Changes In Allele Frequencies Research Articles

Changes in allele frequencies and genetic architecture due to selection in two pig populations

BackgroundGenetic selection improves a population by increasing the frequency of favorable alleles. Understanding and monitoring allele frequency changes is, therefore, important to obtain more insight into the long-term effects of selection. This study aimed to investigate changes in allele frequencies and in results of genome-wide association studies (GWAS), and how those two are related to each other. This was studied in two maternal pig lines where selection was based on a broad selection index. Genotypes and phenotypes were available from 2015 to 2021.ResultsSeveral large changes in allele frequencies over the years were observed in both lines. The largest allele frequency changes were not larger than expected under drift based on gene dropping simulations, but the average allele frequency change was larger with selection. Moreover, several significant regions were found in the GWAS for the traits under selection, but those regions did not overlap with regions with larger allele frequency changes. No significant GWAS regions were found for the selection index in both lines, which included multiple traits, indicating that the index is affected by many loci of small effect. Additionally, many significant regions showed pleiotropic, and often antagonistic, associations with other traits under selection. This reduces the selection pressure on those regions, which can explain why those regions are still segregating, although the traits have been under selection for several generations. Across the years, only small changes in Manhattan plots were found, indicating that the genetic architecture was reasonably constant.ConclusionsNo significant GWAS regions were found for any of the traits under selection among the regions with the largest changes in allele frequency, and the correlation between significance level of marker associations and changes in allele frequency over one generation was close to zero for all traits. Moreover, the largest changes in allele frequency could be explained by drift and were not necessarily a result of selection. This is probably because selection acted on a broad index for which no significant GWAS regions were found. Our results show that selecting on a broad index spreads the selection pressure across the genome, thereby limiting allele frequency changes.

Frequencies of β-casein variants and their influence on genetic merit for production traits in Holstein cows

Context Traits considered for selection are influenced by social, consumer, and breeder demands. In the past decades, there has been increasing global interest in producing milk free from the β-casein (CSN2) A1 allele because of the health benefits it may have. This has encouraged many breeders to select A2A2 cows in their dairy cattle herds. Aims This study aimed to evaluate the genetic variation in the bovine CSN2 gene regarding A1-like and A2-like variants and to assess the potential association between these variants and production traits in Holstein cows. Methods In total, 2600 Holstein cows from three commercial dairy farms with different breeding objectives and phenotypic records taken over different seasons, periods, and lactations were genotyped for single-nucleotide polymorphism rs43703011, which distinguishes A1-like from A2-like β-casein variants. Allele and genotype frequencies were determined and their breeding values for milk, fat, and protein yields, and fat and protein percentages were estimated. The influence of CSN2 genotypes on these breeding values was studied through a one-way ANOVA. For the significant CSN2 genotype–breeding value associations, allele substitution effects were estimated. Key results We found allele frequencies for A1-like and A2-like alleles in the ranges 0.262–0.366 and 0.634–0.738 respectively, and genotype frequencies in the ranges of 0.043–0.125, 0.43–0.537, and 0.393–0.523 for A1A1, A1A2 and A2A2 genotypes respectively. We demonstrated that the A2-like CSN2 variant correlates with higher estimated breeding values (EBVs) for milk, protein, and fat yields, and lower EBVs for fat and protein percentages. Conclusions These results are valuable to visualize the trends in CSN2 allele and genotype frequency changes over the years and to analyze the effect of the different variants of β-casein on production performance. Implications Our findings contribute to evaluating the consequences on dairy performance of selection for the A2-like variant.

Abstract PR009: Application of Liquid Biopsy-RECIST (LB-RECIST) criteria to track metastatic colorectal cancer (mCRC) molecular response in first-line (1L) setting: Findings from the PLATFORM-B study

Abstract Introduction: Circulating tumor DNA (ctDNA) analysis is a minimally invasive and reproducible method to explore tumor molecular biology. Recently, Gouda et al. proposed the LB-RECIST criteria to monitor molecular response, validating them on a heterogeneous metastatic population. However, data on mCRC are lacking. Here, we report the first attempt to apply LB-RECIST in the multicenter prospective PLATFORM-B study, which enrolled 130 mCRC patients (pts) receiving 1L standard therapy, with ctDNA analysis performed at different time points. Materials and Methods: Baseline (BL) and week 8 (W8) plasma samples were analyzed using a targeted NGS-based approach (Ion S5 system). Changes in ctDNA detectability were assessed to determine molecular response as per qualitative LB-RECIST criteria: Group1 (G1, detectable ctDNA at BL and W8); Group2 (G2, detectable BL and undetectable W8); Group3 (G3, undetectable BL and detectable W8); Group4 (G4, undetectable at BL and W8). Changes in aggregate variant allele frequency (VAF) - the sum of all VAFs of the studied genes in a sample - were used to assess quantitative LB-RECIST responses: ctDNA Complete Response (CCR, clearance after initial detectability), Partial Response (CPR, decrease >10%), Stable Disease (CSD, no change or decrease <10%), Progressive Disease (CPD, increase >10% or new mutations), and Non-measurable Disease (CND, undetectable at BL and W8). Molecular results were correlated with clinical outcomes. Statistically significant differences were assessed across different groups using 2-sided P values with an α ≤ .05 level of significance. Results: Overall, 79 pts had paired BL and W8 samples. Quantitative LB-RECIST identified 32 CCR, 18 CND, 20 CPR, 8 CPD, and 1 CSD cases. Qualitative LB-RECIST found 22 G1, 32 G2, 7 G3, and 18 G4 cases. Radiological RECIST identified 6 CR, 47 PR, 21 SD, and 5 PD. CCR showed the highest survival rates: with a median follow-up of 25 months (mo) (range: 1–49), median progression-free survival (mPFS) was not reached (NR) and median overall survival (mOS) was 41.8 mo. The CND group had similar rates (mPFS NR; mOS 41.1 mo). CPR and CPD had the poorest outcomes: for CPR, mPFS was 12.7 and mOS 16.4 mo; for CPD, mPFS and mOS were 11.9 and 25.5 mo, respectively. In the G1, G2, G3, and G4 groups, mPFS was 11.9, NR, 14.2, and NR, respectively, while mOS was 16.4, 41.8, 33.4, and 41.1 mo. Kaplan-Meier analysis of the quantitative groups showed statistically significant differences (P < .0001) for both PFS and OS curves. The same level of significance was found in the qualitative groups. Conclusion: LB- RECIST can be a rapid and reproducible method to assess molecular response in mCRC. However, concerns remain. The CND group (23% of cases) showed survival rates similar to the CCR group, as observed also between G4 and G2. These data suggest that absence of ctDNA at W8 is the best surrogate for OS. Moreover, CPD had higher OS rates than CPR, but similar PFS. Further investigations in larger populations are needed to refine these criteria and improve molecular response stratification Citation Format: Valentino Martelli, Joana Vidal, Maria Concepción Fernández-Rodríguez, Pilar García-Alfonso, David Páez, Joan Gibert, Jennifer Linares, Annarita Sibilio, Vicente Alonso, Maria Teresa Cano, Cristina Santos, Gema Duran, Elena Élez, José Luis Manzano, Rocio Garcia-Carbonero, Reyes Ferreiro, Ferran Losa, Estela Pineda, Javier Sastre, Auxiliadora Gomez-España, Rodrigo Toledo, Fernando Rivera, Beatriz Bellosillo, Josep Tabernero, Ramon Ramon Salazar, Enrique Aranda, Clara Montagut. Application of Liquid Biopsy-RECIST (LB-RECIST) criteria to track metastatic colorectal cancer (mCRC) molecular response in first-line (1L) setting: Findings from the PLATFORM-B study [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR009.

A path integral approach for allele frequency dynamics under polygenic selection.

Many phenotypic traits have a polygenic genetic basis, making it challenging to learn their genetic architectures and predict individual phenotypes. One promising avenue to resolve the genetic basis of complex traits is through evolve-and-resequence experiments, in which laboratory populations are exposed to some selective pressure and trait-contributing loci are identified by extreme frequency changes over the course of the experiment. However, small laboratory populations will experience substantial random genetic drift, and it is difficult to determine whether selection played a role in a given allele frequency change. Predicting allele frequency changes under drift and selection, even for alleles contributing to simple, monogenic traits, has remained a challenging problem. Recently, there have been efforts to apply the path integral, a method borrowed from physics, to solve this problem. So far, this approach has been limited to genic selection, and is therefore inadequate to capture the complexity of quantitative, highly polygenic traits that are commonly studied. Here we extend one of these path integral methods, the perturbation approximation, to selection scenarios that are of interest to quantitative genetics. We derive analytic expressions for the transition probability (i.e., the probability that an allele will change in frequency from x to y in time t) of an allele contributing to a trait subject to stabilizing selection, as well as that of an allele contributing to a trait rapidly adapting to a new phenotypic optimum. We use these expressions to characterize the use of allele frequency change to test for selection, as well as explore optimal design choices for evolve-and-resequence experiments to uncover the genetic architecture of polygenic traits under selection.

Global invasion history with climate-related allele frequency shifts in the invasive Mediterranean fruit fly (Diptera, Tephritidae: Ceratitis capitata)

The Mediterranean fruit fly (Ceratitis capitata) is a globally invasive species and an economically significant pest of fruit crops. Understanding the evolutionary history and local climatic adaptation of this species is crucial for developing effective pest management strategies. We conducted a comprehensive investigation using whole genome sequencing to explore (i) the invasion history of C. capitata with an emphasis on historical admixture and (ii) local climatic adaptation across African, European, Central, and South American populations of C. capitata. Our results suggest a stepwise colonization of C. capitata in Europe and Latin America in which Mediterranean and Central American populations share an ancestral lineage. Conversely, South American invasion history is more complex, and our results partly suggest an old secondary invasion into South America from Europe or a colonization of South America directly from Africa, followed by admixture with an European lineage. Throughout its invasive range, C. capitata is challenged with diverse climatic regimes. A genome wide association study identified a relationship between allele frequency changes and specific bioclimatic variables. Notably, we observed a significant allele frequency shift related to adaptation to cold stress (BIO6), highlighting the species’ ability to rapidly adapt to seasonal variations in colder climates.

Dynamics of tumor in situ fluid circulating tumor DNA in recurrent glioblastomas forecasts treatment efficacy of immune checkpoint blockade coupled with low-dose bevacizumab

PurposeImmune checkpoint blockade (ICB) therapies have shown efficacy in various tumors, but long-term responses in glioblastoma are less than 10%. Quantifying tumor in situ fluid circulating tumor DNA (TISF-ctDNA) and therapeutic dynamics may enable real-time GBM disease burden evaluation. This study explores the potential of tumor in situ fluid circulating tumor DNA (TISF-ctDNA) dynamics in predicting treatment efficacy.MethodsTISF and peripheral blood samples were collected from patients with recurrent glioblastoma (rGBM) undergoing tislelizumab (a programmed death 1 inhibitor) combined with low-dose bevacizumab (an anti-vascular endothelial growth factor antibody) treatment before and during each immunotherapy cycle. Biomarkers evaluated included TISF-ctDNA, measured using Next Generation Sequencing (NGS), and host inflammation markers such as the platelet-to-lymphocyte ratio (PLR).ResultsAll 32 patients received tislelizumab plus low-dose bevacizumab regularly. The median progression-free survival (PFS) was 4.0 months, and overall survival (OS) was 22.3 months. An analysis of 19 patients with continuous evaluable TISF showed baseline TISF-ctDNA abundance did not correlate with OS (p = 0.23) or PFS (p = 0.23). However, a change in TISF-ctDNA maximal Somatic Variant Allelic Frequency (MVAF) after six treatment cycles predicted both PFS (p = 0.02) and OS (p < 0.0001). Lower baseline PLR also correlated with better survival outcomes.ConclusionThe combination of tislelizumab and low-dose bevacizumab therapy appears to be effective in extending both OS and PFS in rGBM patients. Continuous TISF-ctDNA testing shows potential utility in complementing radiological monitoring. The temporal change pattern of TISF MVAF is more predictive of immunotherapy response than imaging. PLR before immunotherapy can screen patients likely to benefit from tislelizumab plus low-dose bevacizumab therapy.Trial registrationThe trial registration number: NCT05502991; Date of registration: 2022-08-14.

Distribution of genotypes by the growth diferential factor 9 (GDF-9) gene locus in the romanov breed sheep population

The FecG gene, also known as GDF-9 (growth factor differentiation factor 9), plays an important role in regulating reproductive function in mammals. This paper presents the results of a study of a point mutation in the differential growth factor gene in Romanov breed sheep. Mutations in exon 1 of the GDF-9 gene can lead to disturbances in ovarian development and ovulation, resulting in infertility or reduced reproductive capacity in animals. The object of the study was Romanov breed sheep in a sample of 30 individuals. For DNA extraction, venous blood samples were taken from the jugular vein. In Romanov breed sheep for the GDF-9 gene, it was found that at the G1 locus of this gene there are two alleles – G and A. Three genotypes were also identified: GG (254 bp/117 bp), AG (410bp/254/117 bp) and AA (410 bp/410 bp). The observed χ2 criterion was less than expected, therefore, the empirical and theoretical frequencies do not differ significantly, and deviations from the distribution according to the Hardy-Weinberg law are not observed. The observed heterozygosity index (Ho) was 0.27. Allele frequencies were 0,8 for G and 0,2 for A. For genotypes the following were obtained: GG – 0,66, GA – 0,27 and AA – 0,07.It can be noted that the data on the frequencies of alleles and genotypes in the population of Romanov breed sheep differ from the results for the Kulunda fine-wool, Dagestan mountain, Salsk, Lacaune and Merino breeds. The research results can be used to monitor changes in allele frequencies and genotypes in sheep during the selection process.

Genome-Wide Search for Gene Mutations Likely Conferring Insecticide Resistance in the Common Bed Bug, Cimex lectularius.

Insecticide resistance in the bed bug Cimex lectularius is poorly understood due to the lack of genome sequences for resistant strains. In Japan, we identified a resistant strain of C. lectularius that exhibits a higher pyrethroid resistance ratio compared to many previously discovered strains. We sequenced the genomes of the pyrethroid-resistant and susceptible strains using long-read sequencing, resulting in the construction of highly contiguous genomes (N50 of the resistant strain: 2.1 Mb and N50 of the susceptible strain: 1.5 Mb). Gene prediction was performed by BRAKER3, and the functional annotation was performed by the Fanflow4insects workflow. Next, we compared their amino acid sequences to identify gene mutations, identifying 729 mutated transcripts that were specific to the resistant strain. Among them, those defined previously as resistance genes were included. Additionally, enrichment analysis implicated DNA damage response, cell cycle regulation, insulin metabolism, and lysosomes in the development of pyrethroid resistance. Genome editing of these genes can provide insights into the evolution and mechanisms of insecticide resistance. This study expanded the target genes to monitor allele distribution and frequency changes, which will likely contribute to the assessment of resistance levels. These findings highlight the potential of genome-wide approaches to understand insecticide resistance in bed bugs.

Selection on the vascular-remodeling BMPER gene is associated with altitudinal adaptation in an insular lizard

Abstract High altitude imposes several extreme constraints on life, such as low oxygen pressure and high levels of ultraviolet radiation, which require specialized adaptations. Many studies have focused on how endothermic vertebrates respond to these challenging environments, but there is still uncertainty on how ectotherms adapt to these conditions. Here, we used whole-genome sequencing of low-altitude (100–600 m) and high-altitude (3,550 m) populations of the wide-ranging Tenerife lizard Gallotia galloti to uncover signatures of selection for altitudinal adaptation. The studied populations show reduced differentiation, sharing similar patterns of genetic variation. Selective sweep mapping suggests that signatures of adaptation to high altitude are not widespread across the genome, clustering in a relatively small number of genomic regions. One of these regions contains BMPER, a gene involved with vascular remodeling, and that has been associated with hypoxia-induced angiogenic response. By genotyping samples across 2 altitudinal transects, we show that allele frequency changes at this locus are not gradual, but rather show a well-defined shift above ca. 1,900 m. Transcript and protein structure analyses on this gene suggest that putative selection likely acts on noncoding variation. These results underline how low oxygen pressure generates the most consistent selective constraint in high-altitude environments, to which vertebrates with vastly contrasting physiological profiles need to adapt in the context of ongoing climate change.

Rapid phenotypic and genotypic change in a laboratory schistosome population.

Genomic analysis has revealed extensive contamination among laboratory-maintained microbes including malaria parasites, Mycobacterium tuberculosis and Salmonella spp. Here, we provide direct evidence for recent contamination of a laboratory schistosome parasite population, and we investigate its genomic consequences. The Brazilian Schistosoma mansoni population SmBRE has several distinctive phenotypes, showing poor infectivity, reduced sporocysts number, low levels of cercarial shedding and low virulence in the intermediate snail host, and low worm burden and low fecundity in the vertebrate rodent host. In 2021 we observed a rapid change in SmBRE parasite phenotypes, with a~10x increase in cercarial production and ~ 4x increase in worm burden. To determine the underlying genomic cause of these changes, we sequenced pools of SmBRE adults collected during parasite maintenance between 2015 and 2023. We also sequenced another parasite population (SmLE) maintained alongside SmBRE without phenotypic changes. While SmLE allele frequencies remained stable over the eight-year period, we observed sudden changes in allele frequency across the genome in SmBRE between July 2021 and February 2023, consistent with expectations of laboratory contamination. (i) SmLE-specific alleles rose in the SmBRE population from 0 to 41-46% across the genome between September and October 2021, documenting the timing and magnitude of the contamination event. (ii) After contamination, strong selection (s=~ 0.23) drove replacement of low fitness SmBRE with high fitness SmLE alleles. (iii) Allele frequency changed rapidly across the whole genome, except for a region on chromosome 4 where SmBRE alleles remained at high frequency. We were able to detect contamination in this case because SmBRE shows distinctive phenotypes. However, this would likely have been missed with phenotypically similar parasites. These results provide a cautionary tale about the importance of tracking the identity of parasite populations, but also showcase a simple approach to monitor changes within populations using molecular profiling of pooled population samples to characterize fixed single nucleotide polymorphisms. We also show that genetic drift results in continuous change even in the absence of contamination, causing parasites maintained in different labs (or sampled from the same lab at different times) to diverge.

Pervasive findings of directional selection realize the promise of ancient DNA to elucidate human adaptation.

We present a method for detecting evidence of natural selection in ancient DNA time-series data that leverages an opportunity not utilized in previous scans: testing for a consistent trend in allele frequency change over time. By applying this to 8433 West Eurasians who lived over the past 14000 years and 6510 contemporary people, we find an order of magnitude more genome-wide significant signals than previous studies: 347 independent loci with >99% probability of selection. Previous work showed that classic hard sweeps driving advantageous mutations to fixation have been rare over the broad span of human evolution, but in the last ten millennia, many hundreds of alleles have been affected by strong directional selection. Discoveries include an increase from ∼0% to ∼20% in 4000 years for the major risk factor for celiac disease at HLA-DQB1 ; a rise from ∼0% to ∼8% in 6000 years of blood type B; and fluctuating selection at the TYK2 tuberculosis risk allele rising from ∼2% to ∼9% from ∼5500 to ∼3000 years ago before dropping to ∼3%. We identify instances of coordinated selection on alleles affecting the same trait, with the polygenic score today predictive of body fat percentage decreasing by around a standard deviation over ten millennia, consistent with the "Thrifty Gene" hypothesis that a genetic predisposition to store energy during food scarcity became disadvantageous after farming. We also identify selection for combinations of alleles that are today associated with lighter skin color, lower risk for schizophrenia and bipolar disease, slower health decline, and increased measures related to cognitive performance (scores on intelligence tests, household income, and years of schooling). These traits are measured in modern industrialized societies, so what phenotypes were adaptive in the past is unclear. We estimate selection coefficients at 9.9 million variants, enabling study of how Darwinian forces couple to allelic effects and shape the genetic architecture of complex traits.

Prediction of additive genetic variances of descendants for complex families based on Mendelian sampling variances.

The ability to predict the outcome of selection and mating decisions enables breeders to make strategically better selection decisions. To improve genetic progress, those individuals need to be selected whose offspring can be expected to show high genetic variance next to high breeding values. Previously published approaches enable to predict the variance of descendants of 2 future generations for up to 4 founding haplotypes, or 2 outbred individuals, based on phased genotypes, allele effects, and recombination frequencies. The purpose of this study was to develop a general approach for the analytical calculation of the genetic variance in any future generation. The core development is an equation for the prediction of the variance of double haploid lines, under the assumption of no selection and negligible drift, stemming from an arbitrary number of founder haplotypes. This double haploid variance can be decomposed into gametic Mendelian sampling variances (MSVs) of ancestors of the double haploid lines allowing usage for non-double haploid genotypes that enables application in animal breeding programs as well as in plant breeding programs. Together with the breeding values of the founders, the gametic MSV may be used in new selection criteria. We present our idea of such a criterion that describes the genetic level of selected individuals in 4 generations. Since breeding programs do select, the assumption made for predicting variances is clearly violated, which decreases the accuracy of predicted gametic MSV caused by changes in allele frequency and linkage disequilibrium. Despite violating the assumption, we found high predictive correlations of our criterion to the true genetic level that was obtained by means of simulation for the "corn" and "cattle" genome models tested in this study (0.90 and 0.97). In practice, the genotype phases, genetic map, and allele effects all need to be estimated meaning inaccuracies in their estimation will lead to inaccurate variance prediction. Investigation of variance prediction accuracy when input parameters are estimated was not part of this study.

Polygenic prediction of human longevity on the supposition of pervasive pleiotropy

The highly polygenic nature of human longevity renders pleiotropy an indispensable feature of its genetic architecture. Leveraging the genetic correlation between aging-related traits (ARTs), we aimed to model the additive variance in lifespan as a function of the cumulative liability from pleiotropic segregating variants. We tracked allele frequency changes as a function of viability across different age bins and prioritized 34 variants with an immediate implication on lipid metabolism, body mass index (BMI), and cognitive performance, among other traits, revealed by PheWAS analysis in the UK Biobank. Given the highly complex and non-linear interactions between the genetic determinants of longevity, we reasoned that a composite polygenic score would approximate a substantial portion of the variance in lifespan and developed the integrated longevity genetic scores (iLGSs) for distinguishing exceptional survival. We showed that coefficients derived from our ensemble model could potentially reveal an interesting pattern of genomic pleiotropy specific to lifespan. We assessed the predictive performance of our model for distinguishing the enrichment of exceptional longevity among long-lived individuals in two replication cohorts (the Scripps Wellderly cohort and the Medical Genome Reference Bank (MRGB)) and showed that the median lifespan in the highest decile of our composite prognostic index is up to 4.8 years longer. Finally, using the proteomic correlates of iLGS, we identified protein markers associated with exceptional longevity irrespective of chronological age and prioritized drugs with repurposing potentials for gerotherapeutics. Together, our approach demonstrates a promising framework for polygenic modeling of additive liability conferred by ARTs in defining exceptional longevity and assisting the identification of individuals at a higher risk of mortality for targeted lifestyle modifications earlier in life. Furthermore, the proteomic signature associated with iLGS highlights the functional pathway upstream of the PI3K-Akt that can be effectively targeted to slow down aging and extend lifespan.

Continuously fluctuating selection reveals fine granularity of adaptation.

Temporally fluctuating environmental conditions are a ubiquitous feature of natural habitats. Yet, how finely natural populations adaptively track fluctuating selection pressures via shifts in standing genetic variation is unknown1,2. Here we generated genome-wide allele frequency data every 1-2 generations from a genetically diverse population of Drosophila melanogaster in extensively replicated field mesocosms from late June to mid-December (a period of approximately 12 total generations). Adaptation throughout the fundamental ecological phases of population expansion, peak density and collapse was underpinned by extremely rapid, parallel changes in genomic variation across replicates. Yet, the dominant direction of selection fluctuated repeatedly, even within each of these ecological phases. Comparing patterns of change in allele frequency to an independent dataset procured from the same experimental system demonstrated that the targets of selection are predictable across years. In concert, our results reveala fitness relevance of standing variation that is likely to be masked by inference approaches based on static population sampling or insufficiently resolved time-series data. We propose that such fine-scaled, temporally fluctuating selection may be an important force contributing to the maintenance of functional genetic variation in natural populations and an important stochastic force impacting genome-wide patterns of diversity at linked neutral sites, akin to genetic draft.

Rapid phenotypic and genotypic change in a laboratory schistosome population.

Genomic analysis has revealed extensive contamination among laboratory-maintained microbes including malaria parasites, Mycobacterium tuberculosis and Salmonella spp. Here, we provide direct evidence for recent contamination of a laboratory schistosome parasite population, and we investigate its genomic consequences. The Brazilian Schistosoma mansoni population SmBRE has several distinctive phenotypes, showing poor infectivity, reduced sporocysts number, low levels of cercarial shedding and low virulence in the intermediate snail host, and low worm burden and low fecundity in the vertebrate rodent host. In 2021 we observed a rapid change in SmBRE parasite phenotypes, with a ~10x increase in cercarial production and ~4x increase in worm burden. To determine the underlying genomic cause of these changes, we sequenced pools of SmBRE adults collected during parasite maintenance between 2015 and 2023. We also sequenced another parasite population (SmLE) maintained alongside SmBRE without phenotypic changes. While SmLE allele frequencies remained stable over the eight-year period, we observed sudden changes in allele frequency across the genome in SmBRE between July 2021 and February 2023, consistent with expectations of laboratory contamination. (i) SmLE-specific alleles rose in the SmBRE population from 0 to 41-46% across the genome between September and October 2021, documenting the timing and magnitude of the contamination event. (ii) After contamination, strong selection (s = ~0.23) drove replacement of low fitness SmBRE with high fitness SmLE alleles. (iii) Allele frequency changed rapidly across the whole genome, except for a region on chromosome 4 where SmBRE alleles remained at high frequency. We were able to detect contamination in this case because SmBRE shows distinctive phenotypes. However, this would likely have been missed with phenotypically similar parasites. These results provide a cautionary tale about the importance of tracking the identity of parasite populations, but also showcase a simple approach to monitor changes within populations using molecular profiling of pooled population samples to characterize fixed single nucleotide polymorphisms. We also show that genetic drift results in continuous change even in the absence of contamination, causing parasites maintained in different labs (or sampled from the same lab at different times) to diverge.

Canine hyper-sociability structural variants associated with altered three-dimensional chromatin state

Strong selection on complex traits can lead to skewed trait means and reduced trait variability in populations. An example of this phenomenon can be evidenced in allele frequency changes and skewed trait distributions driven by persistent human-directed selective pressures in domesticated species. Dog domestication is linked to several genomic variants; however, the functional impacts of these variants may not always be straightforward when found in non-coding regions of the genome. Four polymorphic transposable elements (TE) found within non-coding sites along a 5 Mb region on canine CFA6 have evolved due to directional selection associated with heightened human-directed hyper-sociability in domesticated dogs. We found that the polymorphic TE in intron 17 of the canine GTF2I gene, which was previously reported to be negatively correlated with canid human-directed hyper-sociability, is associated with altered chromatin looping and hence distinct cis-regulatory landscapes. We reported supporting evidence of an E2F1-DNA binding peak concordant with the altered loop and higher expression of GTF2I exon 18, indicative of alternative splicing. Globally, we discovered differences in pathways regulating the extra-cellular matrix with respect to TE copy number. Overall, we reported evidence suggesting an intriguing molecular convergence between the emergence of hypersocial behaviors in dogs and the same genes that, when hemizygous, produce human Williams Beuren Syndrome characterized by cranio-facial defects and heightened social behaviors. Our results additionally emphasize the often-overlooked potential role of chromatin architecture in social evolution.

RB1 circulating-tumor DNA in the blood of Retinoblastoma patients increases in untreated patients.

Circulating tumor DNA (ctDNA) in plasma has been identified in many cancers, including retinoblastoma at diagnosis. We have previously shown that with treatment (enucleation or ophthalmic artery chemosurgery (OAC)) all ctDNA disappears; and if there is persistent plasma ctDNA after treatment metastases develop. The purpose of this study was to determine how the ctDNA RB1 variant allele frequency (VAF) changes in patients with retinoblastoma who have delayed treatment. Circulating tumor DNA RB1 was detected and VAF was measured at diagnosis and again prior to any intervention at some time later ranging from 2 to 28 days. Four patients with five ctDNA RB1 mutations were detected at diagnosis and VAF was increased on re-evaluation of the same RB1 mutations in ctDNA. In this small cohort, every patient (4) and every RB1 mutation (5) plasma level VAF% increased when measured at two time periods before treatment was instituted suggesting that growing tumors demonstrate increasing plasma ctDNA.

Historical museum samples reveal signals of selection and drift in response to changing insecticide use in an agricultural pest moth.

In response to environmental and human-imposed selective pressures, agroecosystem pests frequently undergo rapid evolution, with some species having a remarkable capacity to rapidly develop pesticide resistance. Temporal sampling of genomic data can comprehensively capture such adaptive changes over time, for example, by elucidating allele frequency shifts in pesticide resistance loci in response to different pesticides. Here, we leveraged museum specimens spanning over a century of collections to generate temporal contrasts between pre- and post-insecticide populations of an agricultural pest moth, Helicoverpa armigera. We used targeted exon sequencing of 254 samples collected across Australia from the pre-1950s (prior to insecticide introduction) to the 1990s, encompassing decades of changing insecticide use. Our sequencing approach focused on genes that are known to be involved in insecticide resistance, environmental sensation, and stress tolerance. We found an overall lack of spatial and temporal population structure change across Australia. In some decades (e.g., 1960s and 1970s), we found a moderate reduction of genetic diversity, implying stochasticity in evolutionary trajectories due to genetic drift. Temporal genome scans showed extensive evidence of selection following insecticide use, although the majority of selected variants were low impact. Finally, alternating trajectories of allele frequency change were suggestive of potential antagonistic pleiotropy. Our results provide new insights into recent evolutionary responses in an agricultural pest and show how temporal contrasts using museum specimens can improve mechanistic understanding of rapid evolution.

Mapping quantitative trait loci for seminal root angle in a selected durum wheat population.

Seminal root angle (SRA) is an important root architectural trait associated with drought adaptation in cereal crops. To date, all attempts to dissect the genetic architecture of SRA in durum wheat (Triticum durum Desf.) have used large association panels or structured mapping populations. Identifying changes in allele frequency generated by selection provides an alternative genetic mapping approach that can increase the power and precision of QTL detection. This study aimed to map quantitative trait loci (QTL) for SRA by genotyping durum lines created through divergent selection using a combination of marker-assisted selection (MAS) for the major SRA QTL (qSRA-6A) and phenotypic selection for SRA over multiple generations. The created 11 lines (BC1F2:5) were genotyped with genome-wide single-nucleotide polymorphism (SNP) markers to map QTL by identifying markers that displayed segregation distortion significantly different from the Mendelian expectation. QTL regions were further assessed in an independent validation population to confirm their associations with SRA. The experiment revealed 14 genomic regions under selection, 12 of which have not previously been reported for SRA. Five regions, including qSRA-6A, were confirmed in the validation population. The genomic regions identified in this study indicate that the genetic control of SRA is more complex than previously anticipated. Our study demonstrates that selection mapping is a powerful approach to complement genome-wide association studies for QTL detection. Moreover, the verification of qSRA-6A in an elite genetic background highlights the potential for MAS, although it is necessary to combine additional QTL to develop new cultivars with extreme SRA phenotypes.

Polygenic selection to a changing optimum under self-fertilisation.

Many traits are polygenic, affected by multiple genetic variants throughout the genome. Selection acting on these traits involves co-ordinated allele-frequency changes at these underlying variants, and this process has been extensively studied in random-mating populations. Yet many species self-fertilise to some degree, which incurs changes to genetic diversity, recombination and genome segregation. These factors cumulatively influence how polygenic selection is realised in nature. Here, we use analytical modelling and stochastic simulations to investigate to what extent self-fertilisation affects polygenic adaptation to a new environment. Our analytical solutions show that while selfing can increase adaptation to an optimum, it incurs linkage disequilibrium that can slow down the initial spread of favoured mutations due to selection interference, and favours the fixation of alleles with opposing trait effects. Simulations show that while selection interference is present, high levels of selfing (at least 90%) aids adaptation to a new optimum, showing a higher long-term fitness. If mutations are pleiotropic then only a few major-effect variants fix along with many neutral hitchhikers, with a transient increase in linkage disequilibrium. These results show potential advantages to self-fertilisation when adapting to a new environment, and how the mating system affects the genetic composition of polygenic selection.