scholarly journals Contrasted gene decay in subterranean vertebrates: insights from cavefishes and fossorial mammals

2020 ◽  
Author(s):  
Maxime Policarpo ◽  
Julien Fumey ◽  
Philippe Lafargeas ◽  
Delphine Naquin ◽  
Claude Thermes ◽  
...  
Keyword(s):  
Evolutionary Process ◽  
Sharp Contrast ◽  
Functional Constraints ◽  
Loss Of Function ◽  
Astyanax Mexicanus ◽  
Gene Sets ◽  
Cave Population ◽  
Cave Ecosystems ◽  
Genome Ploidy ◽  
Gene Decay

AbstractEvolution sometimes proceeds by loss, especially when structures and genes become dispensable after an environmental shift relaxing functional constraints. Gene decay can serve as a read-out of this evolutionary process. Animals living in the dark are outstanding models, in particular cavefishes as hundreds of species evolved independently during very different periods of time in absence of light. Here, we sought to understand some general principals on the extent and tempo of decay of several gene sets in cavefishes. The analysis of the genomes of two Cuban species belonging to the genus Lucifuga provides evidence for the most massive loss of eye genes reported so far in cavefishes. Comparisons with a recently-evolved cave population of Astyanax mexicanus and three species belonging to the tetraploid Chinese genus Sinocyclocheilus revealed the combined effects of the level of eye regression, time and genome ploidy on the number of eye pseudogenes. In sharp contrast, most circadian clock and pigmentation genes appeared under strong selection. In cavefishes for which complete genomes are available, the limited extent of eye gene decay and the very small number of loss of function (LoF) mutations per pseudogene suggest that eye degeneration is never very ancient, ranging from early to late Pleistocene. This is in sharp contrast with the identification of several eye pseudogenes carrying many LoF mutations in ancient fossorial mammals. Our analyses support the hypothesis that blind fishes cannot thrive more than a few millions of years in cave ecosystems.

scholarly journals Contrasting Gene Decay in Subterranean Vertebrates: Insights from Cavefishes and Fossorial Mammals

2020 ◽  
Author(s):  
Maxime Policarpo ◽  
Julien Fumey ◽  
Philippe Lafargeas ◽  
Delphine Naquin ◽  
Claude Thermes ◽  
...  
Keyword(s):  
Specific Gene ◽  
Functional Constraints ◽  
Limited Extent ◽  
Loss Of Function ◽  
Astyanax Mexicanus ◽  
Cave Population ◽  
Opsin Genes ◽  
Cave Ecosystems ◽  
Genome Ploidy ◽  
Gene Decay

Abstract Evolution sometimes proceeds by loss, especially when structures and genes become dispensable after an environmental shift relaxes functional constraints. Subterranean vertebrates are outstanding models to analyze this process, and gene decay can serve as a readout. We sought to understand some general principles on the extent and tempo of the decay of genes involved in vision, circadian clock, and pigmentation in cavefishes. The analysis of the genomes of two Cuban species belonging to the genus Lucifuga provided evidence for the largest loss of eye-specific genes and nonvisual opsin genes reported so far in cavefishes. Comparisons with a recently evolved cave population of Astyanax mexicanus and three species belonging to the Chinese tetraploid genus Sinocyclocheilus revealed the combined effects of the level of eye regression, time, and genome ploidy on eye-specific gene pseudogenization. The limited extent of gene decay in all these cavefishes and the very small number of loss-of-function mutations per pseudogene suggest that their eye degeneration may not be very ancient, ranging from early to late Pleistocene. This is in sharp contrast with the identification of several vision genes carrying many loss-of-function mutations in ancient fossorial mammals, further suggesting that blind fishes cannot thrive more than a few million years in cave ecosystems.

Evidence for rapid phenotypic and behavioural shifts in a recently established cavefish population

2019 ◽  
Author(s):  
Suzanne E McGaugh ◽  
Sam Weaver ◽  
Erin N Gilbertson ◽  
Brianna Garrett ◽  
Melissa L Rudeen ◽  
...  
Keyword(s):  
Extreme Environments ◽  
Time Frame ◽  
South Texas ◽  
Astyanax Mexicanus ◽  
North East ◽  
Surface Population ◽  
Cave Population ◽  
Cave Environment ◽  
Central Texas ◽  
Recent Origin

Abstract Cave colonization offers a natural laboratory to study an extreme environmental shift, and diverse cave species from around the world often have converged on robust morphological, physiological and behavioural traits. The Mexican tetra (Astyanax mexicanus) has repeatedly colonized caves in the Sierra de El Abra and Sierra de Guatemala regions of north-east Mexico ~0.20–1 Mya, indicating an ability to adapt to the cave environment. The time frame for the evolution of these traits in any cave animal, however, is poorly understood. Astyanax mexicanus from the Río Grande in South Texas were brought to Central Texas beginning in the early 1900s and colonized underground environments. Here, we investigate whether phenotypic and behavioural differences have occurred rapidly between a surface population and a geographically proximate cave population, probably of recent origin. Fish from the cave and surface populations differ significantly in morphological traits, including coloration, lateral line expansion and dorsal fin placement. Striking behavioural shifts in aggression, feeding and wall-following have also occurred. Together, our results suggest that morphological and behavioural changes accompanying cave colonization can be established rapidly, and this system offers an exciting and unique opportunity for isolating the genetic and environmental contributions to colonization of extreme environments.

scholarly journals Gene regulatory mechanisms underlying the evolutionary loss of a polygenic trait

2018 ◽  
Author(s):  
Mark Lammers ◽  
Ken Kraaijeveld ◽  
Janine Mariën ◽  
Jacintha Ellers
Keyword(s):  
Expression Profiles ◽  
Loss Of Function ◽  
Parasitoid Species ◽  
Sugar Feeding ◽  
Malonyl Coa ◽  
Gene Level ◽  
Combined Action ◽  
Gene Regulatory ◽  
Dietary Sugars ◽  
Gene Decay

AbstractTrait loss is a pervasive phenomenon in evolution, yet the underlying molecular causes have been identified in only a handful of cases. Most of these involve loss-of-function mutations in one or more trait-specific genes. Parasitoid insects are fatty acid auxotrophs: they lost the ability to convert dietary sugars into fatty acids, a trait that is ubiquitous among non-parasitoid animals and is enabled by a highly conserved set of genes. Earlier research suggests that lack of lipogenesis is caused by changes in gene regulation, rather than gene decay. We compared transcriptome-wide responses to sugar-feeding in the non-lipogenic parasitoid species Nasonia vitripennis and the lipogenic Drosophila melanogaster. Both species adjusted their metabolism within four hours after feeding, but there was little overlap at the gene level between the responses of the two species. Even at the pathway-level, there were sharp differences between the expression profiles of the two species, especially in carbohydrate and lipid metabolic pathways. Several genes coding for key enzymes in acetyl-CoA metabolism, such as malonyl-CoA decarboxylase (MCD) and HMG-CoA synthase differed in expression between the two species. Their combined action likely blocks lipogenesis in the parasitoid species. Network analysis indicates most genes involved in these pathways to be highly connected, which suggest they have pleiotropic effects and could explain the absence of gene degradation. Our results indicate that modification of expression levels of only a few non-connected genes, such as MCD, is sufficient to enable complete loss of lipogenesis in N. vitripennis.

scholarly journals Comparative Genome Analysis of the Pathogenic Spirochetes Borrelia burgdorferi and Treponema pallidum

2000 ◽  
Vol 68 (3) ◽  
pp. 1633-1648 ◽  
Author(s):  
G. Subramanian ◽  
Eugene V. Koonin ◽  
L. Aravind
Keyword(s):  
Comparative Analysis ◽  
Borrelia Burgdorferi ◽  
Profile Analysis ◽  
Treponema Pallidum ◽  
Evolutionary Process ◽  
Specific Protein ◽  
Genome Replication ◽  
Ancestral State ◽  
Sequence Profile ◽  
Gene Sets

ABSTRACT A comparative analysis of the predicted protein sequences encoded in the complete genomes of Borrelia burgdorferi andTreponema pallidum provides a number of insights into evolutionary trends and adaptive strategies of the two spirochetes. A measure of orthologous relationships between gene sets, termed the orthology coefficient (OC), was developed. The overall OC value for the gene sets of the two spirochetes is about 0.43, which means that less than one-half of the genes show readily detectable orthologous relationships. This emphasizes significant divergence between the two spirochetes, apparently driven by different biological niches. Different functional categories of proteins as well as different protein families show a broad distribution of OC values, from near 1 (a perfect, one-to-one correspondence) to near 0. The proteins involved in core biological functions, such as genome replication and expression, typically show high OC values. In contrast, marked variability is seen among proteins that are involved in specific processes, such as nutrient transport, metabolism, gene-specific transcription regulation, signal transduction, and host response. Differences in the gene complements encoded in the two spirochete genomes suggest active adaptive evolution for their distinct niches. Comparative analysis of the spirochete genomes produced evidence of gene exchanges with other bacteria, archaea, and eukaryotic hosts that seem to have occurred at different points in the evolution of the spirochetes. Examples are presented of the use of sequence profile analysis to predict proteins that are likely to play a role in pathogenesis, including secreted proteins that contain specific protein-protein interaction domains, such as von Willebrand A, YWTD, TPR, and PR1, some of which hitherto have been reported only in eukaryotes. We tentatively reconstruct the likely evolutionary process that has led to the divergence of the two spirochete lineages; this reconstruction seems to point to an ancestral state resembling the symbiotic spirochetes found in insect guts.

scholarly journals Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

2019 ◽  
Author(s):  
Wai Hoong Chang ◽  
Alvina G. Lai
Keyword(s):  
Circadian Clock ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
Clock Genes ◽  
Tumour Progression ◽  
Prognostic Significance ◽  
Integrated Approach ◽  
Loss Of Function ◽  
Gene Sets

The circadian clock governs a large variety of fundamentally important physiological processes in all three domains of life. Consequently, asynchrony in timekeeping mechanisms could give rise to cellular dysfunction underpinning many disease pathologies including human neoplasms. Yet, detailed pancancer evidence supporting this notion has been limited. In an integrated approach uniting genetic, transcriptomic and clinical data of 21 cancer types (n=18,484), we interrogated copy number and transcript profiles of 32 circadian clock genes to identify putative loss-of-function (ClockLoss) and gain-of-function (ClockGain) players. Kaplan-Meier, Cox regression and receiver operating characteristic analyses were employed to evaluate the prognostic significance of both gene sets. ClockLoss and ClockGain were associated with tumoursuppressing and tumour-promoting roles respectively. Downregulation of ClockLoss genes resulted in significant higher mortality rates in five cancer cohorts (n=2,914): bladder (P=0.027), glioma (P<0.0001), pan-kidney (P=0.011), clear cell renal cell (P<0.0001) and stomach (P=0.0007). In contrast, patients with high expression of oncogenic ClockGain genes had poorer survival outcomes (n=2,784): glioma (P<0.0001), pan-kidney (P=0.0034), clear cell renal cell (P=0.014), lung (P=0.046) and pancreas (P=0.0059). Both gene sets were independent of other clinicopathological features to permit further delineation of tumours within the same stage. Circadian reprogramming of tumour genomes resulted in activation of numerous oncogenic pathways including those associated with cancer stem cells, suggesting that the circadian clock may influence self-renewal mechanisms. Within the hypoxic tumour microenvironment, circadian dysregulation is exacerbated by tumour hypoxia in glioma, renal, lung and pancreatic cancers, resulting in additional death risks. Tumour suppressive ClockLoss genes were negatively correlated with hypoxia inducible factor-1A targets in glioma patients, providing a novel framework for investigating the hypoxia-clock signalling axis. Loss of timekeeping fidelity promotes tumour progression and influences clinical outcomes. ClockLoss and ClockGain may offer novel druggable targets for improving patient prognosis. Both gene sets can be used for patient stratification in adjuvant chronotherapy treatment. Emerging interactions between the circadian clock and hypoxia may be harnessed to achieve therapeutic advantage using hypoxia-modifying compounds in combination with first-line treatments.

scholarly journals In vivo and in vitro human gene essentiality estimations capture contrasting functional constraints

2019 ◽  
Author(s):  
JL Caldu-Primo ◽  
JA Verduzco-Martínez ◽  
ER Alvarez-Buylla ◽  
J Davila-Velderrain
Keyword(s):  
Human Gene ◽  
Human Populations ◽  
Functional Constraints ◽  
Loss Of Function ◽  
Gene Essentiality ◽  
Evolutionary Features ◽  
Cellular Context ◽  
Genome Scale

AbstractGene essentiality estimation is a popular empirical approach to link genotypes to phenotypes. In humans, essentiality is estimated based on loss-of-function (LoF) mutation intolerance, either from population exome sequencing (in vivo) data or CRISPR-based in vitro perturbation experiments. Both approaches identify genes presumed to have strong detrimental consequences on the organism upon mutation. Are these genes functionally distinct and constrained by having key roles? Do in vivo and in vitro estimations equally recover these constraints? To address these questions, here we integrated disparate genome-scale datasets and compared structural, functional, and evolutionary features of essential genes versus genes with extremely high mutational tolerance and proteome expectation. We found that essentiality estimates do recover functional constraints. However, the organismal or cellular context of estimation leads to functionally contrasting properties underlying the constraint. Our results suggest that depletion of LoF mutations in human populations effectively captures developmental, organismal-level functional constraints not experimentally accessible through CRISPR-based screens. Finally, we identify a new set of genes (OrgEssential), which are intolerant of LoF mutation in vivo but highly tolerant in vitro. These genes drive observed functional constraint differences and have an unexpected preference for nervous system expression.

scholarly journals Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance

2021 ◽  
Vol 118 (3) ◽  
pp. e2001248118
Author(s):  
Franck Rapaport ◽  
Bertrand Boisson ◽  
Anne Gregor ◽  
Vivien Béziat ◽  
Stéphanie Boisson-Dupuis ◽  
...  
Keyword(s):  
Negative Selection ◽  
Evolutionary Process ◽  
Integrative Approach ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Complete Penetrance ◽  
Human Genes ◽  
Monogenic Diseases ◽  
Life Threatening ◽  
Better Than

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.

scholarly journals A mutation in monoamine oxidase (MAO) affects the evolution of stress behavior in the blind cavefish Astyanax mexicanus

2020 ◽  
Vol 223 (18) ◽  
pp. jeb226092 ◽  
Author(s):  
Constance Pierre ◽  
Naomie Pradère ◽  
Cynthia Froc ◽  
Patricia Ornelas-García ◽  
Jacques Callebert ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Anatomical Variations ◽  
Loss Of Function ◽  
Partial Loss ◽  
Astyanax Mexicanus ◽  
Excellent Candidate ◽  
Cave Environment ◽  
Blind Cave ◽  
Blind Cavefish ◽  
Subterranean Environment

ABSTRACTThe neurotransmitter serotonin controls a variety of physiological and behavioral processes. In humans, mutations affecting monoamine oxidase (MAO), the serotonin-degrading enzyme, are highly deleterious. Yet, blind cavefish of the species Astyanax mexicanus carry a partial loss-of-function mutation in MAO (P106L) and thrive in their subterranean environment. Here, we established four fish lines, corresponding to the blind cave-dwelling and the sighted river-dwelling morphs of this species, with or without the mutation, in order to decipher the exact contribution of mao P106L in the evolution of cavefish neurobehavioral traits. Unexpectedly, although mao P106L appeared to be an excellent candidate for the genetic determinism of the loss of aggressive and schooling behaviors in cavefish, we demonstrated that it was not the case. Similarly, the anatomical variations in monoaminergic systems observed between cavefish and surface fish brains were independent from mao P106L, and rather due to other, morph-dependent developmental processes. However, we found that mao P106L strongly affected anxiety-like behaviors. Cortisol measurements showed lower basal levels and an increased amplitude of stress response after a change of environment in fish carrying the mutation. Finally, we studied the distribution of the P106L mao allele in wild populations of cave and river A. mexicanus, and discovered that the mutant allele was present – and sometimes fixed – in all populations inhabiting caves of the Sierra de El Abra. The possibility that this partial loss-of-function mao allele evolves under a selective or a neutral regime in the particular cave environment is discussed.

scholarly journals Evidence for Late Pleistocene origin of Astyanax mexicanus cavefish

2016 ◽  
Author(s):  
Julien Fumey ◽  
Hélène Hinaux ◽  
Céline Noirot ◽  
Claude Thermes ◽  
Sylvie Rétaux ◽  
...  
Keyword(s):  
Nuclear Dna ◽  
Middle Pleistocene ◽  
Population Divergence ◽  
Demographic Parameters ◽  
Summary Statistics ◽  
Astyanax Mexicanus ◽  
Phenotypic Changes ◽  
Surface Population ◽  
Cave Population ◽  
Recent Origin

AbstractBackgroundCavefish populations belonging to the Mexican tetra species Astyanax mexicanus are outstanding models to study the tempo and mode of adaptation to a radical environmental change. They share similar phenotypic changes such as blindness and depigmentation resulting from independent and convergent evolution. As such they allow examining whether their evolution involved the fixation of preexisting standing genetic variations and/or de novo mutations. Cavefish populations are currently assigned to two main groups, the so-called "old" and "new" lineages, which would have populated several caves independently and at different times. However, we do not have yet accurate estimations of the time frames of evolution of these populations.ResultsFirst, we reanalyzed the geographic distribution of mitochondrial and nuclear DNA polymorphisms and we found that these data do not support the existence of two cavefish lineages, neither the ancient origin of the “old” lineage. Using IMa2, a program based on a method that does not assume that populations are at mutation/migration/drift equilibrium and thus allows dating population divergence in addition to demographic parameters, we found that microsatellite polymorphism strongly supports a very recent origin of cave populations (i.e. less than 20,000 years). Second, we identified a large number of single-nucleotide polymorphisms (SNPs) in transcript sequences of pools of embryos (Pool-seq) belonging to the “old” Pachón cave population and a surface population from Texas. Pachón cave population has accumulated more neutral substitutions than the surface population and we showed that it could be another signature of its recent origin. Based on summary statistics that can be computed with this SNP data set together with simulations of evolution of SNP polymorphisms in two recently isolated populations, we looked for sets of demographic parameters that allow the computation of summary statistics with simulated populations that are similar to the ones with the sampled populations. In most simulations for which we could find a good fit between the summary statistics of observed and simulated data, the best fit occurred when the divergence between simulated populations was less than 30,000 years.ConclusionsAlthough it is often assumed that some cave populations such as Pachón cavefish have a very ancient origin, within the range of the late Miocene to the middle Pleistocene, a recent origin of these populations is strongly supported by our analyses of two independent sets of nuclear DNA polymorphism using two very different methods of analysis. Moreover, the observation of two divergent haplogroups of mitochondrial and nuclear genes with different geographic distributions support a recent admixture of two divergent surface populations before the isolation of cave populations. If cave populations are indeed only several thousand years old, many phenotypic changes observed in cavefish would thus have mainly involved the fixation of genetic variants present in surface fish populations and within a very short period of time.

scholarly journals Oligogenic rare variant contributions in schizophrenia and their convergence with genes harbouring de novo mutations in schizophrenia, autism and intellectual disability: Evidence from multiplex families

2019 ◽  
Author(s):  
Jibin John ◽  
Prachi Kukshal ◽  
Triptish Bhatia ◽  
Ricardo Harripaul ◽  
V L Nimgaonkar ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Protein Sequence ◽  
De Novo ◽  
Threshold Effect ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Disease Manifestation ◽  
Gene Sets ◽  
Heterogeneous Nature ◽  
Multiplex Families

AbstractClinical and genetic heterogeneity has been documented extensively in schizophrenia, a common behavioural disorder with heritability estimates of about 80%. Common and rare de novo variant based studies have provided notable evidence for the likely involvement of a range of pathways including glutamatergic, synaptic signalling and neurodevelopment. To complement these studies, we sequenced exomes of 11 multimember affected schizophrenia families from India. Variant prioritisation performed based on their rarity (MAF <0.01), shared presence among the affected individuals in the respective families and predicted deleterious nature, yielded a total of 785 inherited rare protein sequence altering variants in 743 genes among the 11 families. These showed an enrichment of genes involved in the extracellular matrix and cytoskeleton components, synaptic and neuron related ontologies and neurodevelopmental pathways, consistent with major etiological hypotheses. We also noted an overrepresentation of genes from previously reported gene sets with de novo protein sequence altering variants in schizophrenia, autism, intellectual disability; FMRP target and loss of function intolerant genes. Furthermore, a minimum of five genes known to manifest behavioural/neurological and nervous system abnormalities in rodent models had deleterious variants in them shared among all affected individuals in each of the families. Majority of such variants segregated within and not across families providing strong suggestive evidence for the genetically heterogeneous nature of disease. More importantly, study findings unequivocally support the classical paradigm of cumulative contribution of multiple genes, notably with an apparent threshold effect for disease manifestation and offer a likely explanation for the unclear mode of inheritance in familial schizophrenia.

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