploinsufficiency scores for genic deletions, which we demonstrate to better discriminate between pathogenic and benign deletions than consideration of the deletion size or numbers of genes deleted. These robust predictions of haploinsufficiency support clinical interpretation of novel loss-of-function variants and prioritization of variants and genes for follow-up studies.
Engineered regulation of an RNA ligase ribozyme
(2001-08) Robertson, Michael Paul; Ellington, Andrew D.
Catalytic RNA has been implicated as a critical component of the origin of life on Earth. Compelling arguments have been made for an ‘RNA world’ era during the early evolution of life in which all living systems consisted solely of RNA functioning as both genetic storage media and catalytic agents. Since the discovery of catalytic RNA in the early 1980s, the types of chemical reactions that RNA has been shown to catalyze has steadily increased and with it the feasibility of an all-RNA metabolism. However, a key aspect of modern biocatalysts is their ability to attenuate their level of activity in response to changing environmental conditions. Presumably, a similar regulation strategy would also be necessary to sustain a reasonably complex RNA-based metabolism. We have isolated and designed several RNA ligase ribozymes whose activities are regulated by the presence of a variety of different effectors. An oligonucleotidedependent ligase (L1) was isolated from a randomized pool of RNA using in vitro selection. Other allosterically regulated ribozymes were engineered by replacing a non-essential stem loop of L1 with various small molecule binding RNA aptamers to create aptamer-ribozyme hybrids (aptazymes). Alternatively, we vi have employed a two stage in vitro selection procedure with a partially randomized pool based on the L1 ligase to isolate protein-activated aptazymes that are extremely dependent on their cognate effector for activity. In addition to the regulation of RNA catalysis, we have been investigating ways to increase the proficiency and versatility of ribozymes by augmenting the chemical functional groups of RNA by the incorporation of modified nucleosides. These modified nucleotides can be efficiently transcribed into RNA using T7 RNA polymerase and have been incorporated into random sequence RNA pools for use in in vitro selection experiments. These results demonstrate that ribozyme activity can be regulated in much the same way that protein enzymes are regulated in contemporary biochemistry. This ability of RNA to be controlled by various potential metabolic intermediates contributes an additional layer of sophistication to ribozyme catalysis and increases the plausibility that a complex metabolism based solely on RNA could have once existed.
Evolution of Competitive Ability: An Adaptation Speed vs. Accuracy Tradeoff Rooted in Gene Network Size
(Public Library of Science, 2011-04-25) Malcom, Jacob W.
Ecologists have increasingly come to understand that evolutionary change on short time-scales can alter ecological dynamics (and vice-versa), and this idea is being incorporated into community ecology research programs. Previous research has suggested that the size and topology of the gene network underlying a quantitative trait should constrain or facilitate adaptation and thereby alter population dynamics. Here, I consider a scenario in which two species with different genetic architectures compete and evolve in fluctuating environments. An important trade-off emerges between adaptive accuracy and adaptive speed, driven by the size of the gene network underlying the ecologically-critical trait and the rate of environmental change. Smaller, scale-free networks confer a competitive advantage in rapidly-changing environments, but larger networks permit increased adaptive accuracy when environmental change is sufficiently slow to allow a species time to adapt. As the differences in network characteristics increase, the time-to-resolution of competition decreases. These results augment and refine previous conclusions about the ecological implications of the genetic architecture of quantitative traits, emphasizing a role of adaptive accuracy. Along with previous work, in particular that considering the role of gene network connectivity, these results provide a set of expectations for what we may observe as the field of ecological genomics develops.
Evolution of Genetic Potential
(Public Library of Science, 2005-08-26) Meyers, Lauren Ancel; Ancel, Fredric D; Lachmann, Michael
Organisms employ a multitude of strategies to cope with the dynamical environments in which they live. Homeostasis and physiological plasticity buffer changes within the lifetime of an organism, while stochastic developmental programs and hypermutability track changes on longer timescales. An alternative long-term mechanism is “genetic potential”—a heightened sensitivity to the effects of mutation that facilitates rapid evolution to novel states. Using a transparent mathematical model, we illustrate the concept of genetic potential and show that as environmental variability decreases, the evolving population reaches three distinct steady state conditions: (1) organismal flexibility, (2) genetic potential, and (3) genetic robustness. As a specific example of this concept we examine fluctuating selection for hydrophobicity in a single amino acid. We see the same three stages, suggesting that environmental fluctuations can produce allele distributions that are distinct not only from those found under constant conditions, but also from the transient allele distributions that arise under isolated selective sweeps.
Evolutionarily Repurposed Networks Reveal the Well-Known Antifungal Drug Thiabendazole to Be a Novel Vascular Disrupting Agent
(Public Library of Science, 2012-08-21) Cha, Hye Ji; Byrom, Michelle; Mead, Paul E.; Ellington, Andrew D.; Wallingford, John B.; Marcotte, Edward M.
Studies in diverse organisms have revealed a surprising depth to the evolutionary conservation of genetic modules. For example, a systematic analysis of such conserved modules has recently shown that genes in yeast that maintain cell walls have been repurposed in vertebrates to regulate vein and artery growth. We reasoned that by analyzing this particular module, we might identify small molecules targeting the yeast pathway that also act as angiogenesis inhibitors suitable for chemotherapy. This insight led to the finding that thiabendazole, an orally available antifungal drug in clinical use for 40 years, also potently inhibits angiogenesis in animal models and in human cells. Moreover, in vivo time-lapse imaging revealed that thiabendazole reversibly disassembles newly established blood vessels, marking it as vascular disrupting agent (VDA) and thus as a potential complementary therapeutic for use in combination with current anti-angiogenic therapies. Importantly, we also show that thiabendazole slows tumor growth and decreases vascular density in preclinical fibrosarcoma xenografts. Thus, an exploration of the evolutionary repurposing of gene networks has led directly to the identification of a potential new therapeutic application for an inexpensive drug that is already approved for clinical use in humans.
Evolutionary Reconstructions of the Transferrin Receptor of Caniforms Supports Canine Parvovirus Being a Re-emerged and Not a Novel Pathogen in Dogs
(Public Library of Science, 2012-05-03) Kaelber, Jason T.; Demogines, Ann; Harbison, Carole E.; Allison, Andrew B.; Goodman, Laura B.; Ortega, Alicia N.; Sawyer, Sara L.; Parrish, Colin R.
Parvoviruses exploit transferrin receptor type-1 (TfR) for cellular entry in carnivores, and specific interactions are key to control of host range. We show that several key mutations acquired by TfR during the evolution of Caniforms (dogs and related species) modified the interactions with parvovirus capsids by reducing the level of binding. These data, along with signatures of positive selection in the TFRC gene, are consistent with an evolutionary arms race between the TfR of the Caniform clade and parvoviruses. As well as the modifications of amino acid sequence which modify binding, we found that a glycosylation site mutation in the TfR of dogs which provided resistance to the carnivore parvoviruses which were in circulation prior to about 1975 predates the speciation of coyotes and dogs. Because the closely-related black-backed jackal has a TfR similar to their common ancestor and lacks the glycosylation site, reconstructing this mutation into the jackal TfR shows the potency of that site in blocking binding and infection and explains the resistance of dogs until recent times. This alters our understanding of this well-known example of viral emergence by indicating that canine parvovirus emergence likely resulted from the re-adaptation of a parvovirus to the resistant receptor of a former host.
From Bad to Good: Fitness Reversals and the Ascent of Deleterious Mutations
(Public Library of Science, 2006-10-20) Cowperthwaite, Matthew C; Bull, J. J; Meyers, Lauren Ancel
Deleterious mutations are considered a major impediment to adaptation, and there are straightforward expectations for the rate at which they accumulate as a function of population size and mutation rate. In a simulation model of an evolving population of asexually replicating RNA molecules, initially deleterious mutations accumulated at rates nearly equal to that of initially beneficial mutations, without impeding evolutionary progress. As the mutation rate was increased within a moderate range, deleterious mutation accumulation and mean fitness improvement both increased. The fixation rates were higher than predicted by many population-genetic models. This seemingly paradoxical result was resolved in part by the observation that, during the time to fixation, the selection coefficient (s) of initially deleterious mutations reversed to confer a selective advantage. Significantly, more than half of the fixations of initially deleterious mutations involved fitness reversals. These fitness reversals had a substantial effect on the total fitness of the genome and thus contributed to its success in the population. Despite the relative importance of fitness reversals, however, the probabilities of fixation for both initially beneficial and initially deleterious mutations were exceedingly small (on the order of 10−5 of all mutations).
Gene Networks and Metacommunities: Dispersal Differences Can Override Adaptive Advantage
(Public Library of Science, 2011-06-28) Malcom, Jacob W.
Dispersal is an important mechanism contributing to both ecological and evolutionary dynamics. In metapopulation and metacommunity ecology, dispersal enables new patches to be colonized; in evolution, dispersal counter-acts local selection, leading to regional homogenization. Here, I consider a three-patch metacommunity in which two species, each with a limiting quantitative trait underlain by gene networks of 16 to 256 genes, compete with one another and disperse among patches. Incorporating dispersal among heterogeneous patches introduces a tradeoff not observed in single-patch simulations: if the difference between gene network size of the two species is greater than the difference in dispersal ability (e.g., if the ratio of network sizes is larger than the ratio of dispersal abilities), then genetic architecture drives community outcome. However, if the difference in dispersal abilities is greater than gene network differences, then any adaptive advantages afforded by genetic architecture are over-ridden by dispersal. Thus, in addition to the selective pressures imposed by competition that shape the genetic architecture of quantitative traits, dispersal among patches creates an escape that may further alter the effects of different genetic architectures. These results provide a theoretical expectation for what we may observe as the field of ecological genomics develops.
How and Why Chromosome Inversions Evolve
(Public Library of Science, 2010-09-28) Kirkpatrick, Mark
Alfred Sturtevant, who invented genetic mapping while still an undergraduate, published the first evidence of a chromosomal inversion in 1921. He suggested then, and later proved, that they have a dramatic effect on transmission: when heterozygous, inversions suppress recombination. Over the next half century, inspired largely by Dobzhansky and his coworkers, much of empirical population genetics devoted itself to studying the abundant polymorphisms within and fixed differences of inversions between species of Drosophila. Starting in the 1970s, this rich literature largely sank from view with the rise of biochemical and then molecular genetics. But inversions are ascendant again. Comparative genomics is now revealing that chromosomes are far more structurally fluid than even Dobzhansky dared to suppose. Where classic cytogenetics identified only nine inversions that distinguish humans and chimpanzees, comparison of their genomic sequences reveals on the order of 1,500. Despite the importance of inversions as a major mechanism for reorganizing the genome, we are still struggling to understand how and why they evolve almost a century after Sturtevant's discovery.
Identification of a Genomic Reservoir for New TRIM Genes in Primate Genomes
(Public Library of Science, 2011-12-01) Han, Kyudong; Lou, Dianne I.; Sawyer, Sara L.
Tripartite Motif (TRIM) ubiquitin ligases act in the innate immune response against viruses. One of the best characterized members of this family, TRIM5α, serves as a potent retroviral restriction factor with activity against HIV. Here, we characterize what are likely to be the youngest TRIM genes in the human genome. For instance, we have identified 11 TRIM genes that are specific to humans and African apes (chimpanzees, bonobos, and gorillas) and another 7 that are human-specific. Many of these young genes have never been described, and their identification brings the total number of known human TRIM genes to approximately 100. These genes were acquired through segmental duplications, most of which originated from a single locus on chromosome 11. Another polymorphic duplication of this locus has resulted in these genes being copy number variable within the human population, with a Han Chinese woman identified as having 12 additional copies of these TRIM genes compared to other individuals screened in this study. Recently, this locus was annotated as one of 34 “hotspot” regions that are also copy number variable in the genomes of chimpanzees and rhesus macaques. Most of the young TRIM genes originating from this locus are expressed, spliced, and contain signatures of positive natural selection in regions known to determine virus recognition in TRIM5α. However, we find that they do not restrict the same retroviruses as TRIM5α, consistent with the high degree of divergence observed in the regions that control target specificity. We propose that this recombinationally volatile locus serves as a reservoir from which new TRIM genes arise through segmental duplication, allowing primates to continually acquire new antiviral genes that can be selected to target new and evolving pathogens.
Lysis time, optimality, and the genetics of evolution in a T7 phage model system
(2007) Heineman, Richard Hugh, 1978-; Bull, James J.
The ability of traits to adapt in response to change is one of the most fundamental aspects of evolution. Optimality models used to predict adaptation frequently make simplifying assumptions about the ability of traits to evolve freely within simple tradeoffs. However, we frequently have little understanding of genomic mechanisms underlying phenotypic evolution. Genetic constraints clearly limit phenotypic change, but the extent to which they do so is unclear. I will explore molecular and phenotypic responses to genomic and environmental perturbations through experimental evolution in T7 bacteriophage. First, I studied evolutionary robustness of the lysis time phenotype when lysin gene lysozyme was deleted. This deletion profoundly delayed lysis and thus decreased fitness. Evolved phages recovered much of the lost fitness and mostly restored lysis timing. The recovery was mediated by changes in a tail fiber gene (gene 16) with muralytic activity that is generally used in genome entry. Next, I extended the work on lysozyme to observe the effect of increasing constraint on evolutionary recovery. The effects of various combinations of deletions of lysozyme, 17.5 (which plays a role in lysis) and 16 suggested that another gene played a role similar to 17.5 in lysis. The phage defective in both lysozyme and 16 did not lyse hosts thoroughly even after long periods of infection, suggesting that these were the only effective lysin genes. Adaptation of this phage on cells expressing the essential gp16 constrained the primary adaptive pathway of recovery from lysozyme deletion. A mutually exclusive alternative pathway involving a variety of different genes evolved. The line recovered the ability to lyse normal hosts, by a mechanism involving multiple mutations. Finally, I tested the ability of T7 to adapt to an optimum lysis time. Based on empirical results from other phages, mature phage virions accumulate linearly inside the cell over time. This assumption underlies a model suggesting that availability of hosts determines optimal lysis time. While adaptation to different host densities caused the expected qualitative evolutionary changes, adaptation to conditions expected to select for slow lysis did not lead to the quantitative optimum. This is probably due to nonlinear virion accumulation.
Rapid Evolution of Coral Proteins Responsible for Interaction with the Environment
(Public Library of Science, 2011-05-25) Voolstra, Christian R.; Sunagawa, Shinichi; Matz, Mikhail V.; Bayer, Till; Aranda, Manuel; Buschiazzo, Emmanuel; DeSalvo, Michael K.; Lindquist, Erika; Szmant, Alina M.; Coffroth, Mary Alice; Medina, Mónica
Background -- Corals worldwide are in decline due to climate change effects (e.g., rising seawater temperatures), pollution, and exploitation. The ability of corals to cope with these stressors in the long run depends on the evolvability of the underlying genetic networks and proteins, which remain largely unknown. A genome-wide scan for positively selected genes between related coral species can help to narrow down the search space considerably. Methodology/Principal Findings -- We screened a set of 2,604 putative orthologs from EST-based sequence datasets of the coral species Acropora millepora and Acropora palmata to determine the fraction and identity of proteins that may experience adaptive evolution. 7% of the orthologs show elevated rates of evolution. Taxonomically-restricted (i.e. lineage-specific) genes show a positive selection signature more frequently than genes that are found across many animal phyla. The class of proteins that displayed elevated evolutionary rates was significantly enriched for proteins involved in immunity and defense, reproduction, and sensory perception. We also found elevated rates of evolution in several other functional groups such as management of membrane vesicles, transmembrane transport of ions and organic molecules, cell adhesion, and oxidative stress response. Proteins in these processes might be related to the endosymbiotic relationship corals maintain with dinoflagellates in the genus Symbiodinium. Conclusion/Relevance -- This study provides a birds-eye view of the processes potentially underlying coral adaptation, which will serve as a foundation for future work to elucidate the rates, patterns, and mechanisms of corals' evolutionary response to global climate change.
Smaller Gene Networks Permit Longer Persistence in Fast-Changing Environments
(Public Library of Science, 2011-04-25) Malcom, Jacob W.
The environments in which organisms live and reproduce are rarely static, and as the environment changes, populations must evolve so that phenotypes match the challenges presented. The quantitative traits that map to environmental variables are underlain by hundreds or thousands of interacting genes whose allele frequencies and epistatic relationships must change appropriately for adaptation to occur. Extending an earlier model in which individuals possess an ecologically-critical trait encoded by gene networks of 16 to 256 genes and random or scale-free topology, I test the hypothesis that smaller, scale-free networks permit longer persistence times in a constantly-changing environment. Genetic architecture interacting with the rate of environmental change accounts for 78% of the variance in trait heritability and 66% of the variance in population persistence times. When the rate of environmental change is high, the relationship between network size and heritability is apparent, with smaller and scale-free networks conferring a distinct advantage for persistence time. However, when the rate of environmental change is very slow, the relationship between network size and heritability disappears and populations persist the duration of the simulations, without regard to genetic architecture. These results provide a link between genes and population dynamics that may be tested as the -omics and bioinformatics fields mature, and as we are able to determine the genetic basis of ecologically-relevant quantitative traits.
Wing Patterns in the Mist
(Public Library of Science, 2010-02-05) Martin, Arnaud; Kapan, Durrell D.; Gilbert, Lawrence E.
The aesthetic appeal of butterfly wing patterns has been costly to their status as a tool of fundamental scientific inquiry. Thus, while mimetic convergence in wing patterns between edible “Batesian” mimics and distasteful models, or between different distasteful “Müllerian” mimics (species that cooperate to educate predators) has long been the subject of genetic analysis [1] and field experiments [2], most biology text books confine mimicry to sections on striking adaptations without applying these examples to broader topics of evolution. Meanwhile, the study of color patterns in animals, often tucked into the same sections of texts, is undergoing a revolution in this age of evo-devo and genomics [3]. Among insect models for studying color pattern, the genus Heliconius is gaining the attention of an ever-widening audience.