Biology subjects

Jang, Y.

Publications and source records attributed to Jang, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Expanding the therapeutic window of bacteria for cancer therapy

Engineered bacteria enable self-amplifying therapeutic delivery and immune activation, yet these same features drive systemic toxicity and off-target growth. Here, we create a "tumorobe" that overcomes these limitations by integrating reduced immunogenicity, tumour-restricted growth, and enhanced payload release. Specifically, we identify lipopolysaccharide modifications that reduce immunogenicity while preserving fitness, restrict growth to tumours using a hypoxia-lactate "AND" gate, and enhance extracellular payload release via lipoprotein deletion. This strain expands the maximum tolerated dose in a route-dependent manner by up to 1,000-fold. Across multiple murine models, including colorectal cancer and glioblastoma, the strain drives robust antitumour efficacy as both a standalone therapeutic and an immunotherapeutic delivery platform, achieving durable complete responses in up to 75% of colorectal tumours when armed with a cytokine payload. Together, these results establish a broadly applicable platform for safe and effective bacterial cancer therapy.

synthetic biology↗

bioRxiv2026

Regulatory T cells establish an IL-10-IL10R immunometabolic checkpoint that limits HSL activation and lipolysis

Adipose tissue harbors a significant population of regulatory T (Treg) cells that enforce immune homeostasis, yet whether Tregs function as an immunometabolic checkpoint to directly regulate core adipocyte signaling programs remains incompletely defined. Here we show that adipose Tregs function as a dominant, time-dependent checkpoint on {beta}-adrenergic signal-driven lipolytic program and signal transduction in adipocytes. Our integrated scRNA-seq, flow cytometry, and phosphoproteomics data show that prolonged adrenergic stimulation induces a progressive attenuation of activation of key lipase hormone-sensitive lipase (HSL) that coincides with Treg depletion in circulation and accumulation within white adipose tissue. Genetic perturbations establish Treg-derived interleukin-10 (IL-10) as the key mediator of this brake. IL-10 signaling through adipocyte IL-10R suppresses adrenergic HSL activation and rewires downstream signaling nodes that govern catecholamine responsiveness, lipolysis, and systemic energy homeostasis. Mechanistically, IL-10R engages a STAT3-dependent transcriptional program that induces the G-protein regulators RGS2 and RGS3, diminished PKA flux to HSL that reinforces suppression of the HSL activation state and lipolysis. Together, these findings define an adrenergic-immune feedback circuit in which Tregs fine tune the amplitude and duration of catecholamine responsiveness in adipocytes, establishing immune control of a core lipolytic pathway with implications for obesity-associated adipose dysfunction.

cell biology↗

bioRxiv2026

Tetherin enforces an immunometabolic checkpoint that coordinates glycolytic and interferon signaling in adipocytes

Coordination between innate immune signaling and glucose metabolism is fundamental to organismal homeostasis, yet despite decades of study linking immunity and metabolism, the mechanisms by which metabolic cells restrain antiviral innate signaling while preserving glycolytic competence during overnutrition remain poorly defined. Here we identify Tetherin (BST2) as a unique cell-intrinsic immunometabolic checkpoint that couples restraint of type I interferon (IFN-I) signaling to preservation of glycolytic capacity in adipocytes. Tetherin localizes to endoplasmic reticulum and organizes an interactome enriched for antiviral sensing regulators and glycolytic control nodes in adipocytes. Mechanistically, Tetherin directly engages the ubiquitin-dependent degradation machinery NDFIP1 and RNF128 to terminate IRF3 activation, thereby limiting pro-inflammatory, anti-glycolytic signaling and protecting adipocytes from metabolic dysfunction. In parallel, multiomics integration reveals that Tetherin also acts as a scaffold that binds and spatially organizes and activates PFKFB3 to increase glycolytic capacity and restrain MAVS-IRF3 innate immune signalling. In vivo, adipocyte-specific loss of Tetherin amplifies high sucrose diet and high-fat-diet-induced glucose intolerance and liver steatosis, whereas overexpression of human Tetherin in adipocyte suppresses obesity-driven interferon signaling, restores glycolytic pathway, and improves metabolic homeostasis. Orthogonal perturbations in cancer and insulinoma cells further confirm an immunometabolic role for Tetherin. Together, these findings define Tetherin as a dual node immunometabolic checkpoint that couples restraint of antiviral innate inflammatory signaling to maintenance of glycolytic competence, thereby safeguarding adipocyte metabolic homeostasis.

cell biology↗

bioRxiv2026

Rapid functional classification of cardiac genetic variants directly informs precision cardiology

Large-scale clinical genome sequencing yields vast numbers of variants of unknown significance (VUSs). The high frequency of VUSs and the paucity of platforms to characterize their functional impact pose significant challenges for clinical decision making. Here, we present an integrated end-to-end platform, REVi-SCOPE (Rapid evaluation of variants in single cells by optogenetics and prime editing), for characterization of the impact of VUSs on cardiac physiology. Our strategy consists of (1) introduction of variants directly into wild-type (WT) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) via prime editing; (2) optogenetic assessment of calcium and membrane voltage dynamics in single hiPSC-CMs within the pool of edited and unedited cells; and (3) in situ single-cell genotyping of the phenotyped hiPSC-CMs with single-allele resolution. By optimizing and integrating each of these steps, we created a platform that enables VUS characterization in 10 days. We validated the REVi-SCOPEs capabilities by analyzing the properties of established arrhythmogenic variants. We then used REVi-SCOPE to reveal the functional impact of a VUS, TRPM4A320V, identified in a child with a conduction block. Together, our results show that REVi-SCOPE enables functional characterization of VUSs linked to cardiac arrhythmias with unprecedented throughput.

bioengineering↗

bioRxiv2026

Somatic mutation landscape revealed by non-invasive iPSC derivation from urine cells

Somatic mutations that arise post-zygotically create genetic diversity among normal human cells and provide key insights into human development and aging. Fibroblast-derived induced pluripotent stem cells (iPSCs) have proved to be a useful system for disease modelling; however, due to their clonal nature, iPSC lines carry somatic mutations inherited from the founder cells, raising concerns about their genomic integrity. At the same time, this clonality enables single-cell-level discovery of somatic mutations and the reconstruction of developmental lineages. In living individuals, though, this approach requires invasive biopsies and is limited to skin-derived lineages. Here, we generated 33 urine-derived iPSC lines from four males representing two father- son relationships, performed shallow whole-genome sequencing of the lines and analyzed somatic mutations. Derived iPSCs representing single cells from urine carried a few hundred of somatic single-nucleotide variants per genome, dominated by endogenous, clock-like mutational signatures and lacking environmental imprints such as UV-associated mutations. Copy-number analysis identified somatic CNVs in most of the lines and revealed higher CNV burdens in fathers than in sons, consistent with age-related structural mosaicism. Shared mutations across lines enabled reconstruction of cell lineage phylogenetic trees. In summary, urine-derived iPSCs showed genomic alterations comparable to those in fibroblast-derived iPSC lines and represent a valuable non-invasive alternative for disease modeling. Overall, this study provides the first genome-wide characterization of somatic mutations in urine-derived iPSCs and establishes them as a practical and non-invasive platform for charting somatic mutation landscapes and tracing developmental lineages in living humans.

genomics↗

bioRxiv2026

Janus kinase 2 regulates Nurr1 protein stability in dopaminergic neurons of the aging midbrain

The nuclear receptor Nurr1 (NR4A2) is an essential transcription factor that governs the differentiation, maturation, and long-term maintenance of midbrain dopaminergic (mDA) neurons in the substantia nigra. Reduced Nurr1 expression has been closely linked to age-related dopaminergic neuronal loss and the pathogenesis of Parkinsons disease. However, the molecular mechanisms regulating Nurr1 expression and protein stability in the aging midbrain remain poorly understood. Here, we identify Janus kinase 2 (JAK2) as a previously unrecognized regulator of Nurr1 in mDA neurons. In the substantia nigra of aged mice (12-and 18-month-old), JAK2 was robustly expressed in Nurr1-positive mDA neurons, whereas its expression was minimal in young adult mice. In SK-N-BE(2)C neuroblastoma cells, overexpression of JAK2 modestly enhanced Nurr1 transcriptional activity, while the constitutively active mutant JAK2V617F markedly increased it. Notably, this effect was not blocked by pharmacological inhibition of STAT, PI3K, or Akt signaling pathways, indicating that JAK2 regulates Nurr1 independently of canonical JAK/STAT or PI3K/Akt signaling. Mechanistically, JAK2 did not promote tyrosine phosphorylation of Nurr1 but instead physically interacted with Nurr1, leading to enhanced nuclear stability of the Nurr1 protein. Consistent with this mechanism, expression of JAK2V617F increased Nurr1 protein levels without altering its mRNA expression. Functionally, co-expression of JAK2V617F and Nurr1 attenuated oxidative stress-induced cytotoxicity and reduced reactive oxygen species accumulation. Together, these findings reveal a phosphorylation-independent mechanism by which JAK2 stabilizes Nurr1 protein and enhances its transcriptional activity. Our results further suggest that age-associated induction of JAK2 in dopaminergic neurons may promote neuronal resilience by maintaining Nurr1 protein stability during aging.

neuroscience↗

bioRxiv2026

Reactive Astrocytes Drive Extracellular Acidification to Mediate α-Synuclein Neurodegeneration

Astrocytes are increasingly recognized as key players in neurodegeneration1-3, yet the molecular mechanisms by which they drive disease remain elusive. Here, we uncover a fundamental pathway in which reactive astrocytes fuel neurodegeneration in -synucleinopathies--including Dementia with Lewy bodies and Parkinsons disease dementia--by acidifying the brains extracellular environment. We demonstrate that both human patient tissue and a gut-to-brain -synuclein mouse model exhibit accumulation of reactive astrocytes and extracellular acidosis. Mechanistically, we show that astrocytic lysosomal exocytosis releases acidic contents, driving a drop in pH that activates neuronal acid-sensing ion channel 1a (ASIC1a), resulting in neuronal loss and behavioral decline. Blocking this pathway--either by inhibiting astrocytic lysosomal exocytosis or genetically or pharmacologically targeting neuronal ASIC1a--mitigates pathology and rescues neurodegenerative phenotypes in vivo. These findings provide a conceptual advance by establishing a mechanistic link between glial inflammation, acid-base homeostasis, and neuronal vulnerability, and suggest that targeting astrocyte-driven acidification or ASIC1a signaling could offer new avenues for disease modification in -synucleinopathies.

neuroscience↗

bioRxiv2025

Identifying membrane-bound transcriptional regulatory proteins from rare but evolutionarily conserved domain combinations

Transcriptional regulatory proteins, including transcription factors (TFs) and chromatin modifiers, must act inside cell nuclei, but membrane-bound transcription factors (MBTFs) are first anchored in membranes before nuclear translocation. Known MBTFs are vital for processes from myelin expression (MYRF) to cholesterol homeostasis (SREBP), yet their overall diversity remains uncharted. We hypothesized that additional membrane-bound transcriptional regulators (MBTRs) might exist, so we developed a bioinformatics screen to prioritize membrane proteins that are likely to regulate transcription. Our approach leverages domain composition by positing that surprising domain combinations suggest novel biological functions. We searched for rare but evolutionarily conserved pairings of transmembrane domains with domains likely involved in transcriptional regulation. Our method rediscovered known MBTFs and membrane-bound histone kinases, and identified novel MBTR candidates, including transmembrane histone N-acetyltransferases, a putative new subclass of MBTFs that share MYRFs DNA-binding domain, and the prolactin regulatory element-binding protein PREB (SEC12). Assays using recombinant PREB demonstrated that the transmembrane domain is the determinant of PREB subcellular localization, governing its distribution between the membrane and the nucleus in mouse embryonic stem cells. These findings underscore the utility of our method and provide a framework for investigating MBTRs that likely facilitate the integration of extracellular signals with transcriptional responses. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/695554v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@15c71e9org.highwire.dtl.DTLVardef@3aa8e8org.highwire.dtl.DTLVardef@1272f0eorg.highwire.dtl.DTLVardef@18246e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Benchmarking datasets for machine learning in protein function prediction

Remarkable progress has been achieved by machine learning, particularly in accurate prediction of protein tertiary structures. Despite these advances, accurately annotating protein functions through machine learning approaches remains challenging, primarily due to the limited availability of large-scale benchmarking data. In this study, we addressed this gap by systematically screening proteins from the UniProt database for functional annotations, resulting in the creation of a benchmarking dataset that includes protein sequences and their corresponding annotations. The Protein Annotation Dataset (PAD) is a resource available to train a wide range of machine learning models for assignment of function annotations to previously unlabeled proteins. We curated a comprehensive dataset comprising four categories of functional annotations using enzyme commission (EC) numbers and gene ontology (GO) terms. The dataset was subsequently partitioned into training, validation, and test subsets. Furthermore, we incorporated an independent set from 12 diverse species, enabling the development and evaluation of innovative machine learning models.

bioinformatics↗

bioRxiv2025

A comprehensive view of somatic mosaicism by single-cell DNA analysis

Single-cell DNA sequencing offers a powerful means of studying somatic mosaicism but requires careful analysis to mitigate DNA amplification-related artifacts. We performed primary template-directed amplification (PTA) and sequencing of 102 nuclei from postmortem lung and colon tissues of a 74-year-old male. Single-cell mutation burdens and spectra were validated by duplex sequencing and revealed heterogeneity across organs and cells, including signatures of APOBEC activity and tobacco exposure. Cells from both tissues exhibited chromosomal aneuploidies, loss of chromosome Y, and chromosomal rearrangements including rearrangements of the T-cell receptor loci indicative of T-cells. Shared embryonic mutations between cells enabled reconstruction of cellular ancestries from the zygote, which were validated by bulk sequencing. Collectively, we demonstrate a comprehensive approach for single-cell genomics that yields an expansive view of diverse somatic mutation types from development through aging across diverse tissues--insights that are obscured in bulk sequencing and only partially captured by other single-cell methods.

genomics↗

bioRxiv2025

Single cell whole genome and transcriptome sequencing links somatic mutations to cell identity and ancestry

The role of somatic mutations in human development and disease is obscured by difficulties in characterizing mutations at the single cell level and identifying cell types carrying them. Here we analysed somatic genomes of clonal iPSC lines and of single-cells after whole-genome amplification (scWGA) by PTA and ResolveOme from skin fibroblasts, blood and urine of a live donor. Mutation burden and spectra converged across approaches, revealing heterogeneous mutational footprints across cells driven by environmental exposures (UV damage and chemotherapy) and lymphocyte differentiation. Aneuploidies in single cells were detected by all the approaches and were orthogonally validated by Strand-seq. Uniquely, ResolveOme enabled cell-type identification using single-cell transcriptomes. Using a newly developed method accounting for noise and allele drop-out in scWGA, we de novo reconstructed the cell phylogenetic tree for this donor. Together, scWGA establishes a powerful foundation for comprehensive, cell type-aware, lineage-aware profiling of somatic mutations at single cell level.

genomics↗

bioRxiv2025

Transitions in human gut viral communities from ancient to industrialized societies

The composition and function of the human gut microbial community (the microbiome) have changed substantially over millennia, with implications for human health. While microbiome research has focused primarily on bacterial dynamics, the long-term history of gut viral communities (the virome) remains largely unexplored, despite their crucial role in shaping bacterial populations. We analyzed gut viromes from 14 pre-modern human coprolites (1301 BCE-1400s CE), as well as 502 non-industrialized and 492 industrialized contemporary human fecal samples. We found that, from pre-modern to contemporary and industrialized populations, human gut viral communities have become more similar in gene content, increasingly dominated by temperate lifestyles, and more supportive of bacterial pathogenicity. These synergistic ecological shifts suggest that long-term changes, especially with industrialization, have fundamentally altered the gut virome, likely affecting human health. These insights into historical shifts in gut viral community and function open potential avenues for ecologically grounded therapeutics to enhance gut microbiome resilience.

microbiology↗

bioRxiv2025

Ubiquitin Receptor-Induced Proximity is Sufficient for Ubiquitin-Independent Targeted Protein Degradation via the 26S Proteasome

The 26S proteasome engages with ubiquitinated substrates primarily through its constituent ubiquitin (Ub) receptors, which initiates a cascade of proteolytic processes. Leveraging this recognition mechanism, we developed a targeted protein degradation (TPD) strategy that recruits substrates directly to the proteasome, thereby bypassing the ubiquitination step. Our proteasome-targeting chimera, Protea-Tac, is a heterobifunctional protein degrader composed of a Ub receptor and an intracellular antibody. This chimera integrates into 26S proteasomes without altering their functional integrity. Localization of target proteins, including c-Fos, BRD4, Flag-TDP43, HA-tau, and GFP-ODC, to the proteasome via Protea-Tac with cognate antibodies resulted in their induced degradation. We demonstrated that this platform is 1) modular, allowing facile switching between targets; 2) Ub-independent; and 3) highly target-specific. Protea-Tac exhibited in vivo anti-tumor efficacy, degrading c-Fos and substantially delaying tumor growth. Overall, these findings identify Protea-Tac as a distinct TPD modality capable of directly degrading intracellular proteins via engineered 26S proteasomes. TeaserProtea-Tac is a heterobifunctional protein degrader that enables Ub-independent TPD, exhibits high specificity and modularity, and demonstrates in vivo applicability.

biochemistry↗

bioRxiv2025

Rational Development of Recombinant ELP Bolaamphiphiles for the Controlled Construction of Multifunctionalized Globular Protein Vesicles

Synthetic biology has enabled the development of new strategies for creating artificial cells that can sense and respond to external stimuli. This study introduces the bottom-up construction of globular protein vesicles (GPVs) that incorporate elastin-like peptide (ELP) bolaamphiphiles as transmembrane components. To enable this strategy, we devised a Golden Gate-based cloning strategy to streamline the design, expression, and purification of ELP bolaamphiphiles. Three ELP bolamphiphiles with varying structural complexity were developed, incorporating fluorescent proteins to facilitate visualization and characterization. The self-assembly of these bolaamphiphiles into GPVs was optimized by varying the molar ratios of recombinant building blocks. Structural characterization confirmed vesicle formation, dynamic light scattering analysis revealed size distributions dependent on modular complexity, and atomic force microscopy demonstrated that the vesicles exhibited MPa-range Youngs moduli, indicative of high mechanical robustness. Our findings demonstrate that multifunctional ELP bolaamphiphiles can be incorporated into GPVs, enabling modular vesicle engineering. This work provides a foundation for designing synthetic cells with customizable bi-functionalities and modularity, advancing compartmentalized systems.

synthetic biology↗

bioRxiv2024

The sodium-glucose cotransporter 2 inhibitor tofogliflozin induces vasodilation by activating Kv channels, the SERCA pump, and the sGC/cGMP pathway

OBJECTIVETofogliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor widely used to treat T2DM, but it also exhibits cardio-protective effects. This study investigated the vasodilatory action of tofogliflozin using rabbit femoral artery rings pre-contracted with phenylephrine. APPROACH AND RESULTSThe femoral artery quickly separated from the rabbit and fix it to the organ bath chamber. Subsequently, administer an inhibitor that modulates vascular tension in the rings or remove the endothelium to assess its impact on vasodilation. The results showed the concentration-dependent induction of vasodilation by tofogliflozin, a response that remained unchanged following endothelial removal, pretreatment with the nitric oxide synthase (NOS) inhibitor L-NAME, or the inhibition of low- and intermediate-conductance Ca2+-activated K+ channels (SKCa and IKCa) using apamin in combination with TRAM-34. Furthermore, pretreatment with the voltage-dependent K+ (Kv) channel inhibitor 4-AP reduced the vasodilatory effects of tofogliflozin whereas pretreatment with the ATP-sensitive K+ (KATP) channel inhibitor glibenclamide or the large-conductance Ca2+-activated K+ (BKCa) channel inhibitor paxilline did not. Notably, our findings indicated that Kv7.X, rather than Kv1.5 or Kv2.1, is the primary Kv subtype involved in tofogliflozin-induced vasodilation. The vasodilatory effects of tofogliflozin were also significantly inhibited in femoral arterial rings pretreated with the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid (CPA). Tofogliflozin-induced vasodilation was unaltered in arterial rings exposed to the adenylyl cyclase inhibitor SQ 22536, the protein kinase A (PKA) inhibitor KT 5720, and the protein kinase G (PKG) inhibitor KT 582 whereas it was effectively reduced by the soluble guanylyl cyclase (sGC) inhibitor ODQ. CONCLUSIONSThese findings suggest that tofogliflozin-induced vasodilation is mediated by the activation of the SERCA pump, the sGC/cGMP pathway, and Kv channels, but not the PKA signaling pathway, other K+ channels, or endothelium-dependent mechanisms.

pharmacology and toxicology↗

bioRxiv2024

Dynamic modulation of IRE1α-XBP1 signaling by adenovirus

The abundant production of foreign proteins and nucleic acids during viral infection elicits a variety of stress responses in host cells. Viral proteins that accumulate in the endoplasmic reticulum (ER) can trigger the unfolded protein response (UPR), a coordinated signaling program that culminates in the expression of downstream genes that collectively restore protein homeostasis. The model pathogen adenovirus serotype 5 (HAdV5) activates the UPR via the signaling axis formed by inositol-requiring enzyme type 1 (IRE1) and the X-box binding protein 1 (XBP1), a transcription factor required for immune function. Recent studies have suggested that IRE1-XBP1 activity supports adenovirus replication. Here, we show that HAdV5 exerted opposing effects on IRE1 and XBP1. IRE1 was activated in response to HAdV5 but the production of the XBP1 isoform, XBP1s, was post-transcriptionally blocked. The tumor suppressor p53, which is eliminated by HAdV5 after infection, inhibited IRE1 activation. The de-repression of IRE1 following the degradation of p53 conceivably reflects a novel antiviral mechanism, which HAdV5 ultimately evades by suppressing XBP1s. Our findings highlight the defective antiviral defenses in cancer cells and further illustrate the opposing mechanisms used by adenoviruses and their host cells to exert control over the UPR, a critical determinant of cell fate.

cancer biology↗

bioRxiv2024

A slippery slope: assessing the amphibian extinction crisis through the lens of climate refugia

In a time of increasing climate uncertainty, it is ever important to identify and preserve refuges for species, optimizing the effort to cover the largest possible number of clades. Climatic refugia are areas of climatic stability that will remain suitable for species over time under multiple climate change scenarios. Amphibians are important indicators of biodiversity and ecosystem health, in addition to being the most threatened class of vertebrates and can therefore serve as proxies to designate protected areas. In this study, we use ecological modeling to delineate current distributions of all amphibian species with adequate data globally. We then projected these distributions to four climate change scenarios, and four time periods, under two climate models representing low and high climate sensitivity. Climate refugia by species were calculated as the average of all climate change scenarios and time periods and were calculated separately for the two climate models of low and high sensitivity. We additionally extracted areas of current distributions and refugia to geographic regions, Udvardy biomes, and global protected areas. With the high climate sensitivity model (CNRM-CM6-1), 2,959 species would experience a refugia area that is reduced from their current distribution, with 139 species having no refugia area. Under the low climate sensitivity model (MIROC6), 2,864 species would have a reduction in area, with 136 having no refugia. While both climate models yielded similar results in terms of percent change, the MIROC6 model overall had less of a negative impact on species refugia. The results of this study present a somber warning of the amphibian extinction crisis in contrast to some of the recent literature, as well as encouragement for managers to act in order to preserve species and the ecosystems they represent.

ecology↗

bioRxiv2024

Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline

Little is known about the origin of germ cells in humans. We previously leveraged post-zygotic mutations to reconstruct zygote-rooted cell lineage ancestry trees in a phenotypically normal woman, termed NC0. Here, by sequencing the genome of her children and their father, we analyzed the transmission of early pre-gastrulation lineages and corresponding mutations across human generations. We found that the germline in NC0 is polyclonal and is founded by at least two cells likely descending from the two blastomeres arising from the first zygotic cleavage. Analyses of public data from several multi-children families and from 1,934 familial quads confirmed this finding in larger cohorts, revealing that known imbalances of up to 90:10 in early lineages allocation in somatic tissues are not reflected in transmission to offspring, establishing a fundamental difference in lineage allocation between the soma and the germline. Analyses of all the data consistently suggest that germline has a balanced 50:50 lineage allocation from the first two blastomeres.

genetics↗