HudsonAlpha Institute for Biotechnology

Aerosol-producing catastrophes like nuclear war or asteroid strikes, though rare, pose serious risks to human survival. The injected aerosols would reduce solar radiation, lower temperatures, and alter precipitation, impacting crop productivity, including for locally adapted traditional crop varieties, i.e. landraces. We assess post-catastrophic climate effects on crops with extensive landrace cultivation, barley, maize, rice, and sorghum, under climate scenarios that differ in the quantity of soot injection. Using a crop growth model, we estimate environmental stress gradients and together with genomic markers apply gradient forest offset methods to predict post-catastrophic maladaptation in landraces over time. We find landraces are most maladapted where soot-induced climate shifts were strongest. Validating our approach, gradient forest models successfully capture a signal of maize landrace adaptation in common gardens across Mexico. We further use our gradient forest models to identify landrace varieties best matched to specific post-catastrophic conditions, indicating potential substitutions for agricultural resilience. The best substituted varieties require long migration distances, often across country borders, though countries with more climatic diversity have better within-country substitutions. Our findings highlight that a soot-producing catastrophe would drive global maladaptation in landraces and suggest current adaptive diversity is insufficient for agricultural resilience.

The thoracic dystrophies are inherited skeletal conditions where abnormal embryonic development of the thoracic skeleton results in a narrow chest, pulmonary hypoplasia, and respiratory insufficiency, which can be severe or lethal. The majority of thoracic dystrophies are due to biallelic alterations in genes needed for normal ciliary function. However, despite the identification of over 20 genes as causal for the thoracic dystrophy phenotype, around 20% of patients remain without a molecular diagnosis. We present two unrelated families with a clinical diagnosis of thoracic dystrophy with associated respiratory insufficiency without a molecular diagnosis on previous genetic testing. Both harbor rare biallelic and predicted deleterious missense substitutions in FGF4, a gene known to be essential for formation of the thoracic skeleton in mice. We demonstrate that the phenotype is restricted to short ribs, abnormally narrow chest, and respiratory insufficiency, without other diagnostic clinical or radiological signs. We suggest that biallelic alterations in FGF4 are a newly identified disease association of thoracic dystrophy.

Estimates of de novo mutation rates are essential for phylogenetic and demographic analyses, but their inference has previously been impeded by high error rates in sequence data and uncertainty in the fossil record. Here, we directly estimate de novo germline mutation rates for all extant members of Panthera, as well as the closely related outgroup Neofelis nebulosa, using pedigrees. We use a previously validated pipeline (RatesTools) to calculate mutation rates for each species and subsequently explore the impacts of the novel rates on historic effective population size estimates in each of these charismatic felids of conservation concern. Importantly, we find that the choice of reference genome, the data type and coverage, and the individual all impact estimates of the mutation rate, but these can be largely ameliorated through extensive manual curation. Despite these stochastic effects, manual validation of de novo mutation candidates permitted the reliable inference of pantherine mutation rates. We inferred that base pair mutation rates for all species fell between 3.6 × 10-9 and 7.6 × 10-9 per generation per base pair (mean 5.5 × 10-9 ± 1.7 × 10-9 across Pantherinae at a mean parental age of 5.5 years). Similar to other studies, we show a positive trend of mean parental age with mutation rate and our inferred rates are well within the expected range for other mammals.

Loss of function variants in the NF1 gene cause neurofibromatosis type 1, a genetic disorder characterized by complete penetrance, characteristic physical exam findings, and a substantially increased risk for malignancy. However, our understanding of the disorder is based on patients ascertained through phenotype-first approaches, which estimate prevalence at 1 in 3000. Leveraging a genotype-first approach in multiple large patient cohorts including over one million individuals, we demonstrate an unexpectedly high prevalence (1 in 1,286) of NF1 pathogenic variants. Half are identified in individuals lacking clinical features of NF1, with many appearing to have post-zygotic mosaicism for the identified variant. Incidentally discovered variants are not associated with classic neurofibromatosis features but are associated with an increased incidence of malignancy compared to control populations. Our findings suggest that NF1 pathogenic variants are substantially more common than previously thought, often characterized by somatic mosaicism and reduced penetrance, and are important contributors to cancer risk in the general population.

Cotton production in the US faces a serious threat from Fusarium oxysporum f. sp. vasinfectum race 4 (FOV4), a soil‐borne fungus causing Fusarium wilt by infecting the roots and vascular system of susceptible cotton, leading to rapid wilting and death. Here, we investigate genetic mechanisms of resistance to FOV4 in the highly resistant upland cotton genotype “U1” using an early‐generation segregating biparental population (“U1” × “CSX8308”) with comprehensive genomic resources. Reference‐grade genomic assemblies of the parents revealed minor structural variations between “U1” haplotypes, a high degree of collinearity at chromosome synteny and micro‐synteny levels, and significant divergence from “CSX8308” with 8.9 million SNPs. QTL analysis identified significant markers on chromosomes D03 and A02 linked to reduced Fusarium wilt severity. Within these regions, two glutamate‐receptor‐like (GLR) genes showed structural variation and overlapped between translocated segments on A02 and D03, suggesting a rare but important reinforcing effect of parallel evolution between susceptible and resistant genotypes. Transcriptome profiles of “U1” under FOV4 infection reveal activation of calcium‐binding proteins and transcription factors regulating plant hormones (ethylene, abscisic acid, jasmonic acid, and salicylic acid), along with enzymes involved in cell wall remodeling and phytoalexin production. Advancing cotton improvement depends on incorporating durable genetic disease resistance into high‐yielding, high‐quality cultivars.

Background Peanut (Arachis hypogaea L.) is a vital global crop, frequently threatened by both abiotic and biotic stresses. Among the most damaging biotic stresses is Tomato spotted wilt virus (TSWV), which causes peanut spotted wilt disease resulting in significant yield loss. Developing TSWV-resistant cultivars is crucial to new cultivar release. Previous studies have used a subset of the “S” recombinant inbred line (RIL) population derived from SunOleic 97R and NC94022 and identified quantitative trait loci (QTLs) for resistance to TSWV. These studies utilized different genotyping techniques and found large consistent genomic regions on chromosome A01. The objective of this study was to fine map the QTL and identify candidate genes using the entire population of 352 RILs and high-density, high-quality peanut SNP arrays. Results We used both versions of the peanut SNP arrays with five years of disease ratings, and successfully mapped the long-sought peanut spotted wilt disease resistance locus, PSWDR-1. QTL analyses identified two major QTLs, explaining 41.43% and 43.69% of the phenotypic variance within 3.6 cM and 0.28 cM intervals using the peanut Axiom_Arachis-v1 and Axiom_Arachis-v2 SNP arrays, respectively, on chromosome A01. These QTLs corresponded to 295 kb and 235 kb physical intervals. The unique overlap region of these two QTLs was 488 kb. A comparison of the genetic linkage map with the reference genome revealed a 1.3 Mb recombination “cold spot” (11.325–12.646 Mb) with only two recombination events of RIL-S1 and RIL-S17, which displayed contrasting phenotypes. Sequencing of these two recombinants confirmed the cold spot with only five SNPs detected within this region. Conclusions This study successfully identified a peanut spotted wilt disease resistance locus, PSWDR-1, on chromosome A01 within a recombination “cold spot”. The PSWDR-1 locus contains three candidate genes, a TIR-NBS-LRR gene (Arahy.1PK53M), a glutamate receptor-like gene (Arahy.RI1BYW), and an MLO-like protein (Arahy.FX71XI). These findings provide a foundation for future functional studies to validate the roles of these candidate genes in resistance and application in breeding TSWV-resistant peanut cultivars.

Common bean (Phaseolus vulgaris L.) market classes have distinct seed coat colors, which are directly related to the diverse flavonoids found in the mature seed coat. To understand and elucidate the molecular mechanisms underlying the regulation of seed coat color, RNA-Seq data was collected from the black bean 5-593 and used for a differential gene expression and enrichment analysis from four different seed coat color development stages. 5-593 carries dominant alleles for 10 of the 11 major genes that control seed coat color and expression and has historically been used to develop introgression lines used for seed coat genetic analysis. Pairwise comparison among the four stages identified 6,294 differentially expressed genes (DEGs) varying from 508 to 5,780 DEGs depending on the compared stages. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that phenylpropanoid biosynthesis, flavonoid biosynthesis, and plant hormone signal transduction comprised the principal pathways expressed during bean seed coat pigment development. Transcriptome analysis suggested that most structural genes for flavonoid biosynthesis and some potential regulatory genes were significantly differentially expressed. Further studies detected 29 DEGs as important candidate genes governing the key enzymatic flavonoid biosynthetic pathways for common bean seed coat color development. Additionally, four gene models, Pv5-593.02G016100, 593.02G078700, Pv5-593.02G090900, and Pv5-593.06G121300, encode MYB-like transcription factor family protein were identified as strong candidate regulatory genes in anthocyanin biosynthesis which could regulate the expression levels of some important structural genes in flavonoid biosynthesis pathway. These findings provide a framework to draw new insights into the molecular networks underlying common bean seed coat pigment development.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease that interferes with the formation of arteries. The ENG gene encodes for the protein endoglin which is used to properly develop and remodel arteries. The removal of endoglin forms telangiectasias that cause bleeding from the nose and vital organs. This study investigates the impact of one of the many variants of uncertain significance of ENG associated with HHT. The missense swap of alanine for valine at position 218 (Ala218Val) was characterized through computational metrics from in silico pathogenicity prediction tools, conservation analysis, and molecular dynamics simulation (MDS). The structural residue is highly conserved over multiple species and buried. The missense swap resulted in a difference in movement from the wild type according to MDS in a simulated aqueous environment. Therefore, it is predicted to be likely pathogenic.

Genomic characterization of Cannabis sativa has accelerated rapidly in the last decade as sequencing costs have decreased and public and private interest in the species has increased. Here, we present seven new chromosome-level haplotype-phased genomes of C. sativa. All of these genotypes were alive at the time of publication, and several have numerous years of associated phenotype data. We performed a k-mer-based pangenome analysis to contextualize these assemblies within over 200 existing assemblies. This allowed us to identify unique haplotypes and genomic diversity among Cannabis sativa genotypes. We leveraged linkage maps constructed from F2 progeny of two of the assembled genotypes to characterize the recombination rate across the genome showing strong periphery-biased recombination. Lastly, we re-aligned a bulk segregant analysis dataset for the major-effect flowering locus Early1 to several of the new assemblies to evaluate the impact of reference bias on the mapping results and narrow the locus to a smaller region of the chromosome. These new assemblies, combined with the continued propagation of the genotypes, will contribute to the growing body of genomic resources for C. sativa to accelerate future research efforts.

The strong correlation between reproductive life cycle type and chromosome numbers in green plants has been a long‐standing mystery in evolutionary biology. Within green plants, the derived condition of heterosporous reproduction has emerged from the ancestral condition of homospory in disparate locations on the phylogenetic tree at least 11 times, of which three lineages are extant. In all green plant lineages where heterospory has emerged, there has been a significant downsizing in chromosome numbers. This dynamic has been investigated without clear answers for many decades. In this study, we combine known ideas from existing literature with novel methods, tools, and data to generate fresh insights into an old question. Using gene family evolution models and selection analyses, we identified gene families that have undergone significant expansion, contraction, or selection in heterosporous lineages. Alongside lineage‐specific genomic changes, our results revealed shared genomic changes/trends among heterosporous lineages. We found expansions in gene families related to developmental regulation, signaling pathways, and stress responses across heterosporous groups. Notably, the MATE efflux family showed consistent expansion and evidence of selection in heterosporous lineages, suggesting a potentially conserved role in heterospory evolution. These findings could provide novel avenues to investigate and probe the underlying mechanism that may underpin the association between heterospory and genomic changes. The general importance of chromosome numbers, structure, and sizes in cellular biology notwithstanding, the association between the emergence of heterosporous reproduction and chromosome number reduction/genome downsizing is not fully understood. It remains unclear why there exists an association between aspects of biology at such disparate levels as reproductive life cycles and chromosome numbers/genome size. Exploring and answering this conundrum of evolutionary biology can add to our broader understanding of life sciences and of biology at different levels. Applying the novel tools and methods emerging from ongoing progress in biotechnology and computational sciences presents an opportunity to make new inroads into this long‐standing question.

Bipolar disorder is a leading contributor to the global burden of disease¹. Despite high heritability (60–80%), the majority of the underlying genetic determinants remain unknown². We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings³, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder⁴, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

Background Predicting Alzheimer's disease (AD) and frontotemporal dementia (FTD) using polygenic risk scores (PRS) for late‐onset forms holds promise, but its accuracy might be influenced by social determinants of health (SDOH). This study explores how considering SDOH alongside genes can improve prediction, focusing on potential differences for each disease. Methods Employing logistic regression in 677 individuals (287 AD, 102 FTD, and 288 controls) aged 40‐80 from the ReDLat study across six Latin American countries, we investigated the potential for SDOH to modify the association between PRS and susceptibility to AD and FTD. Analyses were adjusted for a probabilistic score derived from models comparing disease groups to controls with SDOH data (education, occupation, economic stability, healthcare access and quality, and social context) and APOE ε4 carrier status to account for confounding effects. Results Although univariate association tests revealed robust links between PRS and both diseases, adjusted models presented a nuanced picture. In AD, the SDOH score and APOE ε4 carrier status significantly attenuated the PRS effect (p=0.14), suggesting these factors modify genetic risk. In FTD, however, SDOH did not influence the PRS contribution. These findings highlight the potentially distinct roles of social factors in different neurodegenerative pathways. Conclusion The significant modification of PRS effects in AD by SDOH and APOE ε4 underscores the need for comprehensive approaches in future research and interventions in Latin America. Conversely, the unaltered PRS contribution in FTD emphasizes distinct intricacies in gene‐environment interactions. These findings necessitate considering both realms in future efforts, paving the way for targeted strategies in AD and FTD prevention and treatment.

Background Most research initiatives have emerged from high‐income countries (HIC), leaving a gap in understanding the disease’s genetic basis in diverse populations like those in Latin American countries (LAC). ReDLat tackles this gap, focusing on LAC’s unique genetics and socioeconomic factors to identify specific Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) risk factors in Mexico, Colombia, Peru, Chile, Argentina, and Brazil. Method We employed a comprehensive genetic analysis approach, integrating Whole Genome Sequencing (WGS), Exome Sequencing, and SNP arrays to understand the cohort’s unique genetic architecture. We conducted ancestry analysis and searched for disease‐causing variants with mendelian inheritance, genome‐wide association studies (GWAS), rare variant enrichment, and evaluation of Polygenic Risk Scores (PRS). Results We recruited and genotyped an initial cohort of 1046 participants with AD, 423 with FTD, and 855 healthy controls (HC) between 2020 and 2023. Analysis is ongoing, and we expect to sequence ∼600 additional samples in the coming months. Ancestry analysis revealed tri‐continental admixture, except for Brazil, which showed an additional Asian component (Figure 1). Top candidate gene rare variant enrichment associations (SKAT p < 0.05) were TREM2 for FTD and ABCA7 and ABCA1 for AD. GWAS identified a robust association with the APOE locus on chromosome 19 in AD vs. HC.. We tested an AD PRS developed in European populations by Bellenguez et al (2020). on our cohort using 83 single‐nucleotide polymorphisms.. The PRS modestly distinguishes between all patients and HC (p = 2.4 × 10^‐12), AD vs. HC (p = 2.2 × 10^‐12), and even FTD vs. HC (p = 4.3 × 10^‐5), albeit with modest separation between groups, as expected for its application in a genetically admixed population. Conclusion Our findings represent a pivotal step in understanding the genetic landscape of AD and FTD in admixed populations. They underscore the importance of including diverse populations in genetic research, paving the way for future studies. These findings have the potential to inform more personalized approaches to the diagnosis and treatment of neurodegenerative diseases in diverse global populations, as well as identify novel targets for therapeutic development.

Plants are an important source of food, energy, and bioproducts. Advances in genetics, genomics-assisted breeding, and biotechnology have facilitated the combining of desirable traits into elite cultivars. To ensure sustainable crop production in the face of climate challenges and population growth, it is essential to develop and implement techniques that increase crop yield and resilience in environments facing water scarcity, nutrient deficiencies, and other abiotic and biotic stressors. Plant transformation and genome editing are critical tools in the development of new cultivars. Here, we discuss recent advances in plant transformation technologies aimed at enhancing efficiency, throughput, and the number of transformable genotypes. These advancements include the use of morphogenic regulators, virus-mediated genetic modifications, and in planta transformation with Rhizobium rhizogenes.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder representing a wide spectrum of phenotypes, ranging from isolated thoracic aortic aneurysm or dissection to a more severe syndromic presentation with multisystemic involvement. Significant clinical variability has been noted for both related and unrelated individuals with the same pathogenic variant. We report a family of five affected individuals with notable phenotypic variability who appear to have two distinct molecular causes of LDS, one attributable to a missense variant in TGFBR2 and the other an intronic variant 6 bp upstream from a splice junction in TGFB2. We tested the functional impacts of the variant identified in the proband alongside other variants in the region reported in ClinVar using a splice reporter system, which resulted in non-canonical splicing products for several variants including the proband. Molecular validation of the splicing products suggests that the TGFB2 variants tested impact splicing by reducing efficiency of the canonical acceptor in favor of an alternate acceptor within the exon. These data combined with clinical phenotypes and segregation of the variant with disease support the conclusion that this intronic TGFB2 variant may cause LDS in this patient and her mother. These analyses demonstrate that underappreciated intronic variants that alter splicing can be relevant for clinical phenotypes of connective tissue disease. This case highlights the importance of prompt familial cascade testing, clinical evaluation with detailed dysmorphology exam, comprehensive genetic testing, and collaboration between clinicians and scientists to characterize variants of uncertain significance to properly assess risk in LDS patients.

Pharmacogenomics is central to precision medicine, informing medication safety and efficacy. Pharmacogenomic diplotyping of complex genes requires full-length DNA sequences and detection of structural rearrangements. We introduce StarPhase, a tool that leverages PacBio HiFi sequence data to diplotype 21 CPIC Level A pharmacogenes and provides detailed haplotypes and supporting visualizations for HLA-A, HLA-B, and CYP2D6. StarPhase diplotypes have high concordance with benchmarks where 99.5% are either exact matches or minor discrepancies. Manual inspection of the 0.5% mismatches indicates they were correctly called by StarPhase. With StarPhase, we update or correct 26.2% of GeT-RM pharmacogenomic diplotypes. Population distributions from StarPhase mostly reflect those of the All of Us cohort, while also highlighting gaps in existing pharmacogenomic databases that long-read sequencing can fill. With a single HiFi whole genome sequencing assay, StarPhase enables robust PGx diplotyping even as additional pharmacogenes and haplotypes are discovered.