Search

Type IB topoisomerases relax the torsional stress associated with DNA metabolism in the nucleus and mitochondria and constitute important molecular targets of anticancer drugs. Vertebrates stand out among eukaryotes by having two Type IB topoisomerases acting specifically in the nucleus (TOP1) and mitochondria (TOP1MT). Despite their major importance, the origin and evolution of these paralogues remain unknown. Here, we examine the molecular evolutionary processes acting on both TOP1 and TOP1MT in Chordata, taking advantage of the increasing number of available genome sequences. We found that both TOP1 and TOP1MT evolved under strong purifying selection, as expected considering their essential biological functions. Critical active sites, including those associated with resistance to anticancer agents, were found particularly conserved. However, TOP1MT presented a higher rate of molecular evolution than TOP1, possibly related with its specialized activity on the mitochondrial genome and a less critical role in cells. We could place the duplication event that originated the TOP1 and TOP1MT paralogues early in the radiation of vertebrates, most likely associated with the first round of vertebrate tetraploidization (1R). Moreover, our data suggest that cyclostomes present a specialized mitochondrial Type IB topoisomerase. Interestingly, we identified two missense mutations replacing amino acids in the Linker region of TOP1MT in Neanderthals, which appears as a rare event when comparing the genome of both species. In conclusion, TOP1 and TOP1MT differ in their rates of evolution, and their evolutionary histories allowed us to better understand the evolution of chordates.

Genetic recombination is a common evolutionary mechanism that produces molecular diversity. However, its consequences on protein folding stability have not attracted the same attention as in the case of point mutations. Here, we studied the effects of homologous recombination on the computationally predicted protein folding stability for several protein families, finding less detrimental effects than we previously expected. Although recombination can affect multiple protein sites, we found that the fraction of recombined proteins that are eliminated by negative selection because of insufficient stability is not significantly larger than the corresponding fraction of proteins produced by mutation events. Indeed, although recombination disrupts epistatic interactions, the mean stability of recombinant proteins is not lower than that of their parents. On the other hand, the difference of stability between recombined proteins is amplified with respect to the parents, promoting phenotypic diversity. As a result, at least one third of recombined proteins present stability between those of their parents, and a substantial fraction have higher or lower stability than those of both parents. As expected, we found that parents with similar sequences tend to produce recombined proteins with stability close to that of the parents. Finally, the simulation of protein evolution along the ancestral recombination graph with empirical substitution models commonly used in phylogenetics, which ignore constraints on protein folding stability, showed that recombination favors the decrease of folding stability, supporting the convenience of adopting structurally constrained models when possible for inferences of protein evolutionary histories with recombination. Agencia Estatal de Investigación | Ref. PID2019-107931GA-I00/AEI/10.13039/501100011033 Agencia Estatal de Investigación | Ref. PID2019-109041GBC22/10.13039/501100011033 Ministerio de Economía y Competitividad | Ref. RYC-2015-18241 Financiado para publicación en acceso aberto: Universidade de Vigo/CISUG

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced diverse molecular variants during its recent expansion in humans that caused different transmissibility and severity of the associated disease as well as resistance to monoclonal antibodies and polyclonal sera, among other treatments. In order to understand the causes and consequences of the observed SARS-CoV-2 molecular diversity, a variety of recent studies investigated the molecular evolution of this virus during its expansion in humans. In general, this virus evolves with a moderate rate of evolution, in the order of 10−3–10−4 substitutions per site and per year, which presents continuous fluctuations over time. Despite its origin being frequently associated with recombination events between related coronaviruses, little evidence of recombination was detected, and it was mostly located in the spike coding region. Molecular adaptation is heterogeneous among SARS-CoV-2 genes. Although most of the genes evolved under purifying selection, several genes showed genetic signatures of diversifying selection, including a number of positively selected sites that affect proteins relevant for the virus replication. Here, we review current knowledge about the molecular evolution of SARS-CoV-2 in humans, including the emergence and establishment of variants of concern. We also clarify relationships between the nomenclatures of SARS-CoV-2 lineages. We conclude that the molecular evolution of this virus should be monitored over time for predicting relevant phenotypic consequences and designing future efficient treatments. Ministerio de Economía y Competitividad | Ref. PID2019-107931GA-I00

The current knowledge about how protein structures influence sequence evolution is rarely incorporated into substitution models adopted for phylogenetic inference, which are commonly based on independent with the same substitution process and ignore the known variation of the evolutionary rates across sites with different structural properties. In previous works, we presented site-specific substitution models of protein evolution based on selection on the folding stability of the native state (Stab-CPE), which predict more realistically the evolutionary variability across protein sites. However, those Stab-CPE present qualitative differences from observed data, probably because they ignore changes in the native structure, despite empirical studies suggest that conservation of the native structure is a strong selective force.Here we present novel structurally constrained substitution models (Str-CPE) based on Julián Echave’s model of the structural change due to a mutation as the linear response of the protein to a perturbation and on the explicit model of the perturbation generated by a specific amino-acid mutation. Compared to our previous Stab-CPE models, the novel Str-CPE models are more stringent (they predict lower sequence entropy and substitution rate), provide higher likelihood to multiple sequence alignments (MSA) of the wild-type protein, and better predict the observed substitution rates. Next, we combine Str-CPE and Stab-CPE models to obtain structure and stability constrained substitution models (SSCPE) that fit the empirical MSAs even better. Importantly, these SSCPE models present a relevant improvement of the phylogenetic likelihood for all ten protein families that we analyzed with the program RAxML-NG. We implemented the SSCPE models in the program Prot evol, freely available athttps://github.com/ugobas/Prot_evol.

The reconstruction of genetic material of ancestral organisms constitutes a powerful application of evolutionary biology. A fundamental step in this inference is the ancestral sequence reconstruction (ASR), which can be performed with diverse methodologies implemented in computer frameworks. However, most of these methodologies ignore evolutionary properties frequently observed in microbes, such as genetic recombination and complex selection processes, that can bias the traditional ASR. From a practical perspective, here I review methodologies for the reconstruction of ancestral DNA and protein sequences, with particular focus on microbes, and including biases, recommendations, and software implementations. I conclude that microbial ASR is a complex analysis that should be carefully performed and that there is a need for methods to infer more realistic ancestral microbial sequences.

Heloderma horridum (Beaded Lizard) is a venomous lizard of large size distributed along the Pacific Coast of Mexico from Sinaloa to Chiapas, and in lowlands of the states of Estado de México, Morelos and Puebla (Reiserer et al., 2013). This lizard inhabits mostly in tropical dry forest at lowlands; however, it occasionally occurs in temperate habitats at high elevation up 1800 m (Guadarrama et al., 2019). In this study, we extend the altitudinal range of H. horridum in more than 200 m elevation.

Background: Dementia due to Alzheimer’s disease (AD) is a complex neurodegenerative disorder, which much of heritability remains unexplained. At the clinical level, one of the most common physiological alterations is the slowing of oscillatory brain activity, measurable by electroencephalography (EEG). Relative power (RP) at the conventional frequency bands (i.e., delta, theta, alpha, beta-1, and beta-2) can be considered as AD endophenotypes. Objective: The aim of this work is to analyze the association between sixteen genes previously related with AD: APOE, PICALM, CLU, BCHE, CETP, CR1, SLC6A3, GRIN2 β, SORL1, TOMM40, GSK3 β, UNC5C, OPRD1, NAV2, HOMER2, and IL1RAP, and the slowing of the brain activity, assessed by means of RP at the aforementioned frequency bands. Methods: An Iberian cohort of 45 elderly controls, 45 individuals with mild cognitive impairment, and 109 AD patients in the three stages of the disease was considered. Genomic information and brain activity of each subject were analyzed. Results: The slowing of brain activity was observed in carriers of risk alleles in IL1RAP (rs10212109, rs9823517, rs4687150), UNC5C (rs17024131), and NAV2 (rs1425227, rs862785) genes, regardless of the disease status and situation towards the strongest risk factors: age, sex, and APOE ɛ4 presence. Conclusion: Endophenotypes reduce the complexity of the general phenotype and genetic variants with a major effect on those specific traits may be then identified. The found associations in this work are novel and may contribute to the comprehension of AD pathogenesis, each with a different biological role, and influencing multiple factors involved in brain physiology.

Spatial turnover of biological communities is determined by both dispersal and environmental constraints. However, we lack quantitative predictions about how these factors interact and influence turnover across genealogical scales. In this study, we have implemented a predictive framework based on approximate Bayesian computation (ABC) to quantify the signature of dispersal and environmental constraints in community turnover. First, we simulated the distribution of haplotypes, intra-specific lineages and species in biological communities under different strengths of dispersal and environmental constraints. Our simulations show that spatial turnover rate is invariant across genealogical scales when dispersal limitation determines the species ranges. However, when environmental constraint limits species ranges, spatial turnover rates vary across genealogical scales. These simulations were used in an ABC framework to quantify the role of dispersal and environmental constraints in 16 empirical biological communities sampled from local to continental scales, including several groups of insects (both aquatic and terrestrial), molluscs and bats. In seven datasets, the observed genealogical invariance of spatial turnover, assessed with distance–decay curves, suggests a dispersal-limited scenario. In the remaining datasets, the variance in distance–decay curves across genealogical scales was best explained by various combinations of dispersal and environmental constraints. Our study illustrates how modelling spatial turnover at multiple genealogical scales (species and intraspecific lineages) provides relevant insights into the relative role of dispersal and environmental constraints in community turnover., his research was supported by the Spanish Ministerio de Ciencia e Innovación and the European Regional Development Fund (ERDF) through grants CGL2016-76637-P and PID2020-112935GB-I000. DP and MA receive support from the Xunta de Galicia. MBA and MA acknowledge support from Ministerio de Ciencia, Innovación y Universidades through the grants PGC2018-099363-B-I00 and RYC-2015-18241, respectively.

¿Cumple el Real Decreto 1299/2006 con el principio de igualdad de trato entre hombres y mujeres que impone la Ley orgánica 3/2007 de igualdad efectiva? Aunque anterior en el tiempo a dicha norma, el Real Decreto 1299/2006 nace cuando ya formaban parte de nuestro ordenamiento la Directiva 79/7/CEE del Consejo, de 19 de diciembre de 1978, relativa a la aplicación progresiva del principio de igualdad de trato entre hombres y mujeres en materia de seguridad social, y la Directiva 2006/54/CE del Parlamento Europeo y del Consejo, de 5 de julio de 2006, relativa a la aplicación del principio de igualdad de oportunidades e igualdad de trato entre hombres y mujeres en asuntos de empleo y ocupación. Una lectura del listado de enfermedades profesionales, puesta en relación con la doctrina actual del Tribunal Supremo en materia de determinación de contingencia para profesiones no incluidas en el listado, nos lleva a concluir que la igualdad efectiva queda lejos, aún, de ser real.

Proteins are commonly used as molecular targets against pathogens such as viruses and bacteria. However, pathogens can evolve rapidly permitting their populations to increase in protein diversity over time and thus escape to the activity of a molecular therapy. Subsequently, in order to design more durable and robust therapies as well as to understand viral evolution in a host and subsequent transmission, it is central to understand the evolution of pathogen proteins. This understanding can enable the detection of protein regions that can be potential targets for therapies and predict the emergence of molecular resistance against therapies. In this direction, two articles published recently in the Journal of Molecular Evolution investigated the evolution of proteomes of diverse flaviviruses, including Zika virus, Dengue virus and West Nile virus. Here I discuss the importance of considering the evolution of viral proteins, with the use of as realistic as possible models and methods that mimic protein evolution, to improve the design of antiviral therapies.

Analizamos la especial problemática del reconocimiento de las enfermedades profesionales de las kellys y las directrices de la Dirección General de Ordenación de la Seguridad Social (DGOSS) relativas a la protección de colectivos que no constan expresamente en el listado del Real Decreto 1299/2006, interpretando, con respecto a las actividades reflejadas en el mismo, su carácter de lista abierta. No obstante, teniendo en cuenta pronunciamientos anteriores del Tribunal Supremo, parece que no eran necesarias estas nuevas instrucciones por parte de la DGOSS. Aun así, la práctica diaria nos lleva a concluir que el proceso en vía administrativa de determinación de contingencia es lento, con muy pocas garantías para el trabajador y que desemboca en múltiples ocasiones en la necesidad de articular la vía judicial, eternizando la solución del problema.

The last glacial period (LGP) promoted a loss of genetic diversity in Paleolithic populations of modern humans from diverse regions of the world by range contractions and habitat fragmentation. However, this period also provided some currently submersed lands, such as the Sunda shelf in Southeast Asia (SEA), that could have favored the expansion of our species. Concerning the latter, still little is known about the influence of the lowering sea level on the genetic diversity of current SEA populations. Here, we applied approximate Bayesian computation, based on extensive spatially explicit computer simulations, to evaluate the fitting of mtDNA data from diverse SEA populations with alternative evolutionary scenarios that consider and ignore the LGP and migration through long-distance dispersal (LDD). We found that both the LGP and migration through LDD should be taken into consideration to explain the currently observed genetic diversity in these populations and supported a rapid expansion of first populations throughout SEA. We also found that temporarily available lands caused by the low sea level of the LGP provided additional resources and migration corridors that favored genetic diversity. We conclude that migration through LDD and temporarily available lands during the LGP should be considered to properly understand and model the first expansions of modern humans. Fundação para a Ciência e Tecnologia | Ref. SFRH/BD/143607/2019 Ministerio de Economía, Industria y Competitividad | Ref. HAR2010-21063 Ministerio de Economía, Industria y Competitividad | Ref. CGL2017-83394-P Ministerio de Economía, Industria y Competitividad | Ref. RYC-2015-18241

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUG The selection of the best-fitting substitution model of molecular evolution is a traditional step for phylogenetic inferences, including ancestral sequence reconstruction (ASR). However, a few recent studies suggested that applying this procedure does not affect the accuracy of phylogenetic tree reconstruction. Here, we revisited this debate topic by analyzing the influence of selection among substitution models of protein evolution, with focus on exchangeability matrices, on the accuracy of ASR using simulated and real data. We found that the selected best-fitting substitution model produces the most accurate ancestral sequences, especially if the data present large genetic diversity. Indeed, ancestral sequences reconstructed under substitution models with similar exchangeability matrices were similar, suggesting that if the selected best-fitting model cannot be used for the reconstruction, applying a model similar to the selected one is preferred. We conclude that selecting among substitution models of protein evolution is recommended for reconstructing accurate ancestral sequences. Agencia Estatal de Investigación | Ref. PID2019-107931GA-I00 Ministerio de Economía y Competitividad | Ref. RYC-2015-18241

[Background] Long-Term Non-Progressors (LTNPs) are untreated Human Immunodeficiency virus type 1 (HIV-1) infected individuals able to control disease progression for prolonged periods. However, the LTNPs status is temporary, as viral load increases followed by decreases in CD4 + T-cell counts. Control of HIV-1 infection in LTNPs viremic controllers, have been associated with effective immunodominant HIV-1 Gag-CD8 + T-cell responses restricted by protective HLA-B alleles. Individuals carrying HLA-B*14:02 control HIV-1 infection is related to an immunodominant Env-CD8 + T-cell response. Limited data are available on the contribution of HLA-B*14:02 CD8 + T -cells in LTNPs., [Results] In this study, we performed a virological and immunological detailed analysis of an HLA-B*14:02 LNTP individual that lost viral control (LVC) 27 years after HIV-1 diagnosis. We analysed viral evolution and immune escape in HLA-B*14:02 restricted CD8 + T -cell epitopes and identified viral evolution at the Env-EL9 epitope selecting the L592R mutation. By IFN-γ ELISpot and immune phenotype, we characterized HLA- B*14:02 HIV-1 CD8 + T cell responses targeting, Gag-DA9 and Env-EL9 epitopes before and after LVC. We observed an immunodominant response against the Env-EL9 epitope and a decreased of the CD8 T + cell response over time with LVC. Loss of Env-EL9 responses was concomitant with selecting K588R + L592R mutations at Env-EL9. Finally, we evaluated the impact of Env-EL9 escape mutations on HIV-1 infectivity and Env protein structure. The K588R + L592R escape variant was directly related to HIV-1 increase replicative capacity and stability of Env at the LVC., [Conclusions] These findings support the contribution of immunodominant Env-EL9 CD8 + T-cell responses and the imposition of immune escape variants with higher replicative capacity associated with LVC in this LNTP. These data highlight the importance of Env-EL9 specific-CD8 + T-cell responses restricted by the HLA-B*14:02 and brings new insights into understanding long-term HIV-1 control mediated by Env mediated CD8 + T-cell responses., Molecular Virology Laboratory was supported by grants SAF (2016-77894-R) from Ministerio de Economía y Competitividad (MINECO), ISCIII through the projects PI 13/02269, PI17/00164, PI16/0684, PI19/01127 (Co-funded by European Regional Development Fund/European Social Fund "Investing in your future"). The RIS-RETIC grants RD12/0017/0028, RD16/0025/0020 and RD16CIII/0002/0005. LTD was supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CD20/00025” through the Sara Borrell Program. O.B.L was funded by an AGAUR-FI_B 00582 Ph.D. fellowship from the Catalan Government and the European Social Fund. M.A. was funded by grants RYC-2015-18241 and PID2019-107931GA-I00 from the Spanish Government and, ED431F 2018/08 from the “Xunta de Galicia”. ERM was supported by the Spanish National Research Council (CSIC). JGP laboratory was supported by National Health Institute Carlos III grant PI17/00164 and Redes Temáticas de Investigación en SIDA (ISCIII RETIC RD16/0025/0041).

Motivation The evolutionary processes of mutation and recombination, upon which selection operates, are fundamental to understand the observed molecular diversity. Unlike nucleotide sequences, the estimation of the recombination rate in protein sequences has been little explored, neither implemented in evolutionary frameworks, despite protein sequencing methods are largely used. Results In order to accommodate this need, here I present a computational framework, called ProteinEvolverABC, to jointly estimate recombination and substitution rates from alignments of protein sequences. The framework implements the approximate Bayesian computation approach, with and without regression adjustments and includes a variety of substitution models of protein evolution, demographics and longitudinal sampling. It also implements several nuisance parameters such as heterogeneous amino acid frequencies and rate of change among sites and, proportion of invariable sites. The framework produces accurate coestimation of recombination and substitution rates under diverse evolutionary scenarios. As illustrative examples of usage, I applied it to several viral protein families, including coronaviruses, showing heterogeneous substitution and recombination rates. Availability and implementation ProteinEvolverABC is freely available from https://github.com/miguelarenas/proteinevolverabc, includes a graphical user interface for helping the specification of the input settings, extensive documentation and ready-to-use examples. Conveniently, the simulations can run in parallel on multicore machines. Supplementary information Supplementary data are available at Bioinformatics online.

The relative allocation of energy organisms devote to reproductive processes (aka reproductive effort) constitutes a central topic in life history theory. We document some aspects of the reproductive ecology and investment of 2 viviparous skinks of the genus Plestiodon from Mexico: an undescribed species previously assigned to P. brevirostris(Plestiodon sp., La Malinche, Tlaxcala, 2,700-3,000 m) and P. dugesii (2 populations, Mazamitla and Tapalpa, Jalisco; 2,400-2,500 m). We used relative litter mass (RLM) as a measure of reproductive effort and calculated a body condition index (BCI) as a proxy of the energy status of non-pregnant females, post-parturient females, and neonates. There were no differences in any of the reproductive characteristics between the 2 populations of P. dugesii. Both species lacked sexual size dimorphism, and female body size did not influence RLM, litter size nor litter mass. However, female BCI influenced RLM and, in P. dugesii, a larger litter size correlated with a lower BCI of neonates. Despite their overall similarities in reproductive investment, there seem to be differential selective pressures shaping offspring characteristics of these 2 lizard species.

Diverse phylogenetic methods require a substitution model of evolution that should mimic, as accurately as possible, the real substitution process. At the protein level, empirical substitution models have traditionally been based on a large number of different proteins from particular taxonomic levels. However, these models assume that all of the proteins of a taxonomic level evolve under the same substitution patterns. We believe that this assumption is highly unrealistic and should be relaxed by considering protein-specific substitution models that account for protein-specific selection processes. In order to test this hypothesis, we inferred and evaluated four new empirical substitution models for the protease and integrase of HIV and other viruses. We found that these models more accurately fit, compared with any of the currently available empirical substitution models, the evolutionary process of these proteins. We conclude that evolutionary inferences from protein sequences are more accurate if they are based on protein-specific substitution models rather than taxonomic-specific (generalist) substitution models. We also present four new empirical substitution models of protein evolution that could be useful for phylogenetic inferences of viral protease and integrase. Xunta de Galicia | Ref. ED431F 2018/08 Ministerio de Economía y Competitividad de España | Ref. RYC-2015-18241

TOPIIA topoisomerases are required for the regulation of DNA topology by DNA cleavage and re-ligation and are important targets of antibiotic and anticancer agents. Humans possess two TOPIIA paralogue genes (TOP2A and TOP2B) with high sequence and structural similarity but distinct cellular functions. Despite their functional and clinical relevance, the evolutionary history of TOPIIA is still poorly understood. Here we show that TOPIIA is highly conserved in Metazoa. We also found that TOPIIA paralogues from jawed and jawless vertebrates had different origins related with tetraploidization events. After duplication, TOP2B evolved under a stronger purifying selection than TOP2A, perhaps promoted by the more specialized role of TOP2B in postmitotic cells. We also detected genetic signatures of positive selection in the highly variable C-terminal domain (CTD), possibly associated with adaptation to cellular interactions. By comparing TOPIIA from modern and archaic humans, we found two amino acid substitutions in the TOP2A CTD, suggesting that TOP2A may have contributed to the evolution of present-day humans, as proposed for other cell cycle-related genes. Finally, we identified six residues conferring resistance to chemotherapy differing between TOP2A and TOP2B. These six residues could be targets for the development of TOP2A-specific inhibitors that would avoid the side effects caused by inhibiting TOP2B. Altogether, our findings clarify the origin, diversification and selection pressures governing the evolution of animal TOPIIA.

Motivation The nonsynonymous/synonymous substitution rate ratio (dN/dS) is a commonly used parameter to quantify molecular adaptation in protein-coding data. It is known that the estimation of dN/dS can be biased if some evolutionary processes are ignored. In this concern, common ML methods to estimate dN/dS assume invariable codon frequencies among sites, despite this characteristic is rare in nature, and it could bias the estimation of this parameter. Results Here we studied the influence of variable codon frequencies among genetic regions on the estimation of dN/dS. We explored scenarios varying the number of genetic regions that differ in codon frequencies, the amount of variability of codon frequencies among regions and the nucleotide frequencies at each codon position among regions. We found that ignoring heterogeneous codon frequencies among regions overall leads to underestimation of dN/dS and the bias increases with the level of heterogeneity of codon frequencies. Interestingly, we also found that varying nucleotide frequencies among regions at the first or second codon position leads to underestimation of dN/dS while variation at the third codon position leads to overestimation of dN/dS. Next, we present a methodology to reduce this bias based on the analysis of partitions presenting similar codon frequencies and we applied it to analyze four real datasets. We conclude that accounting for heterogeneous codon frequencies along sequences is required to obtain realistic estimates of molecular adaptation through this relevant evolutionary parameter. Availability and implementation The applied frameworks for the computer simulations of protein-coding data and estimation of molecular adaptation are SGWE and PAML, respectively. Both are publicly available and referenced in the study. Supplementary information Supplementary data are available at Bioinformatics online.