RESUMO
Bats are distinctive among mammals due to their ability to fly, use laryngeal echolocation, and tolerate viruses. However, there are currently no reliable cellular models for studying bat biology or their response to viral infections. Here, we created induced pluripotent stem cells (iPSCs) from two species of bats: the wild greater horseshoe bat (Rhinolophus ferrumequinum) and the greater mouse-eared bat (Myotis myotis). The iPSCs from both bat species showed similar characteristics and had a gene expression profile resembling that of cells attacked by viruses. They also had a high number of endogenous viral sequences, particularly retroviruses. These results suggest that bats have evolved mechanisms to tolerate a large load of viral sequences and may have a more intertwined relationship with viruses than previously thought. Further study of bat iPSCs and their differentiated progeny will provide insights into bat biology, virus host relationships, and the molecular basis of bats' special traits.
Assuntos
Quirópteros , Células-Tronco Pluripotentes , Viroses , Vírus , Animais , Vírus/genética , Transcriptoma , FilogeniaRESUMO
Bats possess extraordinary adaptations, including flight, echolocation, extreme longevity and unique immunity. High-quality genomes are crucial for understanding the molecular basis and evolution of these traits. Here we incorporated long-read sequencing and state-of-the-art scaffolding protocols1 to generate, to our knowledge, the first reference-quality genomes of six bat species (Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pipistrellus kuhlii and Molossus molossus). We integrated gene projections from our 'Tool to infer Orthologs from Genome Alignments' (TOGA) software with de novo and homology gene predictions as well as short- and long-read transcriptomics to generate highly complete gene annotations. To resolve the phylogenetic position of bats within Laurasiatheria, we applied several phylogenetic methods to comprehensive sets of orthologous protein-coding and noncoding regions of the genome, and identified a basal origin for bats within Scrotifera. Our genome-wide screens revealed positive selection on hearing-related genes in the ancestral branch of bats, which is indicative of laryngeal echolocation being an ancestral trait in this clade. We found selection and loss of immunity-related genes (including pro-inflammatory NF-κB regulators) and expansions of anti-viral APOBEC3 genes, which highlights molecular mechanisms that may contribute to the exceptional immunity of bats. Genomic integrations of diverse viruses provide a genomic record of historical tolerance to viral infection in bats. Finally, we found and experimentally validated bat-specific variation in microRNAs, which may regulate bat-specific gene-expression programs. Our reference-quality bat genomes provide the resources required to uncover and validate the genomic basis of adaptations of bats, and stimulate new avenues of research that are directly relevant to human health and disease1.
Assuntos
Adaptação Fisiológica/genética , Quirópteros/genética , Evolução Molecular , Genoma/genética , Genômica/normas , Adaptação Fisiológica/imunologia , Animais , Quirópteros/classificação , Quirópteros/imunologia , Elementos de DNA Transponíveis/genética , Imunidade/genética , Anotação de Sequência Molecular/normas , Filogenia , RNA não Traduzido/genética , Padrões de Referência , Reprodutibilidade dos Testes , Integração Viral/genética , Vírus/genéticaRESUMO
Some organisms in nature have developed the ability to enter a state of suspended metabolism called cryptobiosis when environmental conditions are unfavorable. This state-transition requires execution of a combination of genetic and biochemical pathways that enable the organism to survive for prolonged periods. Recently, nematode individuals have been reanimated from Siberian permafrost after remaining in cryptobiosis. Preliminary analysis indicates that these nematodes belong to the genera Panagrolaimus and Plectus. Here, we present precise radiocarbon dating indicating that the Panagrolaimus individuals have remained in cryptobiosis since the late Pleistocene (~46,000 years). Phylogenetic inference based on our genome assembly and a detailed morphological analysis demonstrate that they belong to an undescribed species, which we named Panagrolaimus kolymaensis. Comparative genome analysis revealed that the molecular toolkit for cryptobiosis in P. kolymaensis and in C. elegans is partly orthologous. We show that biochemical mechanisms employed by these two species to survive desiccation and freezing under laboratory conditions are similar. Our experimental evidence also reveals that C. elegans dauer larvae can remain viable for longer periods in suspended animation than previously reported. Altogether, our findings demonstrate that nematodes evolved mechanisms potentially allowing them to suspend life over geological time scales.
Assuntos
Nematoides , Pergelissolo , Humanos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Larva/genética , Larva/metabolismo , FilogeniaRESUMO
SUMMARY: Sensory receptor gene families have undergone extensive expansion and loss across vertebrate evolution, leading to significant variation in receptor counts between species. However, due to their species-specific nature, conventional reference-based annotation tools often underestimate the true number of sensory receptors in a given species. While there has been an exponential increase in the taxonomic diversity of publicly available genome assemblies in recent years, only â¼30% of vertebrate species on the NCBI database are currently annotated. To overcome these limitations, we developed 'Sensommatic', an automated and accessible sensory receptor annotation pipeline. Sensommatic implements BLAST and AUGUSTUS to mine and predict sensory receptor genes from whole genome assemblies, adopting a one-to-many gene mapping approach. While designed for vertebrates, Sensommatic can be extended to run on non-vertebrate species by generating customized reference files, making it a scalable and generalizable tool. AVAILABILITY AND IMPLEMENTATION: Source code and associated files are available at: https://github.com/GMHughes/Sensommatic.
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Genoma , Software , Animais , Mapeamento Cromossômico , Vertebrados/genética , Anotação de Sequência MolecularRESUMO
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
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Betacoronavirus/fisiologia , Infecções por Coronavirus/metabolismo , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/genética , Pneumonia Viral/metabolismo , Aminoácidos , Animais , Betacoronavirus/metabolismo , Sítios de Ligação , COVID-19 , Infecções por Coronavirus/virologia , Evolução Molecular , Variação Genética , Especificidade de Hospedeiro , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Ligação Proteica , Receptores Virais/química , Receptores Virais/genética , Receptores Virais/metabolismo , SARS-CoV-2 , Seleção Genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , VertebradosRESUMO
Comprising more than 1,400 species, bats possess adaptations unique among mammals including powered flight, unexpected longevity, and extraordinary immunity. Some of the molecular mechanisms underlying these unique adaptations includes DNA repair, metabolism and immunity. However, analyses have been limited to a few divergent lineages, reducing the scope of inferences on gene family evolution across the Order Chiroptera. We conducted an exhaustive comparative genomic study of 37 bat species, one generated in this study, encompassing a large number of lineages, with a particular emphasis on multi-gene family evolution across immune and metabolic genes. In agreement with previous analyses, we found lineage-specific expansions of the APOBEC3 and MHC-I gene families, and loss of the proinflammatory PYHIN gene family. We inferred more than 1,000 gene losses unique to bats, including genes involved in the regulation of inflammasome pathways such as epithelial defence receptors, the natural killer gene complex and the interferon-gamma induced pathway. Gene set enrichment analyses revealed genes lost in bats are involved in defence response against pathogen-associated molecular patterns and damage-associated molecular patterns. Gene family evolution and selection analyses indicate bats have evolved fundamental functional differences compared to other mammals in both innate and adaptive immune system, with the potential to enhance antiviral immune response while dampening inflammatory signalling. In addition, metabolic genes have experienced repeated expansions related to convergent shifts to plant-based diets. Our analyses support the hypothesis that, in tandem with flight, ancestral bats had evolved a unique set of immune adaptations whose functional implications remain to be explored.
Assuntos
Quirópteros , Adaptação Fisiológica/genética , Animais , Quirópteros/genética , Evolução Molecular , Genoma , Genômica , Humanos , FilogeniaRESUMO
Through their unique use of sophisticated laryngeal echolocation bats are considered sensory specialists amongst mammals and represent an excellent model in which to explore sensory perception. Although several studies have shown that the evolution of vision is linked to ecological niche adaptation in other mammalian lineages, this has not yet been fully explored in bats. Recent molecular analysis of the opsin genes, which encode the photosensitive pigments underpinning color vision, have implicated high-duty cycle (HDC) echolocation and the adoption of cave roosting habits in the degeneration of color vision in bats. However, insufficient sampling of relevant taxa has hindered definitive testing of these hypotheses. To address this, novel sequence data was generated for the SWS1 and MWS/LWS opsin genes and combined with existing data to comprehensively sample species representing diverse echolocation types and niches (SWS1 n = 115; MWS/LWS n = 45). A combination of phylogenetic analysis, ancestral state reconstruction, and selective pressure analyses were used to reconstruct the evolution of these visual pigments in bats and revealed that although both genes are evolving under purifying selection in bats, MWS/LWS is highly conserved but SWS1 is highly variable. Spectral tuning analyses revealed that MWS/LWS opsin is tuned to a long wavelength, 555-560 nm in the bat ancestor and the majority of extant taxa. The presence of UV vision in bats is supported by our spectral tuning analysis, but phylogenetic analyses demonstrated that the SWS1 opsin gene has undergone pseudogenization in several lineages. We do not find support for a link between the evolution of HDC echolocation and the pseudogenization of the SWS1 gene in bats, instead we show the SWS1 opsin is functional in the HDC echolocator, Pteronotus parnellii. Pseudogenization of the SWS1 is correlated with cave roosting habits in the majority of pteropodid species. Together these results demonstrate that the loss of UV vision in bats is more widespread than was previously considered and further elucidate the role of ecological niche specialization in the evolution of vision in bats.
Assuntos
Evolução Biológica , Quirópteros/genética , Visão de Cores/genética , Ecolocação , Opsinas/fisiologia , Animais , CavernasRESUMO
SUMMARY: A number of limiting factors mean that traditional genome annotation tools either fail or perform sub-optimally when trying to detect coding sequences in poor quality genome assemblies/genome reports. This means that potentially useful data is accessible only to those with specific skills and expertise in assembly and annotation. We present an Assembled-Genome mIning pipeLinE (AGILE) written in Perl that combines bioinformatics tools with a number of steps to overcome the limitations imposed by such assemblies when applied to highly fragmented genomes. Our methodology uses user-specified query genes from a closely related species to mine and annotate coding sequences that would traditionally be missed by standard annotation packages. Despite a focus on mammalian genomes, the generalized implementation means that it may be applied to any genome assembly, providing a means for non-specialists to gather gene sequences for downstream analyses. AVAILABILITY AND IMPLEMENTATION: Source code and associated files are available at: https://github.com/batlabucd/GenomeMining and https://bitbucket.org/BatlabUCD/genomemining/src. Singularity and Virtual Box images available at https://figshare.com/s/a0004bf93dc43484b0c0. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Genoma , Genômica , Software , Animais , Mineração de Dados , Éxons/genética , Genoma/genética , Genômica/métodosRESUMO
Age-related telomere shortening is considered a hallmark of the ageing process. However, a recent cross-sectional ageing study of relative telomere length (rTL) in bats failed to detect a relationship between rTL and age in the long-lived genus Myotis (M. myotis and M. bechsteinii), suggesting some other factors are responsible for driving telomere dynamics in these species. Here, we test if longitudinal rTL data show signatures of age-associated telomere attrition in M. myotis and differentiate which intrinsic or extrinsic factors are likely to drive telomere length dynamics. Using quantitative polymerase chain reaction, rTL was measured in 504 samples from a marked population, from Brittany, France, captured between 2013 and 2016. These represent 174 individuals with an age range of 0 to 7+ years. We find no significant relationship between rTL and age (p = .762), but demonstrate that within-individual rTL is highly variable from year to year. To investigate the heritability of rTL, a population pedigree (n = 1744) was constructed from genotype data generated from a 16-microsatellite multiplex, designed from an initial, low-coverage, Illumina genome for M. myotis. Heritability was estimated in a Bayesian, mixed model framework, and showed that little of the observed variance in rTL is heritable (h2 = 0.01-0.06). Rather, correlations of first differences, correlating yearly changes in telomere length and weather variables, demonstrate that, during the spring transition, average temperature, minimum temperature, rainfall and windspeed correlate with changes in longitudinal telomere dynamics. As such, rTL may represent a useful biomarker to quantify the physiological impact of various environmental stressors in bats.
Assuntos
Quirópteros , Animais , Teorema de Bayes , Criança , Pré-Escolar , Quirópteros/genética , Estudos Transversais , França , Humanos , Lactente , Recém-Nascido , Telômero/genética , Encurtamento do Telômero/genéticaRESUMO
BACKGROUND: LSVT-BIG® is an intensively delivered, amplitude-oriented exercise therapy reported to improve mobility in individuals with Parkinson's disease (PD). However, questions remain surrounding the efficacy of LSVT-BIG® when compared with similar exercise therapies. Instrumented clinical tests using body-worn sensors can provide a means to objectively monitor patient progression with therapy by quantifying features of motor function, yet research exploring the feasibility of this approach has been limited to date. The aim of this study was to use accelerometer-instrumented clinical tests to quantify features of gait, balance and fine motor control in individuals with PD, in order to examine motor function during and following LSVT-BIG® therapy. METHODS: Twelve individuals with PD undergoing LSVT-BIG® therapy, eight non-exercising PD controls and 14 healthy controls were recruited to participate in the study. Functional mobility was examined using features derived from accelerometry recorded during five instrumented clinical tests: 10 m walk, Timed-Up-and-Go, Sit-to-Stand, quiet stance, and finger tapping. PD subjects undergoing therapy were assessed before, each week during, and up to 13 weeks following LSVT-BIG®. RESULTS: Accelerometry data captured significant improvements in 10 m walk and Timed-Up-and-Go times with LSVT-BIG® (p < 0.001), accompanied by increased stride length. Temporal features of the gait cycle were significantly lower following therapy, though no change was observed with measures of asymmetry or stride variance. The total number of Sit-to-Stand transitions significantly increased with LSVT-BIG® (p < 0.001), corresponding to a significant reduction of time spent in each phase of the Sit-to-Stand cycle. No change in measures related to postural or fine motor control was observed with LSVT-BIG®. PD subjects undergoing LSVT-BIG® showed significant improvements in 10 m walk (p < 0.001) and Timed-Up-and-Go times (p = 0.004) over a four-week period when compared to non-exercising PD controls, who showed no week-to-week improvement in any task examined. CONCLUSIONS: This study demonstrates the potential for wearable sensors to objectively quantify changes in motor function in response to therapeutic exercise interventions in PD. The observed improvements in accelerometer-derived features provide support for instrumenting gait and sit-to-stand tasks, and demonstrate a rescaling of the speed-amplitude relationship during gait in PD following LSVT-BIG®.
Assuntos
Acelerometria/métodos , Terapia por Exercício/métodos , Doença de Parkinson/reabilitação , Dispositivos Eletrônicos Vestíveis , Acelerometria/instrumentação , Idoso , Estudos de Viabilidade , Feminino , Humanos , MasculinoRESUMO
The olfactory receptor (OR) gene families, which govern mammalian olfaction, have undergone extensive expansion and contraction through duplication and pseudogenization. Previous studies have shown that broadly defined environmental adaptations (e.g., terrestrial vs. aquatic) are correlated with the number of functional and non-functional OR genes retained. However, to date, no study has examined species-specific gene duplications in multiple phylogenetically divergent mammals to elucidate OR evolution and adaptation. Here, we identify the OR gene families driving adaptation to different ecological niches by mapping the fate of species-specific gene duplications in the OR repertoire of 94 diverse mammalian taxa, using molecular phylogenomic methods. We analyze >70,000 OR gene sequences mined from whole genomes, generated from novel amplicon sequencing data, and collated with data from previous studies, comprising one of the largest OR studies to date. For the first time, we demonstrate statistically significant patterns of OR species-specific gene duplications associated with the presence of a functioning vomeronasal organ. With respect to dietary niche, we uncover a novel link between a large number of duplications in OR family 5/8/9 and herbivory. Our results also highlight differences between social and solitary niches, indicating that a greater OR repertoire expansion may be associated with a solitary lifestyle. This study demonstrates the utility of species-specific duplications in elucidating gene family evolution, revealing how the OR repertoire has undergone expansion and contraction with respect to a number of ecological adaptations in mammals.
Assuntos
Adaptação Biológica , Evolução Biológica , Mamíferos/genética , Família Multigênica , Receptores Odorantes/genética , Animais , Ecossistema , Duplicação Gênica , Especificidade da EspécieRESUMO
The olfactory bulb (OB) ratio is the size of the OB relative to the cerebral hemisphere, and is used to estimate the proportion of the forebrain devoted to smell. In birds, OB ratio correlates with the number of olfactory receptor (OR) genes and therefore has been used as a proxy for olfactory acuity. By coupling OB ratios with known OR gene repertoires in birds, we infer minimum repertoire sizes for extinct taxa, including non-avian dinosaurs, using phylogenetic modelling, ancestral state reconstruction and comparative genomics. We highlight a shift in the scaling of OB ratio to body size along the lineage leading to modern birds, demonstrating variable OR repertoires present in different dinosaur and crown-bird lineages, with varying factors potentially influencing sensory evolution in theropods. We investigate the ancestral sensory space available to extinct taxa, highlighting potential adaptations to ecological niches. Through combining morphological and genomic data, we show that, while genetic information for extinct taxa is forever lost, it is potentially feasible to investigate evolutionary trajectories in extinct genomes.
Assuntos
Dinossauros/genética , Filogenia , Receptores Odorantes/genética , Olfato/genética , Adaptação Fisiológica , Animais , Evolução Biológica , Simulação por Computador , Dinossauros/anatomia & histologia , Dinossauros/metabolismo , Genômica , Bulbo Olfatório/anatomia & histologiaAssuntos
Acromegalia , Síndrome Antifosfolipídica , Hipertricose , Lúpus Eritematoso Sistêmico , HumanosRESUMO
BACKGROUND: Guide-trees are used as part of an essential heuristic to enable the calculation of multiple sequence alignments. They have been the focus of much method development but there has been little effort at determining systematically, which guide-trees, if any, give the best alignments. Some guide-tree construction schemes are based on pair-wise distances amongst unaligned sequences. Others try to emulate an underlying evolutionary tree and involve various iteration methods. RESULTS: We explore all possible guide-trees for a set of protein alignments of up to eight sequences. We find that pairwise distance based default guide-trees sometimes outperform evolutionary guide-trees, as measured by structure derived reference alignments. However, default guide-trees fall way short of the optimum attainable scores. On average chained guide-trees perform better than balanced ones but are not better than default guide-trees for small alignments. CONCLUSIONS: Alignment methods that use Consistency or hidden Markov models to make alignments are less susceptible to sub-optimal guide-trees than simpler methods, that basically use conventional sequence alignment between profiles. The latter appear to be affected positively by evolutionary based guide-trees for difficult alignments and negatively for easy alignments. One phylogeny aware alignment program can strongly discriminate between good and bad guide-trees. The results for randomly chained guide-trees improve with the number of sequences.
Assuntos
Proteínas/química , Alinhamento de Sequência/métodos , Análise de Sequência de Proteína/métodos , Software , Análise por Conglomerados , Filogenia , Proteínas/genéticaRESUMO
A new, more complete view of the mechanical energy budget for Rayleigh-Bénard convection is developed and examined using three-dimensional numerical simulations at large Rayleigh numbers and Prandtl number of 1. The driving role of available potential energy is highlighted. The relative magnitudes of different energy conversions or pathways change significantly over the range of Rayleigh numbers Ra ~ 10(7)-10(13). At Ra < 10(7) small-scale turbulent motions are energized directly from available potential energy via turbulent buoyancy flux and kinetic energy is dissipated at comparable rates by both the large- and small-scale motions. In contrast, at Ra ≥ 10(10) most of the available potential energy goes into kinetic energy of the large-scale flow, which undergoes shear instabilities that sustain small-scale turbulence. The irreversible mixing is largely confined to the unstable boundary layer, its rate exactly equal to the generation of available potential energy by the boundary fluxes, and mixing efficiency is 50%.
RESUMO
The role of structurally dynamic genomic regions in speciation is poorly understood due to challenges inherent in diploid genome assembly. Here we reconstructed the evolutionary dynamics of structural variation in five cat species by phasing the genomes of three interspecies F1 hybrids to generate near-gapless single-haplotype assemblies. We discerned that cat genomes have a paucity of segmental duplications relative to great apes, explaining their remarkable karyotypic stability. X chromosomes were hotspots of structural variation, including enrichment with inversions in a large recombination desert with characteristics of a supergene. The X-linked macrosatellite DXZ4 evolves more rapidly than 99.5% of the genome clarifying its role in felid hybrid incompatibility. Resolved sensory gene repertoires revealed functional copy number changes associated with ecomorphological adaptations, sociality and domestication. This study highlights the value of gapless genomes to reveal structural mechanisms underpinning karyotypic evolution, reproductive isolation and ecological niche adaptation.
Assuntos
Evolução Molecular , Genômica , Haplótipos/genética , Genoma/genética , Dosagem de GenesRESUMO
High viral tolerance coupled with an extraordinary regulation of the immune response makes bats a great model to study host-pathogen evolution. Although many immune-related gene gains and losses have been previously reported in bats, important gene families such as antimicrobial peptides (AMPs) remain understudied. We built an exhaustive bioinformatic pipeline targeting the major gene families of defensins and cathelicidins to explore AMP diversity and analyze their evolution and distribution across six bat families. A combination of manual and automated procedures identified 29 AMP families across queried species, with α-, ß-defensins, and cathelicidins representing around 10% of AMP diversity. Gene duplications were inferred in both α-defensins, which were absent in five species, and three ß-defensin gene subfamilies, but cathelicidins did not show significant shifts in gene family size and were absent in Anoura caudifer and the pteropodids. Based on lineage-specific gains and losses, we propose diet and diet-related microbiome evolution may determine the evolution of α- and ß-defensins gene families and subfamilies. These results highlight the importance of building species-specific libraries for genome annotation in non-model organisms and shed light on possible drivers responsible for the rapid evolution of AMPs. By focusing on these understudied defenses, we provide a robust framework for explaining bat responses to pathogens.
Assuntos
Quirópteros , beta-Defensinas , Animais , Quirópteros/genética , beta-Defensinas/genética , Peptídeos Antimicrobianos , Peptídeos Catiônicos Antimicrobianos , CatelicidinasRESUMO
Biodiversity loss is now recognised as one of the major challenges for humankind to address over the next few decades. Unless major actions are taken, the sixth mass extinction will lead to catastrophic effects on the Earth's biosphere and human health and well-being. ELIXIR can help address the technical challenges of biodiversity science, through leveraging its suite of services and expertise to enable data management and analysis activities that enhance our understanding of life on Earth and facilitate biodiversity preservation and restoration. This white paper, prepared by the ELIXIR Biodiversity Community, summarises the current status and responses, and presents a set of plans, both technical and community-oriented, that should both enhance how ELIXIR Services are applied in the biodiversity field and how ELIXIR builds connections across the many other infrastructures active in this area. We discuss the areas of highest priority, how they can be implemented in cooperation with the ELIXIR Platforms, and their connections to existing ELIXIR Communities and international consortia. The article provides a preliminary blueprint for a Biodiversity Community in ELIXIR and is an appeal to identify and involve new stakeholders.
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Biodiversidade , Humanos , Conservação dos Recursos NaturaisRESUMO
Although thousands of genomic regions have been associated with heritable human diseases, attempts to elucidate biological mechanisms are impeded by a general inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function that is agnostic to cell type or disease mechanism. Here, single base phyloP scores from the whole genome alignment of 240 placental mammals identified 3.5% of the human genome as significantly constrained, and likely functional. We compared these scores to large-scale genome annotation, genome-wide association studies (GWAS), copy number variation, clinical genetics findings, and cancer data sets. Evolutionarily constrained positions are enriched for variants explaining common disease heritability (more than any other functional annotation). Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.