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Results for “founder effect”

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PubMed2014

Serial founder effects and genetic differentiation during worldwide range expansion of monarch butterflies.

Range expansions can result in founder effects, increasing genetic differentiation between expanding populations and reducing genetic diversity along the expansion front. However, few studies have addressed these effects in long-distance migratory species, for which high dispersal ability might counter the effects of genetic drift. Monarchs (Danaus plexippus) are best known for undertaking a long-distance annual migration in North America, but have also dispersed around the world to form populations that do not migrate or travel only short distances. Here, we used microsatellite markers to assess genetic differentiation among 18 monarch populations and to determine worldwide colonization routes. Our results indicate that North American monarch populations connected by land show limited differentiation, probably because of the monarch's ability to migrate long distances. Conversely, we found high genetic differentiation between populations separated by large bodies of water. Moreover, we show evidence for serial founder effects across the Pacific, suggesting stepwise dispersal from a North American origin. These findings demonstrate that genetic drift played a major role in shaping allele frequencies and created genetic differentiation among newly formed populations. Thus, range expansion can give rise to genetic differentiation and declines in genetic diversity, even in highly mobile species.

Animal Distribution↗

PubMed2025

Combined Evidence Reveals the Origin of a Rapid Range Expansion Despite Retained Genetic Diversity and a Weak Founder Effect.

Many species are currently experiencing range shifts in response to changing environmental conditions with potentially serious genetic consequences. Repeated founder events and strong genetic drift are expected to erode genetic variation at the range front, reducing adaptive potential and slowing or even halting the expansion. However, the severity of these consequences for common and highly mobile species undergoing environment-driven range shifts (c.f. invasions) is less clear. Here, we combined historical observations and contemporary movement data of the common reed warbler (Acrocephalus scirpaceus) with genomic evidence from across its European breeding range to (1) infer the origin and (2) quantify the genetic consequences of a recent and rapid northward range expansion. Although there were no reductions in levels of nucleotide diversity or allelic richness, nor a signal of founder effect in the directionality index (ψ), our combined dataset approach was able to infer an expansion origin from the southwest. Furthermore, we found that private allelic richness retained a slight but significant linear decline along the colonisation route. These results suggest that high dispersal capabilities can allow even philopatric species to avoid the loss of genetic diversity during rapid range expansions. Nevertheless, if multiple lines of evidence enable identification of an expansion pathway, we may still detect genetic signals of expansion.

Founder Effect↗

PubMed2026

Genetic Ancestry and Carrier Variant Frequency Enrichment in a Colombian Andean Population: Insights From the Eje Cafetero.

Colombia is one of the most genetically diverse populations in Latin America, and its demographic process has promoted the persistence and local enrichment of deleterious alleles, increasing the frequency of autosomal recessive disorders, particularly in semi-isolated Andean populations such as the Eje Cafetero. However, exome-based reference data from this region remain scarce, limiting ancestry-aware variant interpretation and carrier screening strategies. We aimed to characterize the ancestry proportions of this population using exome data, and to estimate the carrier frequency and distribution of pathogenic and likely pathogenic (P/LP) variants in clinically relevant recessive genes. We conducted a cross-sectional study with whole-exome sequencing (WES) in 316 unrelated individuals from the Colombian Eje Cafetero. P/LP variants were evaluated in 454 genes associated with autosomal recessive disorders. The global ancestry proportions were estimated using a validated panel of 250 exome-compatible ancestry-informative markers. Carrier frequencies were compared against Non-Finnish Europeans (NFE) and Admixed Americans (AMX) from gnomAD v4. The cohort showed predominant European ancestry (mean 51%), followed by Native American (36%) and African (13%) components. We identified 151 carriers of 89 distinct pathogenic variants across autosomal recessive genes. The most frequent variants were SERPINA1 c.863A>T (5.5%), CFTR c.1210-11T>G (3.5%), and PYGM c.1094C>T (1.5%). Also, recurrent variants were significantly enriched compared with both NFE and AMX populations, supporting regional founder effects. This study represents one of the most comprehensive exome-based genetic characterizations of the Colombian Eje Cafetero, revealing ancestry-specific enrichment of clinically relevant autosomal recessive variants driven by founder effects.

Female↗

PubMed2026

Analysis of APC promoter 1B deletions in Russian families with familial adenomatous polyposis.

OBJECTIVE: Familial adenomatous polyposis (FAP) is a severe autosomal dominant hereditary cancer syndrome. Patients develop hundreds of adenomatous polyps throughout the colon with the risk of colorectal cancer, if untreated, approaching 100%. FAP is caused by pathogenic germline variants in the APC gene. Deletions in the APC 1B promoter cause FAP in a small subgroup of patients. Previous studies suggested that the APC promoter deletions in unrelated FAP patients from the US and Italy are identical and may thus have spread from a single founder. The aim of this study was to investigate whether a similar founder effect can be detected in the Russian population. PATIENTS AND METHODS: We performed whole-genome sequencing on five unrelated patients (three males and two females) with extensive (over 100) colon polyps, family history of FAP, and germline APC 1B promoter deletions previously detected by the multiplex ligation-dependent probe amplification (MLPA) and detected precise deletion boundaries. RESULTS: The patients carried deletions in the APC 1B promoter ranging from ~3 to ~122 kbp. We found no association between the deletion size and either the age of the onset or severity of the disease. All deletions were unique and no identical deletion boundaries were observed. However, in four patients, the right deletion breakpoints fell into a 1 kbp region downstream of the 1B promoter. The right breakpoints of several deletions detected in FAP patients from other countries also fell into this narrow region. CONCLUSION: The APC 1B promoter deletions analyzed in this study had arisen independently and there is thus no evidence of a founder effect. Therefore, at least for the cohort of FAP patients with APC 1B promoter deletions studied here, WGS did not provide an added diagnostic benefit to MLPA aside from precisely determining the deletion breakpoints.

APC promoter 1B deletion↗

PubMed2026

Effect of founder breeds on genotype imputation accuracy in Canchim cattle.

UNLABELLED: Genotype imputation is a technique used to infer unobserved genotypes based on reference panels, allowing increased marker density and cost-effective optimization for genomic selection. This study aimed to evaluate whether the inclusion of genotypes from the founder breeds Nelore (NE) and Charolais (CH) improves the imputation accuracy in the composite beef cattle breed Canchim (CA). The populations studied consisted of 804 NE, 897 CH, and 392 CA animals, all genotyped using high-density panels (777,962 SNP – single nucleotide polymorphisms). CA animals had their genotypes masked to simulate a medium-density panel (54,609 SNP). Fourteen imputation scenarios were evaluated, varying according to breed, sex, year of birth, and lineage. Imputation accuracy was determined based on the percentage of correctly imputed genotypes (PERC) and the squared Pearson’s correlation between observed and imputed genotypes (R2). PERC values ranged from 66.52% to 97.39% and R² from 0.6352 to 0.9780. The scenarios that included NE, CH, and CA (males or animals born before 2004) as the reference population for imputing CA females or CA animals born after 2004 showed the highest imputation accuracies. Therefore, the use of founder breeds in the reference population improves the accuracy of genotype imputation in CA cattle. The results indicate that a multibreed reference population, incorporating founder breeds, could provide a more robust and informative genetic basis for imputing composite cattle. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13353-026-01060-z.

Animal breeding↗

PubMed2025

Cancer spectrum in Mexican patients with the CHEK2 p.(Leu236Pro) variant: a retrospective study.

This study aimed to characterize, for the first time, the cancer spectrum associated with the most frequent pathogenic CHEK2 variant-NM_007194.4(CHEK2):c.707T > C p.(Leu236Pro)-in Mexican individuals. Although this variant is frequently detected through multi-gene panel testing, limited data on its associated cancer risks complicates genetic counseling and surveillance strategies. We retrospectively analyzed 5,759 patients who underwent multi-gene panel testing between August 2015 and August 2024 due to suspected hereditary cancer syndromes. Among them, 58 CHEK2 p.(Leu236Pro) carriers with confirmed cancer diagnoses were identified. Geographical clustering was observed, with 81% of patients originating from central Mexico, suggesting a possible founder effect. Ten distinct clinical indications for genetic testing were identified, with hereditary breast and ovarian cancer (HBOC) syndrome being the most common (74.1%). The mean age at first diagnosis among carriers was 43.8 ± 12 years, and 61.1% of them reported a family history of cancer in first- or second-degree relatives. A second or third primary cancer occurred in 20.7% of cases. Tumors were identified in 12 anatomical sites. Breast cancer predominated (67.6%, including one male case), followed by ovarian (8.1%), prostate (6.7%), gastric (4.1%), thyroid (2.7%), and endometrial (2.7%) cancers. Lymphoma, lung, sacrococcygeal bone, colorectal, and non-melanoma skin cancers each occurred in a single patient. Significant risk association was identified only for breast, ovarian, and gastric cancers. These results highlight the need for personalized surveillance, especially for breast cancer. Incorporating CHEK2 p.(Leu236Pro) into clinical decision-making tools may enhance risk assessment in the Mexican population, but larger studies are needed to refine risk estimates and to clarify the possible founder effect.

Humans↗

PubMed2025

Conservation Arks: Genomic Erosion and Inbreeding in an Abundant Island Population of Koalas.

The persistence of many threatened species depends on isolated habitat patches such as conservation parks, fenced reserves, and islands. While these 'conservation arks' provide refuge from many contemporary threats, they can also pose risks of genetic diversity loss and inbreeding depression, further exacerbating extinction risk. A pertinent example is the Kangaroo Island koala population in South Australia that originated from a few translocated founding individuals in the 1920s but now sustains a large population with a low prevalence of infectious disease. We investigated the extent and consequences of founder effects on genomic diversity, inbreeding, and adaptive potential in Kangaroo Island koalas by comparing them with mainland Australian populations using high-coverage whole genomes. Our findings support sharp, recent declines in effective population sizes (Ne) in both mainland and Kangaroo Island populations. However, Kangaroo Island koalas had much lower individual and population-level diversity. Together with longer and more numerous runs of homozygosity and an increased proportion of homozygous genetic load, these results support the hypothesis that a severe bottleneck has contributed to inbreeding and maladaptation in Kangaroo Island koalas. While Kangaroo Island has the potential to conserve a viable population of koalas, we recommend genetic rescue to restore diversity and mitigate inbreeding depression in this isolated population. Our results emphasise the need for longitudinal genomic monitoring and genetic management to maintain long-term viability and resilience in potential conservation arks. Understanding the demographic history of such populations will help inform future conservation aimed at preventing genetic erosion and preserving biodiversity.

Animals↗

PubMed2026

Genetic structure and selection signatures of Beijing-You chicken populations provide insight into breed conservation.

Preserving genetic diversity and maintaining population viability are critical yet challenging goals that demand rigorous evaluation of conservation strategies. Beijing-You chicken, as the sole indigenous chicken breed originating from Beijing, China, is currently maintained as four independent populations under distinct conservation programs. How different conservation regimes have shaped its genomic architecture remains largely unknown, limiting evidence-based evaluation. Here, we generated whole-genome resequencing data from 240 individuals representing four Beijing-You chicken populations to assess population structure, genetic diversity, and signatures of selection over decades of conservation. All four populations formed distinct clusters, reflecting measurable differentiation after decades of separate conservation. The differences in genetic diversity were broadly consistent with the variation in effective population size estimates. Runs of homozygosity and linkage disequilibrium decay patterns further characterized each population, with extended values indicating reduced effective population size and increased inbreeding under long-term conservation. We applied the fixation index (FST) and pairwise diversity ratio (θπ) methods to identify selection signatures. A total of 171 genes were identified as candidates. These genes were enriched in pathways related to reproduction, growth regulation, and environmental adaptation. These findings highlight patterns of reduced diversity and skewed relatedness, which could arise from management-related factors such as breeding preferences or mating strategies. Still, they are also compatible with neutral processes, including drift and founder effects. Regardless of the underlying cause, integrating scientifically informed conservation strategies with routine genomic monitoring across generations is essential for sustaining genetic diversity in Beijing-You chicken and other indigenous breeds.

Beijing-You chicken↗

PubMed2025

Insights into the heterogeneity of oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is a rare, adult-onset, autosomal dominant myopathy characterized by variability in the age of onset and disease progression. However, its pathogenesis and phenotypic variability remain poorly understood. The disorder is caused by an expansion of a short polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1) gene. This study presents data from 23 patients across 19 Greek families with pathogenic PABPN1 expansions, including demographic and laboratory data, as well as molecular and electron microscopy findings. Eight distinct trinucleotide expansion genotypes were identified. Electron microscopy consistently demonstrated mitochondrial abnormalities, including swelling, disrupted cristae and atypical lipid inclusions. Clinical heterogeneity was observed at both inter- and intrafamilial levels, and milder phenotypes were generally linked to smaller alleles. Notably, maternally inherited expansions were associated with an earlier disease onset and more severe progression in affected offspring. Given the genetic variability observed in the cohort, the presence of a founder effect could not be supported. A significant degree of underdiagnosis or diagnostic delay was noted, largely attributable to the rarity and clinical heterogeneity of the disease. The observed intrafamilial heterogeneity - particularly in maternally inherited expansions - supports previous reports suggesting that mitochondrial dysfunction may contribute to transgenerational disease progression in the context of a dominant, causative nuclear variant.

Humans↗

PubMed2026

WWOX-related developmental and epileptic encephalopathy (WOREE): A case series of seven patients from Argentina.

PURPOSE: WWOX-related developmental and epileptic encephalopathy (WOREE) is a rare autosomal recessive disorder caused by biallelic pathogenic WWOX variants, characterized by very early-onset epilepsy, profound developmental delay, and progressive brain abnormalities. Detailed electroclinical descriptions remain limited. METHODS: We conducted a retrospective study of seven patients with pathogenic/likely pathogenic WWOX variants. Clinical features, seizure evolution, EEG findings, brain MRI, and genetic data were reviewed. Epilepsy syndromes were classified according to International League against Epilepsy (ILAE) criteria. Variants were identified through next-generation sequencing and interpreted following American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Median seizure onset was 3 months (range 2-6). Five patients presented with focal seizures evolving to infantile epileptic spasms syndrome (IESS), while two had IESS at onset. Epilepsy was drug-resistant in all. Developmental delay was evident from birth with generalized hypotonia, acquired microcephaly, and impaired visual attention. Four patients had dysmorphic features. During the IESS period, EEG showed hypsarrhythmia in six patients and a severely disorganized encephalopathic background that did not strictly fulfill the criteria for hypsarrhythmia in one. Brain MRI revealed abnormalities in all patients, including frontotemporal atrophy and corpus callosum hypoplasia; delayed myelination was observed in one case. Eight pathogenic/likely pathogenic WWOX variants were found; including one novel variant (NM_016373.4:c.571C>T, p.(Gln191*)). The recurrent splice-site variant NM_016373.4:c.107+1G>A was identified in five patients, suggesting a possible regional founder effect. CONCLUSION: WOREE shows a recognizable electroclinical and neuroimaging profile with early drug-resistant epilepsy and profound developmental delay. Recognition of this pattern may facilitate early diagnosis and targeted genetic testing, particularly in populations with recurrent variants.

Developmental and epileptic encephalopathy↗

PubMed2025

Founder Homozygous Nonsense CREB3 Variant and Variable-Onset Retinal Degeneration.

IMPORTANCE: Uncovering the genetic basis of inherited retinal diseases (IRDs) can enhance both diagnostic accuracy and the development of targeted treatment strategies. OBJECTIVE: To evaluate the association between a homozygous nonsense variant in CREB3 with IRDs. DESIGN, SETTING, AND PARTICIPANTS: Thirteen patients with a clinical diagnosis of retinitis pigmentosa or cone-rod degeneration were analyzed by whole-genome sequencing (WGS) and whole-exome sequencing (WES). Clinically, patients presented with 2 main phenotypes, rod-cone and cone-rod dystrophies, demonstrating variable electrophysiological and fundoscopic findings. Expression analysis was performed on patient-derived skin fibroblasts using the reverse transcription-polymerase chain reaction and Western blot analysis, and by interrogating previously published retinal single-cell RNA sequence data. Immunohistochemistry staining was performed on wild-type mouse retinal sections using an anti-CREB3 antibody. Patients with variable phenotypes of IRDs were recruited from 3 medical centers in Israel and Italy. Ophthalmologists clinically diagnosed patients at the relevant medical centers and referred them for genetic screening. WES and WGS were performed at different national and international centers, and the findings of the previously unreported gene were shared between investigators. EXPOSURES: CREB3 and IRDs. MAIN OUTCOMES AND MEASURES: The main outcome was evidence supporting an association between CREB3 and IRD. Measures included WES, WGS, and immunohistochemistry staining. RESULTS: A founder homozygous nonsense variant in CREB3 (c.881G>A, p.Trp294*) was identified in 13 patients from 4 unrelated families; 12 descendent from North-African Jewish origins and 1 from Italian origins. All patients manifested retinal degeneration with varying ages at onset. In patient-derived fibroblasts, the variant mRNA transcript generated a truncated CREB3 protein. Expression analysis and immunohistochemistry staining revealed CREB3 RNA and protein expression in various retinal cell types, indicating its vital role in photoreceptor function. CONCLUSIONS AND RELEVANCE: This study found an association between CREB3 and IRDs. CREB3 was previously shown to be upregulated following ultraviolet radiation. This might contribute to the extensive clinical variability observed in this relatively large cohort of homozygous patients with the same truncated variant.

Humans↗

PubMed2025

A founder variant in TBCB is associated with global developmental delay, autism spectrum, and spastic paraparesis.

PURPOSE: Hereditary spastic paraparesis (HSP) is a genetically diverse group of Mendelian disorders characterized by length-dependent axonal degeneration. Microtubule dysfunction is a known mechanism in HSP that impairs axonal dynamics. TBCB encodes tubulin-folding cofactor B (TBCB), which, along with TBCE, regulates αβ-heterodimer dynamics and neuronal axonal growth. Here, we describe a new form of complicated HSP caused by a founder variant in TBCB. METHODS: Exome sequencing revealed a homozygous c.589T>A p.(Tyr197Asn) variant in TBCB in a cohort of 10 individuals assembled through genematching tools. Protein function was assessed using Saccharomyces cerevisiae ortholog ALF1, and a CRISPR-Cas9-generated homologous mutant in Drosophila melanogaster. TBCB expression and localization were examined in fibroblasts using western blot and immunofluorescence. RESULTS: Participants displayed late-childhood-onset spastic paraparesis, global developmental delay, and autism spectrum. TBCB protein levels were reduced in affected fibroblasts. The ALF1 mutant in yeast increased benomyl sensitivity, resembling a loss-of-function phenotype. In Drosophila melanogaster, the homologous mutant led to reduced survival and impaired climbing ability. CONCLUSION: We describe a novel neurodevelopmental disorder with spastic paraparesis and a high carrier rate in the Ashkenazi Jewish population. Our results indicate that TBCB has a vital role in the development of central nervous system and potentially in axonal function in humans.

Humans↗

PubMed2026

Screening for dual sgRNAs with comparable indel efficiencies enhances CRISPR-mediated large-fragment deletion.

CRISPR-mediated large-fragment deletion provides a powerful approach for gene clusters, noncoding regions and structural variants, but its broader application is limited by low and variable deletion efficiency. Here, we systematically designed and evaluated 78 sgRNAs targeting nine representative gene clusters (ttn.1-ttn.2 cluster, 7 hox clusters and nppb-nppa cluster), containing 31 large fragments (5 kb-340 kb) to investigate the determinants of deletion efficiency. We found two key rules for achieving high deletion efficiency: (i) using dual sgRNAs with similar indel efficiencies, and (ii) applying a single sgRNA pair rather than multiple sgRNAs. Based on those rules, a 340 kb deletion is detected in the progenies of 95% of founders. Whereas the deletion size showed no significant linear correlation with deletion efficiency within the tested range. Implementing these rules resulted in an average of 70% of founders transmitting deletions across all tested sgRNA pairs. Therefore, screening sgRNAs can effectively enhance CRISPR utility in deletions, thereby facilitating the application of genomic manipulation in vertebrates and other species.

CRISPR↗

PubMed2026

Mapping genetic modifiers of epimutation rates identifies VIM2/4 as dosage-sensitive negative regulators of CG methylation maintenance.

Spontaneous epimutations are stochastic gains and losses of cytosine methylation that arise from imperfect maintenance across cell divisions. At CG sites, such epimutations can be inherited across generations in plants and constitute a major source of CG methylation (mCG) diversity. However, why the fidelity of mCG inheritance varies among genotypes, and how this variation relates to steady-state mCG levels, remains poorly understood. Here we tracked DNA methylation over 10 generations in ~400 mutation-accumulation lines derived from ~70 Arabidopsis thaliana Ler × Cvi recombinant inbred founders. By treating methylation gain and loss rates as quantitative molecular traits, we mapped a major-effect locus to a Cvi-derived deletion between VARIANT IN METHYLATION (VIM)2 and VIM4, two key components of the METHYLTRANSFERASE 1-dependent mCG maintenance pathway. Lines carrying this deletion showed elevated VIM2/4 (VIM2 and VIM4) expression, a rapid shift of genome-wide mCG towards a lower steady state and reduced fidelity of methylation inheritance across generations. Complementary overexpression and loss-of-function experiments identify VIM2/4 as dosage-sensitive negative regulators of mCG maintenance, in contrast to the canonical positive role of VIM-family proteins in mCG. Together, our results support a punctuated-equilibrium model of DNA methylome evolution, in which naturally segregating modifiers of mCG homeostasis can produce abrupt shifts in methylation state and alter the rate at which heritable epigenetic variation accumulates in plant genomes.

Journal Article↗

PubMed2026

XXYLT1 and Mendelian Retinal Dystrophy.

IMPORTANCE: Substantial unexplained heritability remains for pathogenic inherited retinal disease (IRD) variants. Application of genome-wide association studies (GWAS) could help identify causal genes in rare diseases. OBJECTIVE: To leverage a GWAS for the discovery of IRD-associated genes. DESIGN, SETTING, AND PARTICIPANTS: This GWAS analysis was combined with replication of findings in 2 independent IRD cohorts. The study was conducted from January 2024 to December 2025 in a multicenter setting through FinnGen, 100 000 Genomes Project, and the National Health Service Genomic Medicine Service combined with clinical cohort from the Oulu University Hospital. Using IRD criteria from the International Classification of Diseases, 9th and 10th Revisions, 540 individuals with IRD and 473 945 control individuals were identified in the FinnGen study. For validation of FinnGen results, 49 patients were recruited from Oulu University Hospital. Results were further validated in 2 individuals identified from the UK cohort. MAIN OUTCOMES AND MEASURES: The GWAS and proteomics analysis were performed in the FinnGen cohort. Sanger and whole-genome sequencing and RNA approaches were used in a clinical IRD cohort to validate pathogenicity of the identified XXYLT1 variant. RESULTS: This GWAS identified 13 recessive loci reaching genome-wide significance (defined as P < 5 × 10-8). Of these, 4 (near or within XXYLT1, ANKRD10, DYM, and CBLN4) had not been associated with IRD, including the XXYLT1 c.505-1G>C founder variant. This variant was further genotyped in the clinical replication cohort, leading to identification of 5 more homozygous individuals from 4 families. The phenotype was consistent with a cone-rod or macular dystrophy, with visual deterioration, cystoid macular edema and/or schisislike macular abnormalities. The effect of the XXYLT1 c.505-1G>C variant was further investigated using RNA sequencing and complementary DNA amplicon sequencing, demonstrating exon 2 skipping and a loss-of-function effect. These findings were replicated in an independent population identifying 2 patients from the UK harboring a homozygous XXYLT1 c.766G>A, p.(Glu256Lys) missense variant. CONCLUSIONS AND RELEVANCE: This GWAS identified an association between XXYLT1 and IRD. These results affirm that GWAS in a founder population can be used as a potential tool for the discovery of rare mendelian disease genes and that XXYLT1 should be considered in clinical IRD gene panels.

Humans↗

PubMed2026

Pervasive context-dependent effects in the genetic architecture of complex and quantitative traits revealed by a powerful multiparent mapping population in yeast.

The genetic dissection of complex traits remains a major challenge in basic and biomedical research, but is essential for understanding the molecular pathways that shape phenotypic variation and for developing predictive models of trait and disease susceptibility. Here, we leverage a novel multiparent mapping population of budding yeast, CYClones, comprising 9,344 haploid strains derived from eight genetically diverse founders (~270,000 SNVs, ~ 1 per 44 bp, capturing 56% of common variants and 32% of all variants with a minor allele frequency greater than 0.005 in the global population), to identify quantitative trait loci (QTL) and systematically investigate the genetic architecture of growth rates across ten environmental conditions. In total, we identified 349 QTL (ranging from 18 to 49 QTL per growth condition) that explained between 60% and 100% of narrow sense heritability across traits. The high power and resolution of CYClones revealed that growth traits exhibited distinct, condition-specific genetic architectures with extensive allelic heterogeneity, where a QTL was the result of multiple tightly linked causal variants. We also observed pleiotropy among QTL with complex, trait-dependent allele effects that are also consistent with allelic heterogeneity. Genetic complexity varied widely, with some traits showing nearly Mendelian architectures, while others were highly polygenic. Introgressed loci played a prominent role in the landscape of growth rate QTL, including a QTL localized to a 2.4 kb interval in the PCA1 cadmium transporter that explains 72% of variation in cadmium resistance and is largely driven by an introgression, and a non-additive interaction between the GAL3 regulator and introgressed GAL1/7/10 alleles, extending a previously described three-locus GAL-pathway incompatibility to a four-locus interaction. In both cadmium and galactose conditions, we show that allelic variation at a small number of loci stratifies the population into regulatory or physiological subgroups, each with distinct genetic architectures, a specific manifestation of epistasis we term allele-dependent stratification. Collectively, our results provide novel insights into the genetics of growth rates in budding yeast, the architectural features of genetic complexity, and demonstrate that CYClones is a powerful platform for revealing the molecular basis of complex trait variation.

Quantitative Trait Loci↗

PubMed2025

The CTDP1 Founder Variant in CCFDN: Insights into Pathogenesis, Phenotypic Spectrum and Therapeutic Approaches.

Congenital Cataracts, Facial Dysmorphism, and Neuropathy (CCFDN) syndrome is a rare autosomal recessive disorder predominantly found among Vlax Roma populations, caused by a deep intronic founder variant in the CTDP1 gene. This review synthesizes recent advances in understanding the molecular mechanisms of CTDP1 dysfunction, highlighting its central role in transcriptional regulation, RNA splicing, DNA repair, and genome integrity. The unique splicing defect caused by the founder disease-causing variant in the Roma population results in a multisystem phenotype with early-onset neuropathy, congenital cataracts, and characteristic facial dysmorphism. Beyond its genetic homogeneity, CCFDN displays variable clinical severity and presents diagnostic challenges due to overlapping syndromic features. We discuss the emerging therapeutic landscape, focusing on antisense oligonucleotides, small molecule modulators, gene replacement, and genome or transcriptome editing strategies, while emphasizing the challenges in targeted delivery and efficacy. Ongoing insights into CTDP1's broader biological functions and population genetics inform new directions for diagnosis, genetic counselling, and the development of effective therapies for this severe yet underrecognized disorder.

Humans↗

PubMed2026

Safe and Stable Germline Transmission of MSTN Mutations in Cattle.

With the global population expected to reach 10 billion by 2050, sustainable livestock production is critical. Gene editing of the myostatin (MSTN) gene represents a promising strategy to enhance muscle growth in cattle. In this study, MSTN-mutated founder (F0) cows were used to generate F1 offspring via ovum pick-up, in vitro fertilization, and embryo transfer. Four F1 calves were born, all confirmed to be heterozygous for the MSTN mutation. Long-term monitoring showed normal growth and no visible health abnormalities. Whole-genome sequencing identified SNPs, INDELs, and structural variants, most with minimal predicted functional effects. Proteomic profiling of Longissimus dorsi muscle quantified 2947 proteins, revealing only subtle expression differences between MSTN-mutated and wild-type cattle. These results demonstrate stable inheritance and confirm that MSTN editing does not disrupt genome integrity or protein expression. Overall, our findings support the safety and utility of MSTN gene editing to improve livestock productivity for future food security.

Animals↗