Positive Selection Research Articles

Novel imported clades accelerated the RSV surge in Beijing, China, 2023-2024

ObjectivesDespite the optimisation of the zero-COVID policy in late 2022, there was a subsequent increase noted in the number of respiratory syncytial virus (RSV) cases in Northern China. In this study, we investigated and characterised the dynamics of this surge at the genomic level in Beijing, China. MethodsPatients with acute respiratory tract infections (ARTIs) were enrolled from 35 sentinel hospitals in Beijing, China. Epidemiological investigations, G gene amplification, and whole-genome sequencing were performed, followed by epidemiological analysis, imported clade detection, and mutation identification. We also combined global data to illustrate the biological and epidemiological characteristics of the emerging clades. ResultsA total of 60,423 patients with ARTIs were recruited between January 2015 and January 2024. The RSV peak observed in the winter of 2023 was the highest in the past 9 years. Two novel imported clades, A.D.5.2 and B.D.E.1, were detected for the first time in China. This surge was mainly driven by B.D.E.1, which exhibited a significantly higher proportion of older individuals both in Beijing and globally. Seven non-synonymous mutations in B.D.E.1 were found in Beijing. B.D.E.1 had more sites suffering from positive selection than its parent. ConclusionsThe novel imported clade B.D.E.1 accelerated an unprecedented RSV surge in Beijing, presenting noteworthy epidemiological and biological characteristics. Continuous RSV genome monitoring has important implications for RSV outbreak identification, genetic diversity tracking, vaccine development, and strategy implementation.

Conserved Plastid Genomes of Pourthiaea Trees: Comparative Analyses and Phylogenetic Relationship

The genus Pourthiaea Decne., a deciduous woody group with high ornamental value, belongs to the family Rosaceae. Here, we reported newly sequenced plastid genome sequences of Pourthiaea beauverdiana (C. K. Schneid.) Hatus., Pourthiaea parvifolia E. Pritz., Pourthiaea villosa (Thunb.) Decne., and Photinia glomerata Rehder & E. H. Wilson. The plastomes of these three Pourthiaea species shared the typical quadripartite structures, ranging in size from 159,903 bp (P. parvifolia) to 160,090 bp (P. beauverdiana). The three Pourthiaea plastomes contained a pair of inverted repeat regions (26,394–26,399 bp), separated by a small single-copy region (19,304–19,322 bp) and a large single-copy region (87,811–87,973 bp). A total of 113 unique genes were predicted for the three Pourthiaea plastomes, including four ribosomal RNA genes, 30 transfer RNA genes, and 79 protein-coding genes. Analyses of inverted repeat/single-copy boundary, mVISTA, nucleotide diversity, and genetic distance showed that the plastomes of 13 Pourthiaea species (including 10 published plastomes) are highly conserved. The number of simple sequence repeats and long repeat sequences is similar among 13 Pourthiaea species. The three non-coding regions (trnT-GGU-psbD, trnR-UCU-atpA, and trnH-GUG-psbA) were the most divergent. Only one plastid protein-coding gene, rbcL, was under positive selection. Phylogenetic analyses based on 78 shared plastid protein-coding sequences and 29 nrDNA sequences strongly supported the monophyly of Pourthiaea. As for the relationship with other genera in our phylogenies, Pourthiaea was sister to Malus in plastome phylogenies, while it was sister to the remaining genera in nrDNA phylogenies. Furthermore, significant cytonuclear discordance likely stems from hybridization events within Pourthiaea, reflecting complex evolutionary dynamics within the genus. Our study provides valuable genetic insights for further phylogenetic, taxonomic, and species delimitation studies in Pourthiaea, as well as essential support for horticultural improvement and conservation of the germplasm resources.

Genetic and developmental divergence in the neural crest program between cichlid fish species.

Neural crest (NC) is a vertebrate-specific embryonic progenitor cell population at the basis of important vertebrate features such as the craniofacial skeleton and pigmentation patterns. Despite the wide-ranging variation of NC-derived traits across vertebrates, the contribution of NC to species diversification remains underexplored. Here, leveraging the adaptive diversity of African Great Lakes' cichlid species, we combined comparative transcriptomics and population genomics to investigate the evolution of the NC genetic program in the context of their morphological divergence. Our analysis revealed substantial differences in transcriptional landscapes across somitogenesis, an embryonic period coinciding with NC development and migration. This included dozens of genes with described functions in the vertebrate NC gene regulatory network, several of which showed signatures of positive selection. Among candidates showing between-species expression divergence, we focused on teleost-specific paralogs of the NC-specifier sox10 (sox10a and sox10b) as prime candidates to influence NC development. These genes, expressed in NC cells, displayed remarkable spatio-temporal variation in cichlids, suggesting their contribution to inter-specific morphological differences, such as craniofacial structures and pigmentation. Finally, through CRISPR/Cas9 mutagenesis, we demonstrated the functional divergence between cichlid sox10 paralogs, with the acquisition of a novel skeletogenic function by sox10a. When compared to teleost models zebrafish and medaka, our findings reveal that sox10 duplication, although retained in most teleost lineages, had variable functional fates across their phylogeny. Altogether, our study suggests that NC-related processes - particularly those controlled by sox10s - are involved in generating morphological diversification between species and lays the groundwork for further investigations into the mechanisms underpinning vertebrate NC diversification.

Histidine-rich calcium-binding protein: a molecular integrator of cardiac excitation-contraction coupling.

During mammalian cardiomyocyte excitation-contraction coupling, Ca2+ influx through voltage-gated Ca2+ channels triggers Ca2+ release from the sarcoplasmic reticulum (SR) through ryanodine receptor channels. This Ca2+-induced Ca2+ release mechanism controls cardiomyocyte contraction and is exquisitely regulated by SR Ca2+ levels. The histidine-rich calcium-binding protein (HRC) and its aspartic acid-rich paralogue aspolin are high-capacity, low-affinity Ca2+-binding proteins. Aspolin also acts as a trimethylamine N-oxide demethylase. At low intraluminal Ca2+ concentrations, HRC binds to the SR Ca2+-ATPase 2, inhibiting its Ca2+-pumping activity. At high intraluminal Ca2+ levels, HRC interacts with triadin to reduce Ca2+ release through ryanodine receptor channels. This Review analyses the evolution of these Ca2+-regulatory proteins, to gain insights into their roles. It reveals that HRC homologues are present in chordates, annelid worms, molluscs, corals and sea anemones. In contrast, triadin appears to be a chordate innovation. Furthermore, HRC is evolving more rapidly than other cardiac excitation-contraction coupling proteins. This positive selection (or relaxed negative selection) occurs along most of the mammalian HRC protein sequence, with the exception being the C-terminal cysteine-rich region, which is undergoing negative selection. The histidine-rich region of HRC might be involved in pH sensing, as an adaptation to air-breathing, endothermic and terrestrial life. In addition, a cysteine-rich pattern within HRC and aspolin is also found in a wide range of iron-sulfur cluster proteins, suggesting roles in redox reactions and metal binding. The polyaspartic regions of aspolins are likely to underlie their trimethylamine N-oxide demethylase activity, which might be mimicked by the acidic regions of HRCs. These potential roles of HRCs and aspolins await experimental verification.

LRSDet: lightweight remote sensing target detection network with local-global information awareness and rapid sample assignment

Abstract With the rapid development of aerospace and unmanned aerial vehicles, using neural networks for object detection in optical remote sensing images (O-RSI) has encountered heightened challenges. The optical remote sensing images have the characteristics of complex geometric scenes, dense groups of objects, and significant multi-scale variations of objects; researchers need to use more complex models to achieve higher accuracy. However, this complexity also brings challenges to the application of lightweight scenes. Therefore, to cope with the trade-off challenge between model complexity and detection accuracy, we propose a lightweight network model LRSDet in this study. The model integrates local and global information processing mechanisms and introduces a fast positive sample assignment strategy to adapt to resource-constrained embedded and mobile platforms. By constructing a lightweight feature extraction network and a lightweight path aggregation network and incorporating the ESM-Attention module, the feature extraction capability of the model in complex remote sensing scenarios is significantly improved. In addition, the application of a dynamic soft threshold strategy further optimizes the positive sample selection process and improves the detection efficiency of the model. Experimental on the O-RSI datasets DIOR, NWPU VHR-10, and RSOD, while analyzing model real-time performance on aerial video and embedded devices, outperforming other state-of-the-art methods.

Rapidly Evolved Genes in Three Reaumuria Transcriptomes and Potential Roles of Pentatricopeptide Repeat Superfamily Proteins in Endangerment of R. trigyna.

Reaumuria genus (Tamaricaceae) is widely distributed across the desert and semi-desert regions of Northern China, playing a crucial role in the restoration and protection of desert ecosystems. Previous studies mainly focused on the physiological responses to environmental stresses; however, due to the limited availability of genomic information, the underlying mechanism of morphological and ecological differences among the Reaumuria species remains poorly understood. In this study, we presented the first catalog of expressed transcripts for R. kaschgarica, a sympatric species of xerophyte R. soongorica. We further performed the pair-wise transcriptome comparison to determine the conserved and divergent genes among R. soongorica, R. kaschgarica, and the relict recretohalophyte R. trigyna. Annotation of the 600 relatively conserved genes revealed that some common genetic modules are employed by the Reaumuria species to confront with salt and drought stresses in arid environment. Among the 250 genes showing strong signs of positive selection, eight pentatricopeptide repeat (PPR) superfamily protein genes were specifically identified, including seven PPR genes in the R. soongorica vs. R. trigyna comparison and one PPR gene in the R. kaschgarica vs. R. trigyna comparison, while the cyclin D3 gene was found in the R. soongorica vs. R. trigyna comparison. These findings suggest that genetic variations in PPR genes may affect the fertility system or compromise the extent of organelle RNA editing in R. trigyna. The present study provides valuable genomic information for R. kaschgarica and preliminarily reveals the conserved genetic bases for the abiotic stress adaptation and interspecific divergent selection in the Reaumuria species. The rapidly evolved PPR and cyclin D3 genes provide new insights on the endangerment of R. trigyna and the leaf length difference among the Reaumuria species.

Population Genomics of Adaptive Radiations: Exceptionally High Levels of Genetic Diversity and Recombination in an Endemic Spider From the Canary Islands.

The spider genus Dysdera has undergone a remarkable diversification in the oceanic archipelago of the Canary Islands, with ~60 endemic species having originated during the 20 million years since the origin of the archipelago. This evolutionary radiation has been accompanied by substantial dietary shifts, often characterised by phenotypic modifications encompassing morphological, metabolic and behavioural changes. Hence, these endemic spiders represent an excellent model for understanding the evolutionary drivers and to pinpoint the genomic determinants underlying adaptive radiations. Recently, we achieved the first chromosome-level genome assembly of one of the endemic species, D. silvatica, providing a high-quality reference sequence for evolutionary genomics studies. Here, we conducted a low coverage-based resequencing study of a natural population of D. silvatica from La Gomera island. Taking advantage of the new high-quality genome, we characterised genome-wide levels of nucleotide polymorphism, divergence and linkage disequilibrium, and inferred the demographic history of this population. We also performed comprehensive genome-wide scans for recent positive selection. Our findings uncovered exceptionally high levels of nucleotide diversity and recombination in this geographically restricted endemic species, indicative of large historical effective population sizes. We also identified several candidate genomic regions that are potentially under positive selection, highlighting relevant biological processes, such as vision and nitrogen extraction as potential adaptation targets. These processes may ultimately drive species diversification in this genus. This pioneering study of spiders that are endemic to an oceanic archipelago lays the groundwork for broader population genomics analyses aimed at understanding the genetic mechanisms driving adaptive radiation in island ecosystems.

Comparative analysis of the whole mitochondrial genomes of four species in sect. Chrysantha (Camellia L.), endemic taxa in China

BackgroundThe sect. Chrysantha Chang of plants with yellow flowers of Camellia species as the “Queen of the Tea Family”, most of these species are narrowly distributed endemics of China and are currently listed Grde-II in National Key Protected Wild Plant of China. They are commercially important plants with horticultural medicinal and scientific research value. However, the study of the sect. Chrysantha species genetics are still in its infancy, to date, the mitochondrial genome in sect. Chrysantha has been still unexplored.ResultsIn this study, we provide a comprehensive assembly and annotation of the mitochondrial genomes for four species within the sect. Chrysantha. The results showed that the mitochondrial genomes were composed of closed-loop DNA molecules with sizes ranging from 850,836 bp (C. nitidissima) to 1,098,121 bp (C. tianeensis) with GC content of 45.71–45.78% and contained 48–58 genes, including 28–37 protein-coding genes, 17–20 tRNA genes and 2 rRNA genes. We also examined codon usage, sequence repeats, RNA editing and selective pressure in the four species. Then, we performed a comprehensive comparison of their basic structures, GC contents, codon preferences, repetitive sequences, RNA editing sites, Ka/Ks ratios, haplotypes, and RNA editing sites. The results showed that these plants differ little in gene type and number. C. nitidissima has the greatest variety of genes, while C. tianeensis has the greatest loss of genes. The Ka/Ks values of the atp6 gene in all four plants were greater than 1, indicating positive selection. And the codons ending in A and T were highly used. In addition, the RNA editing sites differed greatly in number, type, location, and efficiency. Twelve, six, five, and twelve horizontal gene transfer (HGT) fragments were found in C. tianeensis, Camellia huana, Camellia liberofilamenta, and C. nitidissima, respectively. The phylogenetic tree clusters the four species of sect. Chrysantha plants into one group, and C. huana and C. liberofilamenta have closer affinities.ConclusionsIn this study, the mitochondrial genomes of four sect. Chrysantha plants were assembled and annotated, and these results contribute to the development of new genetic markers, DNA barcode databases, genetic improvement and breeding, and provide important references for scientific research, population genetics, and kinship identification of sect. Chrysantha plants.

From light into shadow: comparative plastomes in Petrocosmea and implications for low light adaptation

BackgroundPlastids originated from an ancient endosymbiotic event and evolved into the photosynthetic organelles in plant cells. They absorb light energy and carbon dioxide, converting them into chemical energy and oxygen, which are crucial for plant development and adaptation. However, little is known about the plastid genome to light adaptation. Petrocosmea, a member of the Gesneriaceae family, comprises approximately 70 species with diverse light environment, serve as an ideal subject for studying plastomes adapt to light.ResultsIn this study, we selected ten representative species of Petrocosmea from diverse light environments, assembled their plastid genomes, and conducted a comparative genomic analysis. We found that the plastid genome of Petrocosmea is highly conserved in both structure and gene content. The phylogenetic relationships reconstructed based on the plastid genes were divided into five clades, which is consistent with the results of previous studies. The vast majority of plastid protein-coding genes were under purifying selection, with only the rps8 and rps16 genes identified under positive selection in different light environments. Notably, significant differences of evolutionary rate were observed in NADH dehydrogenase, ATPase ribosome, and RNA polymerase between Clade A and the other clades. Additionally, we identified ycf1 and several intergenic regions (trnH-psbA, trnK-rps16, rpoB-trnC, petA-psbJ, ccsA-trnL, rps16-trnQ, and trnS-trnG) as candidate barcodes for this emerging ornamental horticulture.ConclusionWe newly assembled ten plastid genomes of Petrocosmea and identified several hypervariable regions, providing genetic resources and candidate markers for this promising emerging ornamental horticulture. Furthermore, our study suggested that rps8 and rps16 were under positive selection and that the evolutionary patterns of NADH dehydrogenase, ATPase ribosome, and RNA polymerase were related to the diversity light environment in Petrocosmea. This revealed an evolutionary scenario for light adaptation of the plastid genome in plants.

Extensive longevity and DNA virus-driven adaptation in nearctic Myotis bats.

The rich species diversity of bats encompasses extraordinary adaptations, including extreme longevity and tolerance to infectious disease. While traditional approaches using genetic screens in model organisms have uncovered some fundamental processes underlying these traits, model organisms do not possess the variation required to understand the evolution of traits with complex genetic architectures. In contrast, the advent of genomics at tree-of-life scales enables us to study the genetic interactions underlying these processes by leveraging millions of years of evolutionary trial-and-error. Here, we use the rich species diversity of the genus Myotis - one of the longest-living clades of mammals - to study the evolution of longevity-associated traits and infectious disease using functional evolutionary genomics. We generated reference genome assemblies and cell lines for 8 closely-related (∼11 MYA) species of Myotis rich in phenotypic and life history diversity. Using genome-wide screens of positive selection, analysis of structural variation and copy number variation, and functional experiments in primary cell lines, we identify new patterns of adaptation in longevity, cancer resistance, and viral interactions both within Myotis and across bats. We find that the rapid evolution of lifespan in Myotis has some of the most significant variations in cancer risk across mammals, and demonstrate a unique DNA damage response in the long-lived M. lucifugus using primary cell culture models. Furthermore, we find evidence of abundant adaptation in response to DNA viruses, but not RNA viruses, in Myotis and other bats. This is in contrast to these patterns of adaptation in humans, which might contribute to the importance of bats as a reservoir of zoonotic viruses. Together, our results demonstrate the utility of leveraging natural variation to understand the genomics of traits with implications for human health and suggest important pleiotropic relationships between infectious disease tolerance and cancer resistance.

Sperm competition intensity shapes divergence in both sperm morphology and reproductive genes across murine rodents.

It remains unclear how variation in the intensity of sperm competition shapes phenotypic and molecular evolution across clades. Mice and rats in the subfamily Murinae are a rapid radiation exhibiting incredible diversity in sperm morphology and production. We combined phenotypic and genomic data to perform phylogenetic comparisons of male reproductive traits and genes across 78 murine species. We identified several shifts towards smaller relative testes mass, presumably reflecting reduced sperm competition. Several sperm traits were associated with relative testes mass, suggesting that mating system evolution selects for convergent suites of traits related to sperm competitive ability. We predicted that sperm competition would also drive more rapid molecular divergence in species with large testes. Contrary to this, we found that many spermatogenesis genes evolved more rapidly in species with smaller relative testes mass due to relaxed purifying selection. While some reproductive genes evolved rapidly under recurrent positive selection, relaxed selection played a greater role in underlying rapid evolution in small testes species. Our work demonstrates that postcopulatory sexual selection can impose strong purifying selection shaping the evolution of male reproduction, and that broad patterns of molecular evolution may help identify genes that contribute to male fertility.

Rapid evolution of mitochondrion-related genes in haplodiploid arthropods

BackgroundMitochondrial genes and nuclear genes cooperate closely to maintain the functions of mitochondria, especially in the oxidative phosphorylation (OXPHOS) pathway. However, mitochondrial genes among arthropod lineages have dramatic evolutionary rate differences. Haplodiploid arthropods often show fast-evolving mitochondrial genes. One hypothesis predicts that the small effective population size of haplodiploid species could enhance the effect of genetic drift leading to higher substitution rates in mitochondrial and nuclear genes. Alternatively, positive selection or compensatory changes in nuclear OXPHOS genes could lead to the fast-evolving mitochondrial genes. However, due to the limited number of arthropod genomes, the rates of evolution for nuclear genes in haplodiploid species, besides hymenopterans, are largely unknown. To test these hypotheses, we used data from 76 arthropod genomes, including 5 independently evolved haplodiploid lineages, to estimate the evolutionary rates and patterns of gene family turnover of mitochondrial and nuclear genes.ResultsWe show that five haplodiploid lineages tested here have fast-evolving mitochondrial genes and fast-evolving nuclear genes related to mitochondrial functions, while nuclear genes not related to mitochondrion showed no significant evolutionary rate differences. Among hymenopterans, bees and ants show faster rates of molecular evolution in mitochondrial genes and mitochondrion-related nuclear genes than sawflies and wasps. With genome data, we also find gene family expansions and contractions in mitochondrion-related genes of bees and ants.ConclusionsOur results reject the small population size hypothesis in haplodiploid species. A combination of positive selection and compensatory changes could lead to the observed patterns in haplodiploid species. The elevated evolutionary rates in OXPHOS complex 2 genes of bees and ants suggest a unique evolutionary history of social hymenopterans.

Construction of a full-length infectious cDNA clone of zucchini tigre mosaic virus infecting snake gourd and genetic diversity analysis based on complete genome sequences of ZTMV isolates.

Zucchini tigre mosaic virus (ZTMV) is a positive-sense single-stranded RNA virus belonging to the genus Potyvirus. In this study, a full-length infectious cDNA clone of a ZTMV strain infecting snake gourd (Trichosanthes cucumerina var. anguina L.) was constructed and shown to infect snake gourd, chieh-qua, zucchini, ridge gourd, and bitter melon. The complete genome sequence of ZTMV-FS7 (PP291701) showed the highest nucleotide sequence similarity to ZTMV-TW (86.2% identity). Genetic diversity analysis of 12 ZTMV isolates showed that the P1 gene had the highest variability. Selection pressure analysis indicated that all of the ZTMV genes were under negative selection. However, some sites, particularly within the P1 gene, were under positive selection.

Natural selection on apical membrane antigen 1 (AMA1) of an emerging zoonotic malaria parasite Plasmodium inui

Apical membrane antigen 1 (AMA1) of malaria parasites plays an important role in host cell invasion. Antibodies to AMA1 can inhibit malaria merozoite invasion of erythrocytes while vaccine-induced specific cytotoxic T cell responses to this protein are associated with clinical protection. Polymorphisms in AMA1 of Plasmodium falciparum (PfAMA1) and P. vivax (PvAMA1) are of concern for vaccine development. To date, little is known about sequence diversity in ama1 of P. inui (Piama1), an emerging zoonotic malaria parasite. In this study, 80 complete Piama1 coding sequences were obtained from 57 macaques in Thailand that defined 60 haplotypes clustering in two phylogenetic lineages. In total, 74 nucleotide substitutions were identified and distributed unevenly across the gene. Blockwise analysis of the rates of synonymous (dS) and nonsynonymous (dN) nucleotide substitutions did not show a significant deviation from neutrality among Thai isolates. However, significantly negative Tajima’s D values were detected in domain I and the loop region of domain II, implying purifying selection. Codon-based analysis of dN/dS has identified 12 and 14 codons under positive and negative selections, respectively. Meanwhile, 85 amino acid substitutions were identified among 80 Thai and 11 non-Thai PiAMA1 sequences. Of these, 48 substituted residues had a significant alteration in physicochemical properties, suggesting positive selection. More than half of these positively selected amino acids (32 of 48) corresponded to the predicted B-cell or T-cell epitopes, suggesting that selective pressure could be mediated by host immunity. Importantly, 14 amino acid substitutions were singletons and predicted to be deleterious that could be subject to ongoing purifying selection or elimination. Besides genetic drift and natural selection, intragenic recombination identified in domain II could generate sequence variation in Piama1. It is likely that malarial ama1 exhibits interspecies differences in evolutionary histories. Knowledge of the sequence diversity of the Piama1 locus further provides an evolutionary perspective of this important malaria vaccine candidate.

Host-dependent C-to-U RNA editing in SARS-CoV-2 creates novel viral genes with optimized expressibility.

Rampant C-to-U RNA editing drives the mutation and evolution of SARS-CoV-2. While much attention has been paid to missense mutations, the C-to-U events leading to AUG and thus creating novel ORFs were uninvestigated. By utilizing the public time-course mutation data from the worldwide SARS-CoV-2 population, we systematically identified the "AUG-gain mutations" caused by C-to-U RNA editing. Synonymous mutations were of special focus. A total of 58 synonymous C-to-U sites are able to create out-of-frame AUG in coding sequence (CDS). These 58 synonymous sites showed significantly higher allele frequency (AF) and increasing rate (dAF/dt) than other C-to-U synonymous sites in the SARS-CoV-2 population, suggesting that these 58 AUG-gain events conferred additional benefits to the virus and are subjected to positive selection. The 58 predicted new ORFs created by AUG-gain events showed the following advantages compared to random expectation: they have longer lengths, higher codon adaptation index (CAI), higher Kozak scores, and higher tRNA adaptation index (tAI). The 58 putatively novel ORFs have high expressibility and are very likely to be functional, providing an explanation for the positive selection on the 58 AUG-gain mutations. Our study proposed a possible mechanism of the emergence of de novo genes in SARS-CoV-2. This idea should be helpful in studying the mutation and evolution of SARS-CoV-2.

Search for signals of positive selection of circadian rhythm genes PER1, PER2, PER3 in different human populations.

The diversity of geographically distributed human populations shows considerable variation in external and internal traits of individuals. Such differences are largely attributed to genetic adaptation to various environmental influences, which include changes in climatic conditions, variations in sleep and wakefulness, dietary variations, and others. Whole-genome data from individuals of different populations make it possible to determine the specific genetic sites responsible for adaptations and to further understand the genetic structure underlying human adaptive characteristics. In this article, we searched for signals of single nucleotide polymorphisms (SNPs) under selection pressure in people of different populations. To identify selection signals in different population groups, the PER1, PER2 and PER3 genes that are involved in the coordination of thermogenic functions and regulation of circadian rhythms, which is directly reflected in the adaptive abilities of the organism, were investigated. Data were analyzed using publicly available data from the 1000 Genomes Project for 23 populations. The Extended Haplotype Homozygosity Score statistical method was chosen to search for traces of selection. The comparative analysis performed identified points subject to selection pressure. The SNPs were annotated through the GWAS catalog and manually by analyzing Internet resources. This study suggests that living conditions, climate, and other external factors directly influence the genetic structure of populations and vary across races and geographic locations. In addition, many of the selection variants in the PER1, PER2, PER3 genes appear to regulate biological processes that are associated with major modern diseases, including obesity, cancer, metabolic syndrome, bipolar personality disorder, depression, rheumatoid arthritis, diabetes mellitus, lupus erythematosus, stroke and Alzheimer's disease, making them extremely interesting targets for further research aimed at identifying the genetic causes of human disease.

Assessment of inbreeding coefficients and inbreeding depression on complex traits from genomic and pedigree data in Nelore cattle.

Nelore cattle play a key role in tropical production systems due to their resilience to harsh conditions, such as heat stress and seasonally poor nutrition. Monitoring their genetic diversity is essential to manage the negative impacts of inbreeding. Traditionally, inbreeding and inbreeding depression are assessed by pedigree-based coefficients (F), but recently, genetic markers have been preferred for their precision in capturing the inbreeding level and identifying animals at risk of reduced productive and reproductive performance. Hence, we compared the inbreeding and inbreeding depression for productive and reproductive performance traits in Nelore cattle using different inbreeding coefficient estimation methods from pedigree information (FPed), the genomic relationship matrix (FGRM), runs of homozygosity (FROH) of different lengths (> 1Mb (genome), between 1 and 2Mb - FROH 1-2; 2-4 Mb FROH 2-4 or > 8 Mb FROH >8) and excess homozygosity (FSNP). The correlation between FPed and FROH was lower when the latter was based on shorter segments (r = 0.15 with FROH 1-2, r = 0.20 with FROH 2-4 and r = 0.28 with FROH 4-8). Meanwhile, the FPed had a moderate correlation withFSNP (r = 0.47) and high correlation withFROH >8 (r = 0.58)and FROH-genome (r = 0.60). The FROH-genome was highly correlated with inbreeding based on FROH>8 (r = 0.93) and FSNP (r = 0.88). The FGRM exhibited a high correlation with FROH-genome (r = 0.55)and FROH >8 (r = 0.51) and a lower correlation with other inbreeding estimators varying from 0.30 for FROH 2-4 to 0.37 for FROH 1-2. Increased levels of inbreeding had a negative impact on the productive and reproductive performance of Nelore cattle. The unfavorable inbreeding effect on productive and reproductive traitsranged from 0.12 to 0.51 for FPed, 0.19-0.59 for FGRM, 0.21-0.58 for FROH-genome, and 0.19-0.54 for FSNP per 1% of inbreeding scaled on the percentage of the mean. When scaling the linear regression coefficients on the standard deviation, the unfavorable inbreeding effect varied from 0.43 to 1.56% for FPed, 0.49-1.97% for FGRM, 0.34-2.2% for FROH-genome, and 0.50-1.62% for FSNP per 1% of inbreeding.The impact of the homozygous segments on reproductive and performance traits varied based on the chromosomes. This shows that specific homozygous chromosome segments can be signs of positive selection due to their beneficial effects on the traits. The low correlation observed between FPed and genomic-based inbreeding estimates suggests that the presence of animals with one unknown parent (sire or dam) in the pedigree does not account for ancient inbreeding. The ROH hotspots surround genes related to reproduction, growth, meat quality, and adaptation to environmental stress. Inbreeding depression has adverse effects on productive and reproductive traits in Nelore cattle, particularly on age at puberty in young bulls and heifer calving at 30 months, as well as on scrotal circumference and body weight when scaled on the standard deviation of the trait.

Complete chloroplast genomes of Desmidorchis penicillata (Deflers) plowes and Desmidorchis retrospiciens Ehrenb.: comparative and phylogenetic analyses among subtribe Stapeliinae (Ceropegieae, Asclepiadoideae, Apocynaceae)

The succulent shrubs Desmidorchis penicillata and D. retrospiciens, part of the taxonomically challenging genus Desmidorchis, are well‐known for their ecological resilience and medicinal significance. This study sequences the first complete chloroplast genomes of these species, shedding light on their genomic characteristics and evolutionary relationships. The circular genomes of D. penicillata (161 776 bp) and D. retrospiciens (162 277 bp) display a quadripartite structure typical of Angiosperms. Gene content, order, and GC content are consistent, featuring 114 unique genes, including 80 protein‐coding, 30 transfer RNAs, and four ribosomal RNAs genes. Codon usage analysis underscores A/U‐rich preferences, while RNA editing sites, predominantly in ndhB and ndhD genes, suggest post‐transcriptional modifications. Analysis of long repeated sequences reveals a predominance of forward and palindromic repeats. Simple sequence repeats (SSRs), particularly A/T motifs, are abundant, with high presence of mononucleotide, offering potential molecular markers. Comparative analysis with their relatives in subtribe Stapeliinae identifies mutational hotspots such as ycf1, ndhF, trnG(GCC)‐trnfM(CGA) and ndhG‐ndhI that could be potential DNA barcoding markers. The inverted repeat (IR) boundaries analysis revealed an expansion of IR on the small single copy region, leading to the formation of a pseudogene. Overall, substitution rate analysis indicated purifying selection, with a few genes (rpl22, clpP and rps11) showing signatures of positive selection. Additionally, the phylogenetic analysis positioned Desmidorchis within the Stapeliinae clade and strongly supported the sister relationship between D. penicillata and D. retrospiciens. This study provides comprehensive molecular data for future research in Desmidorchis.

Positive selection, genetic recombination, and intra-host evolution in novel equine coronavirus genomes and other members of the Embecovirus subgenus.

There are several examples of coronaviruses in the Betacoronavirus subgenus Embecovirus that have jumped from an animal to the human host. Studying how evolutionary factors shape coronaviruses in non-human hosts may provide insight into the coronavirus host-switching potential. Equids, such as horses and donkeys, are susceptible to equine coronaviruses (ECoVs). With increased testing prevalence, several ECoV genome sequences have become available for molecular evolutionary analyses, especially those from the United States of America (USA). To date, no analyses have been performed to characterize evolution within coding regions of the ECoV genome. Here, we obtain and describe four new ECoV genome sequences from infected equines from across the USA presenting clinical symptoms of ECoV, and infer ECoV-specific and Embecovirus-wide patterns of molecular evolution. Within two of the four data sets analyzed, we find evidence of intra-host evolution within the nucleocapsid (N) gene, suggestive of quasispecies development. We also identify 12 putative genetic recombination events within the ECoV genome, 11 of which fall in ORF1ab. Finally, we infer and compare sites subject to positive selection on the ancestral branch of each major Embecovirus member clade. Specifically, for the two currently identified human coronavirus (HCoV) embecoviruses that have spilled from animals to humans (HCoV-OC43 and HCoV-HKU1), we find that there are 42 and 2 such sites, respectively, perhaps reflective of the more complex ancestral evolutionary history of HCoV-OC43, which involves several different animal hosts.IMPORTANCEThe Betacoronavirus subgenus Embecovirus contains coronaviruses that not only pose a health threat to animals and humans, but also have jumped from animal to human host. Equids, such as horses and donkeys are susceptible to equine coronavirus (ECoV) infections. No studies have systematically examined evolutionary patterns within ECoV genomes. Our study addresses this gap and provides insight into intra-host ECoV evolution from infected horses. Further, we identify and report natural selection pattern differences between two embecoviruses that have jumped from animals to humans [human coronavirus OC43 and HKU1 (HCoV-OC43 and HCoV-HKU1, respectively)], and hypothesize that the differences observed may be due to the different animal host(s) that each virus circulated in prior to its jump into humans. Finally, we contribute four novel, high-quality ECoV genomes to the scientific community.

7065 Eradication Of Metastatic ER-Positive Breast, Ovarian, Endometrial And Lung Cancer In Mouse Xenografts And Patient Derived Organoids

Abstract Disclosure: D.J. Shapiro: None. D. Duraki: None. S. Ghosh: None. J. Zhu: None. C. Mao: None. J. Kim: None. M. Jabeen: None. M.W. Boudreau: None. M.P. Mulligan: None. R. Romero: None. Y. Han: None. J. Zhang: None. E.R. Nelson: None. O. Olopade: None. G. Chang: None. P.J. Hergenrother: Advisory Board Member; Self; Systems Oncology. We described the tumor protective estrogen-ER activated anticipatory Unfolded Protein Response (a-UPR) pathway. Here we report a previously undescribed multistep pathway by which very rapid estrogen-ER activation of the a-UPR authorizes and regulates subsequent transcription of the estrogen-ER transcriptome. We repurposed the tumor protective a-UPR through identification and optimization of the small molecule ErSO and its family of agents. ErSO acts non-competitively with estrogen to induce lethal hyperactivation of the a-UPR. In orthotopic mouse xenografts containing wild type or mutant ER, ErSO often induced complete regression without recurrence of large primary breast tumors and of most lung, bone and liver metastases, near complete regression of normally lethal brain metastases and complete destruction of patient derived organoids (PDOs) in Matrigel. Six research teams in four locations have confirmed the remarkable effectiveness of ErSO in ER-positive breast cancer. We next evaluated ErSO in diverse ER containing cancers in which estrogen is not the primary driver of proliferation. ErSO often induced complete regression in multiple orthotopic xenograft models of primary and metastatic ovarian cancer. Using fresh ovarian cancer organoids immediately after removal from patients by paracentesis, ErSO destroyed the organoids from some patients with advanced stage III and stage IV disease. ErSO was effective in a mouse xenograft model of endometrial cancer and, surprisingly, even in ERalpha positive lung cancer. Our ongoing studies demonstrate ErSO induces complete, or near complete regression, of primary and metastatic lung cancer in mice. Studies of ErSO’s mechanism of action using genome-wide CRISPR screens with positive selection, and other techniques, unveil a novel death pathway in which ErSO activation of the a-UPR triggers rapid calcium release into the cell body. The calcium opens the plasma membrane TRPM4 sodium channel, leading to an influx of extracellular sodium. This swells the cells, resulting in osmotic stress that sustains lethal a-UPR activation. A little-studied cytoskeleton regulator we identified, FGD3, plays a pivotal role in whether the cells rupture their membranes, inducing necrotic cell death. Notably, medium from diverse cancer cells killed by ErSO-induced necrosis robustly activates human macrophage and induces their migration - potentially facilitating immunotherapy. These studies describe a pathway from a multiprotein ER-SRC-PLC complex, through the a-UPR, to a novel cell swelling and necrosis pathway, that we are exploiting to target diverse, therapeutically challenging, ER-positive human cancers. Presentation: 6/2/2024