A Past Genetic Bottleneck from Argentine Beans and a Selective Sweep Led to the Race Chile of the Common Bean (Phaseolus vulgaris L.).

The domestication process of the common bean gave rise to six different races which come from the two ancestral genetic pools, the Mesoamerican (Durango, Jalisco, and Mesoamerica races) and the Andean (New Granada, Peru, and Chile races). In this study, a collection of 281 common bean landraces from Chile was analyzed using a 12K-SNP microarray. Additionally, 401 accessions representing the rest of the five common bean races were analyzed. A total of 2543 SNPs allowed us to differentiate a genetic group of 165 accessions that corresponds to the race Chile, 90 of which were classified as pure accessions, such as the bean types 'Tórtola', 'Sapito', 'Coscorrón', and 'Frutilla'. Our genetic analysis indicates that the race Chile has a close relationship with accessions from Argentina, suggesting that nomadic ancestral peoples introduced the bean seed to Chile. Previous archaeological and genetic studies support this hypothesis. Additionally, the low genetic diversity (π = 0.053; uHe = 0.53) and the negative value of Tajima' D (D = -1.371) indicate that the race Chile suffered a bottleneck and a selective sweep after its introduction, supporting the hypothesis that a small group of Argentine bean genotypes led to the race Chile. A total of 235 genes were identified within haplotype blocks detected exclusively in the race Chile, most of them involved in signal transduction, supporting the hypothesis that intracellular signaling pathways play a fundamental role in the adaptation of organisms to changes in the environment. To date, our findings are the most complete investigation associated with the origin of the race Chile of common bean.

Reconstructing the ancestral gene pool to uncover the origins and genetic links of Hmong-Mien speakers.

BACKGROUND: Hmong-Mien (HM) speakers are linguistically related and live primarily in China, but little is known about their ancestral origins or the evolutionary mechanism shaping their genomic diversity. In particular, the lack of whole-genome sequencing data on the Yao population has prevented a full investigation of the origins and evolutionary history of HM speakers. As such, their origins are debatable. RESULTS: Here, we made a deep sequencing effort of 80 Yao genomes, and our analysis together with 28 East Asian populations and 968 ancient Asian genomes suggested that there is a strong genetic basis for the formation of the HM language family. We estimated that the most recent common ancestor dates to 5800 years ago, while the genetic divergence between the HM and Tai-Kadai speakers was estimated to be 8200 years ago. We proposed that HM speakers originated from the Yangtze River Basin and spread with agricultural civilization. We identified highly differentiated variants between HM and Han Chinese, in particular, a deafness-related missense variant (rs72474224) in the GJB2 gene is in a higher frequency in HM speakers than in others. CONCLUSIONS: Our results indicated complex gene flow and medically relevant variants involved in the HM speakers' evolution history.

Increasing the meat productivity of young sheep based on the use of the gene pool of the Dorper and Hissar breeds.

In the pursuit of enhanced mutton production, improving the genetic reservoir of sheep with early maturation and high meat productivity is imperative. This study aims to assess the efficacy of integrating Dorper and Hissar rams into the breeding program of Kazakh fat-tailed coarse-haired ewes for generating young mutton. The research involved forming three groups, each comprising 40 ewes of the Kazakh fat-tailed coarse-haired breed, based on analog pairs. Ewes in Group I were inseminated with Dorper ram semen, those in Group II were inseminated with Hissar ram semen, and Group III served as a control with purebred Kazakh fat-tailed coarse-haired sheep breeding. Results revealed that crossbred rams in Group II achieved a significantly higher live weight of 45.2 kg at 120 days of age, surpassing the other groups by 9.7 kg and 10.6 kg. Crossbred gimmers in Group II reached a live weight of 42.0 kg by 4 months, outpacing the other groups by 12.2 kg. The crossbred lambs exhibited an expansive, deep, and sturdy physique, indicative of elevated meat productivity. Physique index analysis displayed that crossbred rams exhibited elongated limbs, bulkiness, and massiveness compared to purebred Kazakh fat-tailed coarse-haired lambs. In the 4.0-4.5-month age range, crossbred rams demonstrated a higher carcass muscle yield than their purebred counterparts, albeit the latter exhibited a 0.18% greater bone yield. Moreover, the meat of groups I and II sheep contained 19.6% and 20.1% protein content, respectively, surpassing the local Kazakh fat-tailed sheep population by 0.7% and 1.2% in absolute terms.

The evolutionary impact of childhood cancer on the human gene pool.

Germline pathogenic variants associated with increased childhood mortality must be subject to natural selection. Here, we analyze publicly available germline genetic metadata from 4,574 children with cancer [11 studies; 1,083 whole exome sequences (WES), 1,950 whole genome sequences (WGS), and 1,541 gene panel] and 141,456 adults [125,748 WES and 15,708 WGS]. We find that pediatric cancer predisposition syndrome (pCPS) genes [n = 85] are highly constrained, harboring only a quarter of the loss-of-function variants that would be expected. This strong indication of selective pressure on pCPS genes is found across multiple lines of germline genomics data from both pediatric and adult cohorts. For six genes [ELP1, GPR161, VHL and SDHA/B/C], a clear lack of mutational constraint calls the pediatric penetrance and/or severity of associated cancers into question. Conversely, out of 23 known pCPS genes associated with biallelic risk, two [9%, DIS3L2 and MSH2] show significant constraint, indicating that they may monoallelically increase childhood cancer risk. In summary, we show that population genetic data provide empirical evidence that heritable childhood cancer leads to natural selection powerful enough to have significantly impacted the present-day gene pool.

The role of introgressive hybridization in shaping the geographically isolated gene pools of wax palm populations (genus Ceroxylon).

The speciation continuum is the process by which genetic groups diverge until they reach reproductive isolation. It has become common in the literature to show that this process is gradual and flickering, with possibly many instances of secondary contact and introgression after divergence has started. The level of divergence might vary among genomic regions due to, among others, the different forces and roles of selection played by the shared regions. Through hybrid capture, we sequenced ca. 4,000 nuclear regions in populations of six species of wax palms, five of which form a monophyletic group (genus Ceroxylon, Arecaceae: Ceroxyloideae). We show that in this group, the different populations show varying degrees of introgressive hybridization, and two of them are backcrosses of the other three 'pure' species. This is particularly interesting because these three species are dioecious, have a shared main pollinator, and have slightly overlapping reproductive seasons but highly divergent morphologies. Our work supports shows wax palms diverge under positive and background selection in allopatry, and hybridize due to secondary contact and inefficient reproductive barriers, which sustain genetic diversity. Introgressed regions are generally not under positive selection. Peripheral populations are backcrosses of other species; thus, introgressive hybridization is likely modulated by demographic effects rather than selective pressures. In general, these species might function as an 'evolutionary syngameon' where expanding, peripheral, small, and isolated populations maintain diversity by crossing with available individuals of other wax palms. In the Andean context, species can benefit from gained variation from a second taxon or the enhancement of population sizes by recreating a common genetic pool.

Repeat turnover meets stable chromosomes: repetitive DNA sequences mark speciation and gene pool boundaries in sugar beet and wild beets.

Sugar beet and its wild relatives share a base chromosome number of nine and similar chromosome morphologies. Yet, interspecific breeding is impeded by chromosome and sequence divergence that is still not fully understood. Since repetitive DNAs are among the fastest evolving parts of the genome, we investigated, if repeatome innovations and losses are linked to chromosomal differentiation and speciation. We traced genome and chromosome-wide evolution across 13 beet species comprising all sections of the genera Beta and Patellifolia. For this, we combined short and long read sequencing, flow cytometry, and cytogenetics to build a comprehensive framework that spans the complete scale from DNA to chromosome to genome. Genome sizes and repeat profiles reflect the separation into three gene pools with contrasting evolutionary patterns. Among all repeats, satellite DNAs harbor most genomic variability, leading to fundamentally different centromere architectures, ranging from chromosomal uniformity in Beta and Patellifolia to the formation of patchwork chromosomes in Corollinae/Nanae. We show that repetitive DNAs are causal for the genome expansions and contractions across the beet genera, providing insights into the genomic underpinnings of beet speciation. Satellite DNAs in particular vary considerably between beet genomes, leading to the evolution of distinct chromosomal setups in the three gene pools, likely contributing to the barriers in beet breeding. Thus, with their isokaryotypic chromosome sets, beet genomes present an ideal system for studying the link between repeats, genomic variability, and chromosomal differentiation and provide a theoretical fundament for understanding barriers in any crop breeding effort.

Molecular evidence depicts genetic divergence among Agropyron elongatum and A. cristatum accessions from gene pool of Iran.

The genus Agropyron has an important role in soil protection and forage production in rangelands. The investigation utilized 37 ISSR primers, resulting in the detection of 956 loci within the A. elongatum genome and 705 loci within the A. cristatum genome. The findings revealed a high level of polymorphism, with 97% of loci in A. elongatum and 84% of loci in A. cristatum exhibiting variability. Notably, the primer (AC)8GCT emerged as a promising candidate for evaluating genetic diversity due to its ability to amplify numerous loci in both species. Using both the UPGMA algorithm and Bayesian analysis, the examined Agropyron accessions were categorized into two subgroups based on their respective species. The Q values associated with these subgroups suggested that certain accessions, namely "G16," "G19," "G20," "G21," "G22," "G23," "G24," and "G25," displayed potential admixture genomes. An analysis of molecular variance (AMOVA) underscored the significance of within-species variability, which accounted for 69% of the overall diversity, compared to between-species variability at 31%. Various genetic diversity parameters, including Na, Ne, I, He, and the number of private loci, were found to be higher in A. elongatum when compared to A. cristatum. Furthermore, Jaccard similarity coefficients ranged from 0.33 to 0.66 in A. cristatum and from 0.25 to 0.7 in A. elongatum, indicating the extent of genetic relatedness among these species. Intriguingly, the study identified two and three heterotic groups in A. cristatum and A. elongatum, respectively, which could be harnessed in the development of synthetic varieties to exploit heterosis. The results also indicated that a small proportion of ISSR loci pairs (5.2% in A. elongatum and 0.5% in A. cristatum) exhibited significant levels of linkage disequilibrium (LD) (P≤0.05), suggesting the potential utility of LD-based association mapping in Agropyron species. In conclusion, this research sheds light on the genetic diversity of Agropyron species and provides valuable insights into their potential applications in soil protection and forage production, as well as the prospects for enhancing genetic variability and heterosis in these species.

Origins of East Caucasus Gene Pool: Contributions of Autochthonous Bronze Age Populations and Migrations from West Asia Estimated from Y-Chromosome Data.

The gene pool of the East Caucasus, encompassing modern-day Azerbaijan and Dagestan populations, was studied alongside adjacent populations using 83 Y-chromosome SNP markers. The analysis of genetic distances among 18 populations (N = 2216) representing Nakh-Dagestani, Altaic, and Indo-European language families revealed the presence of three components (Steppe, Iranian, and Dagestani) that emerged in different historical periods. The Steppe component occurs only in Karanogais, indicating a recent medieval migration of Turkic-speaking nomads from the Eurasian steppe. The Iranian component is observed in Azerbaijanis, Dagestani Tabasarans, and all Iranian-speaking peoples of the Caucasus. The Dagestani component predominates in Dagestani-speaking populations, except for Tabasarans, and in Turkic-speaking Kumyks. Each component is associated with distinct Y-chromosome haplogroup complexes: the Steppe includes C-M217, N-LLY22g, R1b-M73, and R1a-M198; the Iranian includes J2-M172(×M67, M12) and R1b-M269; the Dagestani includes J1-Y3495 lineages. We propose J1-Y3495 haplogroup's most common lineage originated in an autochthonous ancestral population in central Dagestan and splits up ~6 kya into J1-ZS3114 (Dargins, Laks, Lezgi-speaking populations) and J1-CTS1460 (Avar-Andi-Tsez linguistic group). Based on the archeological finds and DNA data, the analysis of J1-Y3495 phylogeography suggests the growth of the population in the territory of modern-day Dagestan that started in the Bronze Age, its further dispersal, and the microevolution of the diverged population.

Multi-host infection and phylogenetically diverse lineages shape the recombination and gene pool dynamics of Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus can infect and adapt to multiple host species. However, our understanding of the genetic and evolutionary drivers of its generalist lifestyle remains inadequate. This is particularly important when considering local populations of S. aureus, where close physical proximity between bacterial lineages and between host species may facilitate frequent and repeated interactions between them. Here, we aim to elucidate the genomic differences between human- and animal-derived S. aureus from 437 isolates sampled from disease cases in the northeast region of the United States. RESULTS: Multi-locus sequence typing revealed the existence of 75 previously recognized sequence types (ST). Our population genomic analyses revealed heterogeneity in the accessory genome content of three dominant S. aureus lineages (ST5, ST8, ST30). Genes related to antimicrobial resistance, virulence, and plasmid types were differentially distributed among isolates according to host (human versus non-human) and among the three major STs. Across the entire population, we identified a total of 1,912 recombination events that occurred in 765 genes. The frequency and impact of homologous recombination were comparable between human- and animal-derived isolates. Low-frequency STs were major donors of recombined DNA, regardless of the identity of their host. The most frequently recombined genes (clfB, aroA, sraP) function in host infection and virulence, which were also frequently shared between the rare lineages. CONCLUSIONS: Taken together, these results show that frequent but variable patterns of recombination among co-circulating S. aureus lineages, including the low-frequency lineages, that traverse host barriers shape the structure of local gene pool and the reservoir of host-associated genetic variants. Our study provides important insights to the genetic and evolutionary factors that contribute to the ability of S. aureus to colonize and cause disease in multiple host species. Our study highlights the importance of continuous surveillance of S. aureus circulating in different ecological host niches and the need to systematically sample from them. These findings will inform development of effective measures to control S. aureus colonization, infection, and transmission across the One Health continuum.

Morphological and molecular diversity in mid-late and late maturity genotypes of cauliflower.

Genetic diversity is the prerequisite for the success of crop improvement programmes. Keeping in view, the current investigation was undertaken to assess the agro-morphological and molecular diversity involving 36 diverse mid-late and late cauliflower genotypes following α-RBD design during winter season 2021-22. Six morphological descriptors predicted as polymorphic using Shannon diversity index with maximum for leaf margin (0.94). The genotypes grouped into nine clusters based on D2 analysis with four as monogenotypic and gross plant weight (32.38%) revealed maximum contribution towards the genetic diversity. Molecular diversity analysis revealed 2-7 alleles among 36 polymorphic simple sequence repeats (SSR) with average of 4.22. Primer BoESSR492 (0.77) showed maximum polymorphic information content (PIC) with mean of 0.58. SSR analysis revealed two clusters each with two subclusters with a composite pattern of genotype distribution. STRUCTURE analysis showed homogenous mixture with least amount of gene pool introgression within the genotypes. Thus, based on morphological and molecular studies, the diverse genotypes namely, DPCaCMS-1, DPCaf-W4, DPCaf-US, DPCaf-W131W, DPCaf-S121, DPCaf-18, DPCaf-13, DPCaf-29 and DPCaf-CMS5 can be utilized in hybridization to isolate potential transgressive segregants to broaden the genetic base of cauliflower or involve them to exploit heterosis.

Characterization of the genetic pool of the Canadienne dairy cattle breed.

BACKGROUND: Canadienne cattle are the oldest breed of dairy cattle in North America. The Canadienne breed originates from cattle that were brought to America by the mid-seventeenth century French settlers. The herd book was established in 1886 and the current breed characteristics include dark coat color, small size compared to the modern Holstein breed, and overall rusticity shaped by the harsh environmental conditions that were prevalent during the settlement of North America. The Canadienne breed is an invaluable genetic resource due to its high resilience, longevity and fertility. However, it is heavily threatened with a current herd limited to an estimated 1200 registered animals, of which less than 300 are fullblood. To date, no effort has been made to document the genetic pool of this heritage breed in order to preserve it. RESULTS: In this project, we used genomic data, which allow a precise description of the genetic makeup of a population, to provide valuable information on the genetic diversity of this heritage breed and suggest management options for its long-term viability. Using a panel that includes 640,000 single nucleotide polymorphisms (SNPs), we genotyped 190 animals grouped into six purity ranges. Unsupervised clustering analyses revealed three genetically distinct groups among those with the higher levels of purity. The observed heterozygosity was higher than expected even in the 100% purebreds. Comparison with Holstein genotypes showed significantly shorter runs of homozygosity for the Canadienne breed, which was unexpected due to the high inbreeding value calculated from pedigree data. CONCLUSIONS: Overall, our data indicate that the fullblood gene pool of the Canadienne breed is more diversified than expected and that bloodline management could promote breed sustainability. In its current state, the Canadienne is not a dead-end breed but remains highly vulnerable due to its small population size.

Utilizing Genomics to Characterize the Common Oat Gene Pool-The Story of More Than a Century of Polish Breeding.

This study was undertaken to investigate the diversity and population structure of 487 oat accessions, including breeding lines from the ongoing programs of the three largest Polish breeding companies, along with modern and historical Polish and foreign cultivars. The analysis was based on 7411 DArTseq-derived SNPs distributed among three sub-genomes (A, C, and D). The heterogeneity of the studied material was very low, as only cultivars and advanced breeding lines were examined. Principal component analysis (PCA), principal coordinate analysis (PCoA), and cluster and STRUCTURE analyses found congruent results, which show that most of the examined cultivars and materials from Polish breeding programs formed major gene pools, that only some accessions derived from Strzelce Plant Breeding, and that foreign cultivars were outside of the main group. During the 120 year oat breeding process, only 67 alleles from the old gene pool were lost and replaced by 67 new alleles. The obtained results indicate that no erosion of genetic diversity was observed within the Polish native oat gene pool. Moreover, current oat breeding programs have introduced 673 new alleles into the gene pool relative to historical cultivars. The analysis also showed that most of the changes in relation to historical cultivars occurred within the A sub-genome with emphasis on chromosome 6A. The targeted changes were the rarest in the C sub-genome. This study showed that Polish oat breeding based mainly on traditional breeding methods-although focused on improving traits typical to this crop, i.e., enhancing the grain yield and quality and improving adaptability-did not significantly narrow the oat gene pool and in fact produced cultivars that are not only competitive in the European market but are also reservoirs of new alleles that were not found in the analyzed foreign materials.

Kazakh national dog breed Tazy: What do we know?

The Tazy or Kazakh National sighthound has been officially recognized as the national heritage of Kazakhstan. Comprehensive genetic studies of genetic diversity and population structure that could be used for selection and conservation of this unique dog breed have not been conducted so far. The aim of this study was to determine the genetic structure of the Tazy using microsatellite and SNP markers and to place the breed in the context of the world sighthound breeds. Our results showed that all 19 microsatellite loci examined were polymorphic. The observed number of alleles in the Tazy population varied from 6 (INU030 locus) to 12 (AHT137, REN169D01, AHTh260, AHT121, and FH2054 loci) with a mean of 9.778 alleles per locus. The mean number of effective alleles was 4.869 and ranged from 3.349 f to 4.841. All markers were highly informative (PIC values greater than 0.5) and ranged from 0.543 (REN247M23 locus) to 0.865 (AHT121 locus). The observed and expected heterozygosities in a total population were 0.748 and 0.769 and ranged from 0.746 to 0.750 and 0.656 to 0.769, respectively. Overall, the results confirmed that the Tazy breed has a high level of genetic diversity, no significant inbreeding, and a specific genetic structure. Three gene pools underlie the genetic diversity of the Tazy breed. SNP analysis using the CanineHD SNP array, which contains more than 170,000 SNP markers, showed that the Tazy breed is distinct from other sighthound breeds and genetically related to ancient eastern sighthound breeds sharing the same branch with the Afghan Hound and the Saluki. The results, together with archeological findings, confirm the ancient origin of the breed. The findings can be used for the conservation and international registration of the Tazy dog breed.

Palaeogenomics of Upper Palaeolithic to Neolithic European hunter-gatherers.

Modern humans have populated Europe for more than 45,000 years1,2. Our knowledge of the genetic relatedness and structure of ancient hunter-gatherers is however limited, owing to the scarceness and poor molecular preservation of human remains from that period3. Here we analyse 356 ancient hunter-gatherer genomes, including new genomic data for 116 individuals from 14 countries in western and central Eurasia, spanning between 35,000 and 5,000 years ago. We identify a genetic ancestry profile in individuals associated with Upper Palaeolithic Gravettian assemblages from western Europe that is distinct from contemporaneous groups related to this archaeological culture in central and southern Europe4, but resembles that of preceding individuals associated with the Aurignacian culture. This ancestry profile survived during the Last Glacial Maximum (25,000 to 19,000 years ago) in human populations from southwestern Europe associated with the Solutrean culture, and with the following Magdalenian culture that re-expanded northeastward after the Last Glacial Maximum. Conversely, we reveal a genetic turnover in southern Europe suggesting a local replacement of human groups around the time of the Last Glacial Maximum, accompanied by a north-to-south dispersal of populations associated with the Epigravettian culture. From at least 14,000 years ago, an ancestry related to this culture spread from the south across the rest of Europe, largely replacing the Magdalenian-associated gene pool. After a period of limited admixture that spanned the beginning of the Mesolithic, we find genetic interactions between western and eastern European hunter-gatherers, who were also characterized by marked differences in phenotypically relevant variants.

Development and characterization of a sorghum multi-parent advanced generation intercross (MAGIC) population for capturing diversity among seed parent gene pool.

Multiparent advanced eneration inter-cross (MAGIC) populations improve the precision of quantitative trait loci (QTL) mapping over biparental populations by incorporating increased diversity and opportunities to reduce linkage disequilibrium among variants. Here, we describe the development of a MAGIC B-Line (MBL) population from an inter-cross among 4 diverse founders of grain sorghum [Sorghum bicolor (L.) Moench] across different races (kafir, guinea, durra, and caudatum). These founders were selected based on genetic uniqueness and several distinct qualitative features including panicle architecture, plant color, seed color, endosperm texture, and awns. A whole set of MBL (708 F6) recombinant inbred lines along with their founders were genotyped using Diversity Arrays Technology (DArTseq) and 5,683 single-nucleotide polymorphisms (SNPs) were generated. A genetic linkage map was constructed using a set of polymorphic, quality-filtered markers (2,728 SNPs) for QTL interval-mapping. For population validation, 3 traits (seed color, plant color, and awns) were used for QTL mapping and genome-wide association study (GWAS). QTL mapping and GWAS identified 4 major genomic regions located across 3 chromosomes (Chr1, Chr3, and Chr6) that correspond to known genetic loci for the targeted traits. Founders of this population consist of the fertility maintainer (A/B line) gene pool and derived MBL lines could serve as female/seed parents in the cytoplasmic male sterility breeding system. The MBL population will serve as a unique genetic and genomic resource to better characterize the genetics of complex traits and potentially identify superior alleles for crop improvement efforts to enrich the seed parent gene pool.

Evolutionary dynamics and adaptive benefits of deleterious mutations in crop gene pools.

Mutations with deleterious consequences in nature may be conditionally deleterious in crop plants. That is, while some genetic variants may reduce fitness under wild conditions and be subject to purifying selection, they can be under positive selection in domesticates. Such deleterious alleles can be plant breeding targets, particularly for complex traits. The difficulty of distinguishing favorable from unfavorable variants reduces the power of selection, while favorable trait variation and heterosis may be attributable to deleterious alleles. Here, we review the roles of deleterious mutations in crop breeding and discuss how they can be used as a new avenue for crop improvement with emerging genomic tools, including HapMaps and pangenome analysis, aiding the identification, removal, or exploitation of deleterious mutations.

Disentangling clustering configuration intricacies for divergently selected chicken breeds.

Divergently selected chicken breeds are of great interest not only from an economic point of view, but also in terms of sustaining diversity of the global poultry gene pool. In this regard, it is essential to evaluate the classification (clustering) of varied chicken breeds using methods and models based on phenotypic and genotypic breed differences. It is also important to implement new mathematical indicators and approaches. Accordingly, we set the objectives to test and improve clustering algorithms and models to discriminate between various chicken breeds. A representative portion of the global chicken gene pool including 39 different breeds was examined in terms of an integral performance index, i.e., specific egg mass yield relative to body weight of females. The generated dataset was evaluated within the traditional, phenotypic and genotypic classification/clustering models using the k-means method, inflection points clustering, and admixture analysis. The latter embraced SNP genotype datasets including a specific one focused on the performance-associated NCAPG-LCORL locus. The k-means and inflection points analyses showed certain discrepancies between the tested models/submodels and flaws in the produced cluster configurations. On the other hand, 11 core breeds were identified that were shared between the examined models and demonstrated more adequate clustering and admixture patterns. These findings will lay the foundation for future research to improve methods for clustering as well as genome- and phenome-wide association/mediation analyses.

Correlated substitutions reveal SARS-like coronaviruses recombine frequently with a diverse set of structured gene pools.

Quantifying SARS-like coronavirus (SL-CoV) evolution is critical to understanding the origins of SARS-CoV-2 and the molecular processes that could underlie future epidemic viruses. While genomic analyses suggest recombination was a factor in the emergence of SARS-CoV-2, few studies have quantified recombination rates among SL-CoVs. Here, we infer recombination rates of SL-CoVs from correlated substitutions in sequencing data using a coalescent model with recombination. Our computationally-efficient, non-phylogenetic method infers recombination parameters of both sampled sequences and the unsampled gene pools with which they recombine. We apply this approach to infer recombination parameters for a range of positive-sense RNA viruses. We then analyze a set of 191 SL-CoV sequences (including SARS-CoV-2) and find that ORF1ab and S genes frequently undergo recombination. We identify which SL-CoV sequence clusters have recombined with shared gene pools, and show that these pools have distinct structures and high recombination rates, with multiple recombination events occurring per synonymous substitution. We find that individual genes have recombined with different viral reservoirs. By decoupling contributions from mutation and recombination, we recover the phylogeny of non-recombined portions for many of these SL-CoVs, including the position of SARS-CoV-2 in this clonal phylogeny. Lastly, by analyzing >400,000 SARS-CoV-2 whole genome sequences, we show current diversity levels are insufficient to infer the within-population recombination rate of the virus since the pandemic began. Our work offers new methods for inferring recombination rates in RNA viruses with implications for understanding recombination in SARS-CoV-2 evolution and the structure of clonal relationships and gene pools shaping its origins.

Expansion of interferon inducible gene pool via USP18 inhibition promotes cancer cell pyroptosis.

While immunotherapy has emerged as a breakthrough cancer therapy, it is only effective in some patients, indicating the need of alternative therapeutic strategies. Induction of cancer immunogenic cell death (ICD) is one promising way to elicit potent adaptive immune responses against tumor-associated antigens. Type I interferon (IFN) is well known to play important roles in different aspects of immune responses, including modulating ICD in anti-tumor action. However, how to expand IFN effect in promoting ICD responses has not been addressed. Here we show that depletion of ubiquitin specific protease 18 (USP18), a negative regulator of IFN signaling, selectively induces cancer cell ICD. Lower USP18 expression correlates with better survival across human selected cancer types and delays cancer progression in mouse models. Mechanistically, nuclear USP18 controls the enhancer landscape of cancer cells and diminishes STAT2-mediated transcription complex binding to IFN-responsive elements. Consequently, USP18 suppression not only enhances expression of canonical IFN-stimulated genes (ISGs), but also activates the expression of a set of atypical ISGs and NF-κB target genes, including genes such as Polo like kinase 2 (PLK2), that induce cancer pyroptosis. These findings may support the use of targeting USP18 as a potential cancer immunotherapy.