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Results for “mutation load”

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PubMed2026

Sexual selection purges mutation load, but not overall genetic diversity, decreasing vulnerability to extinction.

Theory suggests sexual selection will enhance population viability by purging deleterious alleles. However, direct genomic evidence for this fundamental idea is scarce and contradictory. We combined long-term experimental evolution with whole-genome resequencing to directly test how sexual selection affects mutation load, genomic divergence, and extinction risk in small populations (maximum Ne = 40) of Tribolium castaneum. After 156 generations, populations evolving under strong sexual selection carried substantially fewer deleterious alleles than populations under weak sexual selection, based on both individual-level estimates of missense and nonsense variants and population-level Rxy analyses, indicating more efficient purging of deleterious alleles. In contrast, nucleotide diversity and runs of homozygosity were similar across treatments, indicating that purging acted most strongly on deleterious variation, and that reduced mutation load in these small populations under strong sexual selection was not explained by demographic effects. Importantly, population-level mutation load estimates best explained extinction risk under inbreeding, directly linking sexual selection to purging and population viability. Genome scans of high and low sexual selection populations revealed peaks of divergence, which included genes involved in courtship, sex discrimination, and seminal fluid proteins. Our results provide direct genomic evidence that sexual selection can reduce mutation load without eroding standing genetic diversity and thus adaptive potential, while driving adaptive divergence in reproductive traits. This beneficial purging may help explain the widespread prevalence of sexual reproduction in nature despite inherent costs and have important ramifications as to how we manage populations of conservation concern.

Animals↗

PubMed2026

Large-scale simulation of coverage and error rate tradeoffs for cancer detection in cell-free DNA whole-genome sequencing.

MOTIVATION: Cell-free DNA (cfDNA) whole-genome sequencing (WGS) is a promising approach for detecting cancer recurrence. It enables cancer detection by identifying all tumor-derived cfDNA (ctDNA) molecules carrying somatic single nucleotide variants (sSNVs). While ideally, a sequencing platform should be highly accurate for reliable ctDNA detection, in reality, all sequencing platforms introduce sequencing errors that generate false positives indistinguishable from true SNVs. Understanding how sequencing parameters influence ctDNA detection sensitivity at low tumor fractions (TFs) in cfDNA samples is essential for guiding sequencing strategies in clinical contexts. To model cfDNA sequencing for tumor detection, which contains asymmetric noise and multiple interacting parameters, analytical modeling is intractable, motivating large-scale parallelized simulation. RESULTS: We developed a simulation framework to generate in silico cfDNA data across 10 cancer types. In total, 480 million cfDNA samples were simulated from tumor WGS profiles. Overall, the lowest detectable TF differs substantially between cancer types under identical sequencing conditions due to variations in mutational load. For cancers with high mutational load, 3× coverage with low-error techniques reliably detects TFs below 0.1%. In contrast, cancers with low mutational load require at least six-fold higher coverage to achieve comparable detection thresholds. Increasing sequencing quality scores from Q30 to Q55 at 30× coverage further enhances sensitivity, enabling detection of TFs as low as 1 × 10-5. This study provides a comprehensive framework for optimizing sequencing parameters, offering valuable guidance for tailoring future technology development for specific cancer types and clinical applications. AVAILABILITY AND IMPLEMENTATION: The code is publicly available at https://github.com/UMCUGenetics/cfdetect/tree/main.

Whole Genome Sequencing↗

PubMed1979

'Our load of mutation': reappraisal of an old problem.

H. J. Muller, in a paper in 1950 entitled 'Our load of mutation', predicted the genetic decay of the human species due to increasing mutation pressure combined with relaxation of natural selection. In the meantime, much information on spontaneous and induced mutations in humans has been accumulated, and a reappraisal of Muller's conclusions gives a much less gloomy overall picture. However, a certain increase of malformation and disease can be predicted as a result of ionizing radiation and chemical mutagens. On the other hand, genetic counselling and antenatal diagnosis of genetic anomalies may help to keep the genetic risks within tolerable limits. Research on the biological conditions for the untoward effects of mutagenic chemicals considered necessary for the wellbeing of humans may also help to reduce genetic risks. The extent and kind of the risks as well as possibilities for prevention are discussed with a few examples.

Animals↗

PubMed2025

Bistable Mutation-Selection Equilibria and Violations of Fisher's Theorem in Tetraploids: Insights from Nonlinear Dynamics.

Polyploidy and whole genome duplication (WGD) are widespread biological phenomena with substantial cellular, meiotic, and genetic effects. Despite their prevalence and significance across the tree of life, population genetics theory for polyploids is not well developed. The lack of theoretical models limits our understanding of polyploid evolution and restricts our ability to harness polyploidy for crop improvement amidst increasing environmental stress. To address this gap, we developed and analyzed deterministic models of mutation-selection balance for tetraploids under polysomic (autotetraploid) and disomic (allotetraploid) inheritance patterns and arbitrary dominance relationships. We also introduced a new mathematical framework based on ordinary differential equations and nonlinear dynamics for analyzing the models. We find that autotetraploids approach Hardy-Weinberg Equilibrium 33% faster than allotetraploids, but the different tetraploid inheritance models show little differences in mutation load and allele frequency at mutation-selection balance. Our model also reveals two bistable points of mutation-selection balance for dominant alleles with biased mutation rates over a wide range of selection coefficients in the tetraploid models compared to bistability in only a narrow range for diploids. Finally, using discrete time simulations, we explore the temporal dynamics of allele frequency and fitness change and compare these dynamics to the predictions of Fisher's Fundamental Theorem of Natural Selection. While Fisher's predictions generally hold, we show that the bistable dynamics for dominant mutations fundamentally alter the associated temporal dynamics. Overall, this work develops foundational theoretical models that will facilitate the development of population genetic models and methodologies to study evolution in empirical tetraploid populations.

Fisher’s Fundamental Theorem↗

PubMed2025

Stochastic epigenetic mutation profiles as biomarkers of clinical activity in juvenile idiopathic arthritis: a multi-omic machine learning approach for gene prioritization.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a rare autoimmune disease arising from a complex interplay between genetic and environmental factors. Epigenetic modifications such as DNA methylation (DNAm) have been described as potential mediators in gene-environment interactions, contributing to immune system dysregulation. Emerging evidence suggests that DNAm profiles also predict therapeutic responses in autoimmune diseases. This study aims to identify epigenetic biomarkers and epigenetic-driven gene expression changes associated with JIA clinical activity. METHODS: We reanalyzed a publicly available dataset of 44 JIA patients, with whole-genome DNAm and gene expression from CD4 + T cells measured at two points: at anti-TNF therapy withdrawal (T0) and eight months later (Tend). At Tend, 30 patients maintained inactive disease (ID) while 14 did not (NO ID). We investigated differences between ID and NO ID patients in the epigenetic mutation load and various epigenetic clocks through linear regression models, and prioritized genomic regions with significantly higher number of epimutations in NO ID patients through machine learning. RESULTS: We found a higher mutation load in NO ID than ID patients, both at T0 and at Tend, with the differences at Tend reaching statistical significance (p = 0.02). In contrast, we found no evidence of association between epigenetic clocks and JIA clinical activity. Using a multi-omic approach, we identified a List of candidate epigenetically-driven differentially expressed genes, 80 up-regulated and 77 down-regulated, in NO ID patients. Finally, comparing our candidate gene list with the Connectivity Map database, we identified new candidate potential therapeutic targets. Key findings were validated in independent datasets: DNAm profiles from CD4 + T cells (56 JIA patients, 57 controls) and transcriptomic data from PBMCs of JIA patients with active or inactive disease, confirming dysregulation of pathways such as TNF-α signaling via NF-kB and TGF-β signaling among others. CONCLUSIONS: We described a significant association of epigenetic mutations with JIA clinical activity, indicating that epigenetic changes might precede clinical symptoms and may serve as biomarkers for early disease monitoring. Further, our results shed light on biomolecular mechanisms of JIA, supporting the development of more effective treatments.

Humans↗

PubMed1979

Presidential address. Our load of mutations and its burden of disease.

Explore the source record for details and available documents.

Congenital Abnormalities↗

PubMed2026

Hepatitis B virus genome mutations in precore and basal core promoter regions among HBeAg-negative chronic hepatitis B patients with high viral load in Indonesia.

Hepatitis B e antigen (HBeAg) is widely used as a marker for active HBV replication and serves as a surrogate for HBV DNA > 200,000 IU/mL to determine eligibility for tenofovir disoproxil fumarate (TDF) prophylaxis to prevent vertical transmission, according to WHO guidelines. However, some HBeAg-negative patients still harbor high viral loads. Mutations in the precore (PC) and basal core promoter (BCP) regions may reduce or abolish HBeAg expression without necessarily suppressing viral replication. Next-generation sequencing (NGS)-based characterization of these mutations remains limited in Indonesia. This study aimed to analyze the mutation prevalence in the BCP and PC regions associated with HBeAg negativity in Indonesian patients. We conducted a cross-sectional study of 32 chronic HBV treatment-naïve, unvaccinated patients with HBV DNA > 200,000 IU/mL (16 HBeAg-negative, 16 HBeAg-positive) at Cipto Mangunkusumo General Hospital. BCP and PC mutations were analyzed using NGS, classifying mutations as major (mutation frequency index [MFI] ≥20%) or minor (MFI 1- < 20%). Associations were analyzed using the Chi-square or Fisher's exact test and p-values were adjusted using the Benjamini-Hochberg procedure. Among 29 major mutation sites, PC mutations A1846T/C and G1896A were more frequent in HBeAg-negative than HBeAg-positive patients (81.3% vs 6.3% and 75.0% vs 12.5%, respectively; all adjusted p = 0.019). Combined analysis showed higher mutation frequencies in HBeAg-negative patients (93.8%, 81.3%, and 62.5% for A1846T/C, G1896A, and G1899A, respectively; all adjusted p = 0.015). In conclusion, HBeAg-negative patients with high viral loads are strongly associated with PC mutations, particularly G1896A, A1846T/C, and G1899A. These exploratory findings provide regional NGS-based molecular evidence that established PC mutations may contribute to the coexistence of HBeAg negativity and continued high-level HBV replication in Indonesian patients. Larger studies incorporating broader virological and clinical comparison groups are required to determine the clinical significance of these findings.

Humans↗

PubMed2024

Genetic linkage disequilibrium of deleterious mutations in threatened mammals.

The impact of negative selection against deleterious mutations in endangered species remains underexplored. Recent studies have measured mutation load by comparing the accumulation of deleterious mutations, however, this method is most effective when comparing within and between populations of phylogenetically closely related species. Here, we introduced new statistics, LDcor, and its standardized form nLDcor, which allows us to detect and compare global linkage disequilibrium of deleterious mutations across species using unphased genotypes. These statistics measure averaged pairwise standardized covariance and standardize mutation differences based on the standard deviation of alleles to reflect selection intensity. We then examined selection strength in the genomes of seven mammals. Tigers exhibited an over-dispersion of deleterious mutations, while gorillas, giant pandas, and golden snub-nosed monkeys displayed negative linkage disequilibrium. Furthermore, the distribution of deleterious mutations in threatened mammals did not reveal consistent trends. Our results indicate that these newly developed statistics could help us understand the genetic burden of threatened species.

Animals↗

PubMed2025

Temporal Genomics Reveal a Century of Genomic Diversity Shifts Across a Biodiversity Hotspot Avian Assemblage.

Biodiversity has experienced tremendous shifts in community, species, and genetic diversity during the Anthropocene. Understanding temporal diversity shifts is especially critical in biodiversity hotspots, i.e., regions that are exceptionally biodiverse and threatened. Here, we use museomics and temporal genomics approaches to quantify temporal shifts in genomic diversity in an assemblage of eight generalist highland bird species from the Ethiopian Highlands (part of the Eastern Afromontane Biodiversity Hotspot). With genomic data from contemporary and historical samples, we demonstrate an assemblage-wide trend of increased genomic diversity through time, potentially due to improved habitat connectivity within highland regions. Genomic diversity shifts in these generalist species contrast with general trends of genomic diversity declines in specialist or imperiled species. In addition to genetic diversity shifts, we found an assemblage-wide trend of decreased realized mutational load, indicative of overall trends for potentially deleterious variation to be masked or selectively purged. Across this avian assemblage, we also show that shifts in population genomic structure are idiosyncratic, with species-specific trends. These results are in contrast with other charismatic and imperiled African taxa that have largely shown strong increases in population genetic structure over the recent past. This study highlights that not all taxa respond the same to environmental change, and generalists, in some cases, may even respond positively. Future comparative conservation genomics assessments on species groups or assemblages with varied natural history characteristics would help us better understand how diverse taxa respond to anthropogenic landscape changes.

Animals↗

PubMed2025

Reproductive Isolation due to Divergent Ecological Selection Is Accompanied by Vast Genomic Instability in Experimentally Evolved Yeast Populations.

Populations evolving independently in divergent environments accumulate genetic differences and potentially evolve reproductive isolation as a by-product of divergence. The speed and mechanisms underlying this process are difficult to investigate because we rarely get the opportunity to witness them in natural settings, and histories of selection and gene flow between populations are often unknown. Here, we experimentally evolved yeast for 1000 generations of evolution in both divergent and parallel environments. At regular time points during experimental evolution, we made crosses between parallel- and divergent-evolving populations to measure postzygotic reproductive isolation (gamete viability). We used whole genome population sequencing to determine the mutational load, the number and types of structural variation, and other genomic features of the parent, F1 and F2 intraspecific hybrids. We found evidence for large-scale phenotypic and genome-wide differentiation in response to divergent laboratory selection. Divergent-selected populations produced hybrids with reduced gamete viability-a classic signature of postzygotic reproductive isolation in the form of hybrid breakdown. Parallel-selected populations, on the other hand, remained more reproductively compatible (with exceptions). We found that F2 hybrid genomes contained vast genomic instability, that is, new structural variants (especially insertions, deletions and interchromosomal translocations) that were not observed in parent and F1 genomes, which is likely a result of chromosome missegregation and recombination errors in hybrid meiosis. Our results provide phenotypic and genomic evidence that partial reproductive isolation evolved due to adaptation to divergent environments, consistent with predictions of ecological speciation theory.

Reproductive Isolation↗

PubMed2026

RNF43 Mutations Are Associated With the Classical Molecular Subtype, Vigorous Antitumor Immune Responses, and Prolonged Survival in Pancreatic Adenocarcinoma.

RNF43 mutations were correlated with microsatellite status in colorectal cancer and with fewer and later recurrences in pancreatic ductal adenocarcinoma (PDAC). Here, we undertake a detailed assessment of RNF43 mutations in PDAC. A total of 313 PDACs (308 microsatellite stable [MSS] and 5 microsatellite-instable [MSI] cases) underwent next-generation sequencing (Oncomine Tumor Mutation Load assay; Thermo Fisher). Spatial analyses (NanoString) classified PDACs according to their transcriptomic and proteomic immune signaling. Fluorescent imaging was used to define spatial compartments (tumor: pancytokeratin+/CD45- and leukocytes: pancytokeratin-/CD45+). Each of 20 PDACs with RNF43 mutations (RNF43mut) and without RNF43 mutations (RNF43wt) underwent multiplex immunofluorescence analysis to determine immune status. A total of 153 PDACs (22 RNF43mut and 131 RNF43wt cases) underwent bulk RNA sequencing to assign into molecular subtypes. Overall, 24 RNF43 mutations were identified (22 MSS PDACs and 2 MSI PDACs). The incidence of RNF43 mutations in MSS PDACs (7.1%) was consistent with The Cancer Genome Atlas (6.7%). However, RNF43 mutations were more frequent among MSI PDACs (40%). Additionally, RNF43mut had differential frequencies of other mutations (including Wnt pathway genes), higher tumor mutational burden values (5.5 mut/mb vs 1.67 mut/mb; P < .01), and significantly longer overall survival (47 vs 18 months; P < .0001) than RNF43wt. Moreover, RNF43mut exhibited significantly higher densities of CD8+ T lymphocytes, dendritic cells, and B lymphocytes (P < .001) and an upregulation of ITGAX, CD11c, CD8, and HLA-DR compared with RNF43wt. Patients with RNF43mut PDACs were more often of the classical molecular subtype (20/22, 90.9%). RNF43mut PDACs showed high tumor mutational burden values, suggesting increased neoantigen load coupled with an abundance of antigen-presenting immune cells and an upregulation of immune determinants promoting antigen presentation. All this contributes to stronger antitumor immune responses and improved clinical outcomes.

Humans↗

PubMed2026

Motif-centered analyses reveal universal and tissue-specific mutagenic mechanisms operating in the human body.

Somatic mutations are inevitable in human genomes and can lead to cancer initiation and tumor progression. Although many mutagenic processes have been linked to cancer, their activities in normal tissues before malignant transformation remain poorly characterized. Here, we analyzed the mutation profiles of 10,625 normal samples across 25 tissues obtained from whole-genome and whole-exome sequencing datasets. We applied stringent statistical hypothesis for detecting enrichment and enrichment-adjusted Minimal Estimate of Mutation Load in trinucleotide motifs preferred by known mutagenic processes. We found several cancer-associated mutational motifs in cancer-free tissues. Samples enriched with C→T mutations in nCg motif associated with clock-like spontaneous meCpG deamination were detected across all tissues. We also identified a second clock-like motif, T→C substitutions in aTn motif associated with exposure to small epoxides and other SN2 electrophiles, in several tissues. Motifs associated with other environmental and chemical mutagens showed sporadic and tissue-specific mutagenesis. APOBEC-induced C→T and C→G mutations in tCw motif were enriched in bladder, lung, small intestine, liver, and breast with preference for APOBEC3A-like mutagenesis in most tissues. Together, our analyses elucidated several cancer-associated mutagenic processes in normal tissues and provided a robust analytical framework for quantifying mutagenic activities from somatic mutation catalogs.

Humans↗

PubMed1978

Screening aquatic ecosystems for mutagens with fern bioassays.

Recent researches on the royal fern, Osmunda regalis, have documented a high incidence of post-zygotic mutational damage in a population growing in a river heavily polluted with paper processing wastes, whereas genetic studies of nearby populations in nonpolluted environments failed to detect mutational damage. Intensive genetic and cytogenetic studies of mutation in O. regalis indicates that natural populations of homosporous ferns may be useful in situ bioassay systems for monitoring the presence of mutagens in aquatic ecosystems. Since these organisms are long-lived perennials with an ontogenetic system which stores mutational damage, they can be manipulated to give an integrated estimate of mutational damage for specified blocks of time (in units of years). Thus, the fern bioassay may be an inexpensive means of detecting both chronic low dose and episodic high dose inputs of mutagenic pollutants into aquatic ecosystems. The fern mutagen bioassay is based upon the detection of numerous categories of post-zygotic mutation load in natural fern populations. The frequency of sporophytic and embryonic lethals, leaf or root mutations, auxotrophic gametophytic mutations as well as numerous phenotypic alterations of gametophyte morphology can be routinely detected and quantified. In addition, various two-break chromosome aberrations (paracentric inversions, reciprocal translocations and ring chromosomes) can be readily screened for in the spore mother cells of many homosporous ferns.

Biological Assay↗

PubMed2026

Motif-Centered Analyses Reveal Universal and Tissue-Specific Mutagenic Mechanisms Operating in the Human Body.

Somatic mutations are inevitable in human genomes and can lead to tumorigenesis, yet baseline mutagenesis in non-cancerous normal cells remain poorly understood. Here, we analyzed the mutation profiles of 11,949 normal samples across 25 tissues obtained from whole-genome and whole-exome sequencing datasets. We applied stringent statistical hypothesis for detecting enrichment and enrichment-adjusted Minimal Estimate of Mutation Load (MEML) in trinucleotide motifs preferred by known mutagenic processes. We found several cancer-associated mutational motifs in cancer-free tissues. Samples enriched with C→T mutations in nCg motif associated with clock-like spontaneous meCpG deamination were detected across all tissues. We revealed another clock-like motif, T→C substitutions in aTn motif associated with exposure to small epoxides and other SN2 electrophiles, in several tissues. Donors with several non-cancerous diseases showed significantly higher, age-independent, and concordant accumulation of aTn and nCg motifs compared to healthy donors. Motifs associated with chemical exposures showed sporadic, tissue and disease-specific mutagenesis. APOBEC-induced C→T and C→G mutations in tCw motif were enriched in bladder, lung, small intestine, liver, and breast with preference for APOBEC3A-like mutagenesis in most. Together, our analyses elucidated several ongoing mutagenic processes in normal human tissues and provided a robust analytical framework for identifying mutagenic sources from somatic mutation catalogues.

Journal Article↗

PubMed2025

A transient mutational burst occurs during yeast colony development.

Characterizing the contribution of mutators to mutation accumulation is essential for understanding cellular adaptation and diseases like cancer. By measuring single and double mutation rates, including point mutations, segmental duplications, and reciprocal translocations, we found that wild-type yeast colonies exhibit double mutation rates up to 17 times higher than expected from experimentally determined single mutation rates. These double mutants retained wild-type mutation rates, indicating they originated from genetically normal cells that transiently expressed a mutator phenotype. Numerical simulations suggest that transient mutator subpopulations likely consist of less than a few thousand cells, and experience high-intensity mutational bursts for less than five generations. Most double mutations accumulated sequentially across cell cycles, with simultaneous acquisition being rare and likely linked to systemic genomic instability. Additionally, we explored the genetic control of transient hypermutation and found that the excess of double mutants can be modulated by replication stress and the DNA damage tolerance pathway. Our findings suggest that transient mutators play a significant role in genomic instability and contribute to the mutational load accumulating in growing isogenic populations.

Saccharomyces cerevisiae↗

PubMed2025

Experimental Test of Evolutionary Safety of a CRISPR-Cas9 Gene-Drive Element.

CRISPR-Cas9 gene drives (CCGDs) are powerful tools for genetic control of wild populations, with applications from disease eradication to species conservation. However, Cas9 alone and in a complex with gRNA can cause double-stranded DNA breaks at off-target sites, which could increase the mutational load and lead to unintended loss-of-heterozygosity (LOH) events. These undesired effects raise potential concerns about the long-term evolutionary safety of CCGDs, but the magnitude of these effects is unknown. To measure how the presence of a CCGD or a Cas9 alone in the genome affects the rates of LOH events and de novo mutations, we carried out a mutation accumulation experiment in yeast Saccharomyces cerevisiae. We found no detectable effects on the genome-wide rates of mutations or LOH events. Our power calculations suggest that CCGD or Cas9 affect these rates by less than 30%, which is much less than natural variation for these traits in yeast. A more detailed examination shows that CCGD or Cas9 may alter the lengths and genomic distributions of LOH events, but the statistical support for these effects is weak. Thus, our results demonstrate that CCGDs impose at most a weak additional mutational burden in the yeast model. Although mutagenic effects of gene drives need to be further evaluated in other systems, our results add credence to the proposition that the evolutionary risks posed by well designed gene drives are likely acceptable.

Journal Article↗

PubMed1975

Human genetic studies in areas of high natural radiation. VIII. Genetic load not related to radiation.

The genetic load disclosed by inbreeding has been analyzed in a multiple regression model for a population involving several localities in the state of Espírito Santo, Brazil. The inbreeding load has been estimated for number of pregnancies, abortions, stillbirths, children born alive, anomalies in general, sex ratio, infant mortality, post-infant mortality, and sterility and infertility of the couple. There was no evidence of either maternal or paternal inbreeding effects on the variables analyzed. The effect of inbreeding of the zygote was significant only for anomalies in general (B = 2.29 +/- 0.45) and infant mortality (B = 3.19 +/- 1.39). The latter result must be accepted with caution because of the many environmental causes affecting infant mortality. The B/A ratio suggested a predominantly mutational load for anomalies in general (B/A = 25), but with respect to infant mortality (B/A = 6), the ratio is regarded as an underestimate because of the environmental contribution to A and therefore not supportive of the segregational interpretation.

Abnormalities, Radiation-Induced↗

PubMed2025

Comparative genomic analysis of Acer tsinglingense and A. davidii provides insights into nervonic acid biosynthesis, population evolution and genome vulnerability of endangered A. tsinglingense.

Global biodiversity is facing threats from climate change, habitat fragmentation, and anthropogenic activities-pressures that particularly endanger endemic and narrowly distributed species. In this study, the high-quality chromosome-level genomes of two ecologically divergent maples were assembled: the endangered and range-restricted Acer tsinglingense (791.40 Mb) and its widespread congener Acer davidii (1291.99 Mb). Phylogenomic analysis indicates that the two species diverged ~16.3 million years ago, with A. tsinglingense showing notable gene family expansions in secondary metabolite pathways. Notably, the 3-ketoacyl-CoA synthase gene family, which is involved in nervonic acid biosynthesis, underwent significant expansion and tandem duplication in A. tsinglingense, exhibiting high expression in buds. Population genomic analysis revealed that, compared with the widely distributed A. davidii, A. tsinglingense possesses lower genetic diversity, higher harmful mutation load, and signatures of a severe population bottleneck during the Late Pleistocene. Genome-environment association analysis further identified climate-adaptive genomic variations linked to five key environmental factors and projected potential genomic offsets under future climate scenarios. The southern lineage of A. tsinglingense exhibited greater climate sensitivity and genomic vulnerability under strong selective pressures, underscoring its importance as a conservation priority. Our research reveals that metabolic specializations in A. tsinglingense (such as the synthesis of nervonic acid) may confer competitive advantages in specific habitats. However, factors including its restricted distribution, historical population bottlenecks, and accumulated genetic load severely constrain its evolutionary potential to cope with rapid climate change. These findings emphasize the importance of elucidating the genomic basis and mechanisms of endangerment in metabolically specialized and threatened plant species to inform effective conservation strategies.

Genome, Plant↗