Biology subjects

Dean, M.

Publications and source records attributed to Dean, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Early Ontogenetic Development of Tessellated Calcified Cartilage in Chondrichthyans

Tessellated calcified cartilage (TCC) is a hallmark of the chondrichthyan skeleton, yet its development early in ontogeny across the four major groups (batoids, galeomorphs, squalomorphs, and holocephalans) remains poorly understood. Specialised traits of TCC, such as multi-layered TCC and internal mineralised trabeculae, typically develop in response to feeding mechanics. In this study, we evaluated TCC morphology in the jaws of 12 representative taxa to observe its structure at an early ontogenetic stage to determine whether these specialised features had yet developed. Batoids consistently exhibited well-developed, homogeneous, polygonal tesserae early in ontogeny regardless of jaw morphology or feeding habit. In contrast, galeomorphs displayed high morphological heterogeneity. Notably, we document the first report of an extensive internal trabecular network in a non-batoid elasmobranch, observed in Ginglymostoma cirratum, which may serve to resist the mechanical pressures of specialised suction feeding. Furthermore, we identified voussoir tesserae in galeomorphs for the first time, extending their documented presence across all elasmobranch groups, where they display an inverted aspect ratio (wider than tall) compared to mature forms. The durophagous Mustelus mustelus exhibited surprisingly poor TCC development despite being a durophagous feeder, pointing to a pronounced ontogenetic lag. In Squatina oculata, TCC was characterised by large and thick tesserae and extensive fused tesseral regions which may relate to its explosive ambush predation mode, whereas the holocephalan Chimaera exhibited a poorly mineralized, mesh-like structure without resolvable discrete tesserae or trabeculae-matching findings from previous studies. Across all specimens, multi-layered TCC was absent, confirming that multi-layering develops later in ontogeny. These results demonstrate that generalised models of TCC development based on one group or a few taxa fail to capture the broader diversity of TCC morphology. It also opens up many exciting avenues for further study, and forms the basis for comparisons with fossil chondrichthyans, to investigate the evolution of TCC.

zoology↗

bioRxiv2025

Proximity proteomics reveals the molecular architecture of phytochrome B photobodies in Arabidopsis thaliana

The red/far-red light photoreceptor phytochrome B (phyB) forms light-induced subnuclear condensates, termed photobodies, that coordinate plant responses to light and temperature. Despite their central role in environmental signaling, the molecular composition of phyB photobodies during their early formation has remained unknown. Here, we established an in planta proximity labeling approach using miniTurbo-based biotinylation in Arabidopsis thaliana to capture proteins associated with phyB photobodies during early de-etiolation. Mass spectrometry identified 42 high-confidence proximal proteins, including 11 known core components and 31 previously unrecognized photobody-associated proteins. Among these, the co-chaperone HOP1 forms light-dependent nuclear condensates that partially co-localize with phyB photobodies. HOP1 condensates are smaller in the wild-type background than in phyB-overexpressing seedlings, and HOP1 overexpression enhanced cotyledon expansion under red light. These findings suggest that HOP1 contributes to photomorphogenesis by stabilizing phyB photobodies and sustaining active phyB signaling. Together, our results reveal that nascent large phyB photobodies function as dynamic hubs integrating chaperone-mediated protein quality control with transcriptional regulation, providing the first in planta proteomic framework for understanding photobody assembly and signaling in plants.

plant biology↗

bioRxiv2024

Analysis of the progression of cervical cancer in Guatemala- from pre-malignancy to invasive disease

To better understand cervical cancer progression, we analyzed RNA from 262 biopsies from women referred for colposcopy We determined HPV type and analyzed the expression of 51 genes. HPV31 was significantly more prevalent in precancer than stage 1 cancer and invasive cancer (p < 0.0001) and HPV16 increased in invasive disease (p < 0.0001). CCNE1, MELTF, and ULBP2 were significantly increased in HPV16-positive compared to HPV31 precancers while NECTIN2 and HLA-E expression decreased. Markers of the innate immune system, DNA repair genes, and cell cycle genes are significantly increased during cancer progression (p = 0.0001). In contrast, the TP53 and RB1 tumor suppressor gene expression is significantly decreased in cancer cells. TheT cell markers CD28 and FLT3LG expression decreased in cancer while FOXP3, IDO1, and ULBP2 expression increased. There is a significantly higher survival rate in individuals with increased expression of CD28 (p = 0.0005), FOXP3 (p = 0.0002), IDO1 (p = 0.038), FLT3LG (p = 0.026), APOBEC3B (p = 0.0011), and RUNX3 (p = 0.019), and a significantly lower survival rate in individuals with increased expression of ULBP2 (p = 0.035). These results will help us understand the molecular factors influencing the progression of cervical precancer to cancer.

cancer biology↗

bioRxiv2023

Genetics of Latin American Diversity (GLAD) Project: insights into population genetics and association studies in recently admixed groups in the Americas

Latin America is underrepresented in genetic studies, which can exacerbate disparities in personalized genomic medicine. However, genetic data of thousands of Latin Americans are already publicly available, but require a bureaucratic maze to navigate all the data access and consenting issues. We present the Genetics of Latin American Diversity (GLAD) Project, a platform that compiles genome-wide information of 54,077 Latin Americans from 39 studies representing 45 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene-flow across the Americas. Also, we developed a simulated-annealing-based algorithm to match the genetic background of external samples to our database and share summary statistics without transferring individual-level data. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic softwares in the presence of admixture. By making this resource available, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people.

genetics↗

bioRxiv2021

Extrachromosomal Amplification of Human Papillomavirus Episomes as a Mechanism of Cervical Carcinogenesis

Integration of Human Papillomaviruses (HPV) is an important mechanism of carcinogenesis but is absent in a significant fraction of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors. In two HPV16+ cell lines, we identified large tandem arrays of full-length and truncated viral genomes integrated into multiple locations indicating formation as extrachromosomal DNA (HPV superspreading). An HPV16+ cell line with episomal DNA has tandem arrays of full-length, truncated, and rearranged HPV16 genomes (multimer episomes). WGS of HPV16+ cervical tumors revealed that 11/20 with only episomal HPV (EP) have intact monomer episomes. The remaining nine EP tumors have multimer and rearranged HPV genomes. Most HPV rearrangements disrupt the E1 and E2 genes, and EP tumors overexpress the E6 and E7 viral oncogenes. Tumors with both episomal and integrated HPV16 display multimer episomes and concatemers of human and viral sequences. One tumor has a recurrent deletion of an inhibitory site regulating E6 and E7 expression, and another has a recurrent duplication consistent with HPV superspreading. Therefore, HPV16 can cause cancer without integration through aberrant episomal replication, forming rearranged and multimer episomes.

cancer biology↗

bioRxiv2020

High-throughput Single-cell CNV Detection Reveals Clonal Evolution During Hepatocellular Carcinoma Recurrence

Single-cell genomics provides substantial resources for dissecting cellular heterogeneity and cancer evolution, but classical DNA amplification-based methods are low-throughput and introduce coverage bias during sample preamplification. We developed a single-cell DNA library preparation method without preamplification in nanolitre scale (scDPN). The method has a throughput of up to 1,800 cells per run for copy number variation (CNV) detection. Also, it has a lower level of amplification bias and noise than the multiple displacement amplification (MDA) method and showed high sensitivity and accuracy based on evaluation in cell lines and tumour tissues. We used this approach to profile the tumour clones in paired primary and relapsed tumour samples of hepatocellular carcinoma (HCC). We identified 3 clonal subpopulations with a multitude of aneuploid alterations across the genome. Furthermore, we observed that a minor clone of the primary tumour containing additional alterations in chromosomes 1q, 10q, and 14q developed into the dominant clone in the recurrent tumour, indicating clonal selection during recurrence in HCC. Overall, this approach provides a comprehensive and scalable solution to understand genome heterogeneity and evolution.

cell biology↗

bioRxiv2020

Genome Diversity in Ukraine

The main goal of this collaborative effort is to provide genome wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for the public data release. DNBSEQ-G50 sequences, and genotypes by an Illumina GWAS chip were cross-validated on multiple samples, and additionally referenced to one sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage. The genome data has been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, CNVs, SNPs and microsatellites. This study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for historic and medical research in a large understudied population. While most of the common variation is shared with other European populations, this survey of population variation contributes a number of novel SNPs and structural variants that have not been reported in the gnomAD/1KG databases representing global distribution of genomic variation. These endemic variants will become a valuable resource for designing future population and clinical studies, help address questions about ancestry and admixture, and will fill a missing place in the puzzle characterizing human population diversity in Eastern Europe. Our results indicate that genetic diversity of the Ukrainian population is uniquely shaped by the evolutionary and demographic forces, and cannot be ignored in the future genetic and biomedical studies. This data will contribute a wealth of new information bringing forth different risk and/or protective alleles. The newly discovered low frequency and local variants can be added to the current genotyping arrays for genome wide association studies, clinical trials, and in genome assessment of proliferating cancer cells.

genomics↗

bioRxiv2020

Mineralisation of the Callorhinchus vertebral column (Holocephali; Chondrichthyes)

Chondrichthyes (Elasmobranchii and Holocephali) are distinguished by their largely cartilaginous endoskeleton that comprises an uncalcified core overlain by a mineralised layer; in the Elasmobranchii (sharks, skates, rays) this mineralisation takes the form of calcified polygonal tiles known as tesserae. In recent years, these skeletal tissues have been described in ever increasing detail in sharks and rays but those of Holocephali (chimaeroids) have been less well-described, with conflicting accounts as to whether or not tesserae are present. During embryonic ontogeny in holocephalans, cervical vertebrae fuse to form a structure called the synarcual. The synarcual mineralises early and progressively, anteroposteriorly and dorsoventrally, and therefore presents a good skeletal structure in which to observe mineralised tissues in this group. Here we describe the development and mineralisation of the synarcual in an adult and stage 36 elephant shark embryo (Callorhinchus milii). Small, discrete, but irregular blocks of cortical mineralisation are present in stage 36, similar to what has been described recently in embryos of other chimaeroid taxa such as Hydrolagus, while in Callorhinchus adults, the blocks of mineralisation have become more irregular, but remain small. This differs from fossil members of the holocephalan crown group (Edaphodon), as well as from stem group holocephalans (e.g., Symmorida, Helodus, Iniopterygiformes), where tessellated cartilage is present, with tesserae being notably larger than in Callorhinchus and showing similarities to elasmobranch tesserae, for example with respect to polygonal shape.

zoology↗

bioRxiv2020

Single-cell regulatory landscape and disease vulnerability map of adult Macaque cortex

Single cell approaches have increased our knowledge about the cell type composition of the non-human primate (NHP), but a detailed characterization of area-specific regulatory features remains outstanding. We generated single-cell chromatin accessibility (single-cell ATAC) and transcriptomic data of 358,237 cells from prefrontal cortex (PFC), primary motor cortex (M1) and primary visual cortex (V1) of adult cynomolgus monkey brain, and integrated this dataset with Stereo-seq (Spatio-Temporal Enhanced REsolution Omics-sequencing) of the corresponding cortical areas to assign topographic information to molecular states. We identified area-specific chromatin accessible sites and their targeted genes, including the cell type-specific transcriptional regulatory network associated with excitatory neurons heterogeneity. We reveal calcium ion transport and axon guidance genes related to specialized functions of PFC and M1, identified the similarities and differences between adult macaque and human oligodendrocyte trajectories, and mapped the genetic variants and gene perturbations of human diseases to NHP cortical cells. This resource establishes a transcriptomic and chromatin accessibility combinatory regulatory landscape at a single-cell and spatially resolved resolution in NHP cortex.

neuroscience↗

bioRxiv2020

Tumor heterogeneity assessed by sequencing and fluorescence in situ hybridization (FISH) data

Computational reconstruction of clonal evolution in cancers has become a crucial tool for understanding how tumors initiate and progress and how this process varies across patients. The field still struggles, however, with special challenges of applying phylogenetic methods to cancers, such as the prevalence and importance of copy number alteration (CNA) and structural variation (SV) events in tumor evolution, which are difficult to profile accurately by prevailing sequencing methods in such a way that subsequent reconstruction by phylogenetic inference algorithms is accurate. In the present work, we develop computational methods to combine sequencing with multiplex interphase fluorescence in situ hybridization (miFISH) to exploit the complementary advantages of each technology in inferring accurate models of clonal CNA evolution accounting for both focal changes and aneuploidy at whole-genome scales. We demonstrate on simulated data that incorporation of FISH data substantially improves accurate inference of focal CNA and ploidy changes in clonal evolution from deconvolving bulk sequence data. Analysis of real glioblastoma data for which FISH, bulk sequence, and single cell sequence are all available confirms the power of FISH to enhance accurate reconstruction of clonal copy number evolution in conjunction with bulk and optionally single-cell sequence data. Availabilitygithub.com/CMUSchwartzLab/FISH_deconvolution Contactrussells@andrew.cmu.edu

bioinformatics↗

bioRxiv2020

The genetic structure and adaptation of Andean highlanders and Amazonian dwellers is influenced by the interplay between geography and culture

Western South America was one of the worldwide cradles of civilization. The well known Inca Empire was the tip of the iceberg of a cultural and biological evolutionary process that started 14-11 thousand years ago. Genetic data from 18 Peruvian populations reveal that: (1) The between-population homogenization of the central-southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes and Amazonia accompanied cultural and socioeconomic interactions revealed by archeological studies. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower; and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia (2). The genetic homogenization between the populations of the arid Andes is not only due to migration during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the pre-Inca Wari Empire (600-1000 YBP) (3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes, HAND2-AS1 (heart and neural crest derivatives expressed 2 antisense RNA1, related with cardiovascular function) and DUOX2 (dual oxidase 2, related to thyroid function and innate immunity) genes; in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T/B lymphocytes in viral-host interaction, consistent with the host-virus arms race hypothesis.

evolutionary biology↗

bioRxiv2020

Human papillomavirus 16 positive cervical cancer in Guatemala: The D2 and D3 sublineages differ in integration rate and age of diagnosis

Human papillomavirus (HPV) 16 displays substantial sequence variation; four HPV16 lineages (A, B, C, D) have been described, as well as multiple sub-lineages. To identify molecular events associated with HPV16 carcinogenesis we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala. A total of 64% (60/94) of the samples had integrated HPV16 sequences, and integration was associated with an earlier age of diagnosis (P=0.0007) and pre-menopausal disease. HPV16 integration sites were broadly distributed in the genome but in one tumor, HPV16 integrated into the promoter of the interferon regulatory factor 4 (IRF4) gene, which plays an important role in the regulation of the interferon response to viral infection. The HPV16 D2 and D3 sub-lineages were found in 23% and 30% of the tumors, respectively and were significantly associated with adenocarcinoma. D2-positive tumors had a higher rate of integration (P=0.011), earlier age of diagnosis (P=0.012), and a lower rate of somatic mutation (P=0.03). Whereas D3-positive tumors are less likely to integrate, have later age-of-diagnosis, and a higher rate of somatic mutation. In conclusion, Guatemalan cervical tumors have a high frequency of the very high-risk HPV16 D2 and D3 sub-lineages and cervical cancer patients with these variants of HPV16 differ in histology, age of- diagnosis, integration, and somatic mutation frequency. In summary, related lineages of HPV16 have different features of oncogenicity.

cancer biology↗

bioRxiv2019

Global kinome silencing combined with 3D invasion screening of the tumor microenvironment identifies fibroblast-expressed PIK3Cδ involvement in triple-negative breast cancer progression

As there is growing evidence for the tumor microenvironments (TME) role in tumorigenesis, we sought to investigate the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3C{delta} (f-PIK3C{delta}) as a key regulator of progression. Although PIK3C{delta} has been mainly described in leucocytes, we detected high expression in primary fibroblasts derived from TNBC patients, while PIK3C{delta} was undetectable in cancer epithelial cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3C{delta} in TNBC cell invasion. By employing an integrated secretomics and transcriptomics analysis, we revealed a paracrine mechanism via which f-PIK3C{delta} confers its pro-tumorigenic effects. Inhibition of f-PIK3C{delta} promoted the secretion of factors, including PLGF and BDNF, which subsequently led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3C{delta} in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3C{delta} in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, in addition to a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3C{delta} inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3C{delta} (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.

cancer biology↗

bioRxiv2019

Androgen Receptor Signaling Regulates the Transcriptome of Prostate Cancer Cells by Modulating Global Alternative Splicing

Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen-deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line anti-androgen therapies, including bicalutamide (CASODEX(R)) and enzalutamide (XTANDI(R)). However, the progression-free survival rate for the CRPC patients on anti-androgen therapies is only 8 to 19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR-signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation- and inhibition-of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D-invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist driven tumor invasion. In conclusion, until now, AR signaling has been primarily thought to modulate transcriptome of prostate epithelial cells by inducing or suppressing gene expression. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide.

cancer biology↗

bioRxiv2019

Characterizing the Emergence of Liver and Gallbladder from the Embryonic Endoderm through Single-Cell RNA-Seq

The liver and gallbladder are among the most important internal organs derived from the endoderm. Several inductive signals regulate liver development, yet the pure nascent hepatic and gallbladder cells are unable to be isolated due to limited cell markers and cell numbers. The transcriptome networks of the hepatic lineage in the endoderm, and how the gallbladder differentiates from the adjacent endoderm population, are not fully understood. Using a transgenic Foxa2eGFP reporter mouse line, we performed deep single-cell RNA sequencing on 1,966 individual cells, including nascent hepatic and gallbladder cells, isolated from the endoderm and hepatic regions from ten embryonic stages, ranging from day E7.5 to E15.5. We identified the embryonic liver developmental trajectory from primitive streak to hepatoblasts and characterized the transcriptome of the hepatic lineage. During pre-hepatogenesis (5-6 somite stage), we have identified two groups of foregut endoderm cells, one derived from visceral endoderm and the second derived from primitive streak via a mesenchymal-epithelial transition (MET). During the liver specification stages, liver primordium was identified to share both foregut and liver features. We also documented dynamic gene expression during the epithelial-hepatic transition (EHT). Six gene groups were found to switch on or off at different stages during liver specification. Importantly, we found that RXR complex signaling and newly identified transcription factors associated with liver specification. Moreover, we revealed the gallbladder primordium cells at E9.5 and found genes that transcriptionally distinguish them from the liver primordium. The present data provides a high-resolution resource and critical insights for understanding the emergence of the endoderm, liver and gallbladder development.

developmental biology↗

bioRxiv2019

Origins, admixture dynamics and homogenization of the African gene pool in the Americas

The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed genome-wide analysis of 6,267 individuals from 22 populations and observed an enrichment in West-African ancestry in northern latitudes of the Americas, whereas South/East African ancestry is more prevalent in southern South-America. This pattern results from distinct geographic and geopolitical factors leading to population differentiation. However, we observed a decrease of 68% in the African gene pool between-population diversity within the Americas when compared to the regions of origin from Africa, underscoring the importance of historical factors favoring admixture between individuals with different African origins in the New World. This is consistent with the excess of West-Central Africa ancestry (the most prevalent in the Americas) in the US and Southeast-Brazil, respect to historical-demography expectations. Also, in most of the Americas, admixture intensification occurred between 1,750 and 1,850, which correlates strongly with the peak of arrivals from Africa. This study contributes with a population genetics perspective to the ongoing social, cultural and political debate regarding ancestry, race, and admixture in the Americas.\n\nSignificance StatementDifferently from most genetic studies, that have estimated the overall African ancestry in the Americas, we perform a finer geographic analysis and infer how different African groups contributed to North-, South-American and Caribbean populations, in the context of geographic and geopolitical factors. We also perform a formal comparison of information from demographic history records of the Transatlantic Slave Trade with inferences based on genomic diversity of current populations. Our approach reveals the distinct regional African ancestry roots of different populations from North-, South-America and the Caribe and other important aspects of the historical process of mestizaje and its dynamics in the American continent.

genetics↗

bioRxiv2019

High prevalence of precocious menarche in Puerto Barrios, Guatemala

BackgroundAge of menarche is variable between women with a median age of 14 years old worldwide, and averages ranging from 12-13 years old in developed countries to 15-16 years old in low and middle-income countries. Precocious menarche, occurring before age 11, is rare, with a prevalence of 1.4 to 2.3% in most worldwide populations. Precocious menarche is poorly understood but is associated with early puberty and is a risk factor for pre-teen birth. In studying HPV prevalence in Latin America, we identified a community with a very high rate of precocious menarche. Objective(s)Describe the patterns of precocious menarche in Guatemala. Study DesignReproductive histories were collected from 3385 cancer-free women at the time of routine Pap smear from 4 sites in Guatemala including hospitals in Guatemala City and Puerto Barrios, Izabal. Statistical analyses included determination of the age-specific prevalence of menarche and linear regression to determine the effect of year of birth, study site, number of births and miscarriages, on the age at menarche. ResultsCompared with a low prevalence of precocious menarche observed in Guatemala City (3.1%, 88/2834), we observed a high prevalence of precocious menarche in the city of Puerto Barrios, Izabal, Guatemala (88%, 486/551). We observed a high prevalence of precocious menarche in Puerto Barrios across all age groups. In contrast in Guatemala City, the median age at menarche declined from the age of 14 in 50-60-year-old women to 13 in women under 40 years of age. Hospital records show that the occurrence of both miscarriage and pregnancy under age 14 is substantially higher in Izabal. In addition, the main public hospital in Puerto Barrios accounts for a high fraction of the early pregnancies and miscarriages seen in Guatemala. ConclusionsIn Puerto Barrios, Izabal, Guatemala, the prevalence of menarche before age 11 is dramatically elevated compared to Guatemala City and substantially higher than other worldwide populations. We observed precocious menarche in Puerto Barrios in all age groups examined, indicating that this condition has been common for decades. This finding is supported by the comparatively higher occurrence of early pregnancy and miscarriage in Puerto Barrios compared with Guatemala City. The cause is unknown, but precocious menarche is associated with adverse reproductive outcome in young women and warrants further investigation.

epidemiology↗

bioRxiv2019

Tumor Copy Number Deconvolution Integrating Bulk and Single-Cell Sequencing Data

Characterizing intratumor heterogeneity (ITH) is crucial to understanding cancer development, but it is hampered by limits of available data sources. Bulk DNA sequencing is the most common technology to assess ITH, but mixes many genetically distinct cells in each sample, which must then be computationally deconvolved. Single-cell sequencing (SCS) is a promising alternative, but its limitations -- e.g., high noise, difficulty scaling to large populations, technical artifacts, and large data sets -- have so far made it impractical for studying cohorts of sufficient size to identify statistically robust features of tumor evolution. We have developed strategies for deconvolution and tumor phylogenetics combining limited amounts of bulk and single-cell data to gain some advantages of single-cell resolution with much lower cost, with specific focus on deconvolving genomic copy number data. We developed a mixed membership model for clonal deconvolution via non-negative matrix factorization (NMF) balancing deconvolution quality with similarity to single-cell samples via an associated efficient coordinate descent algorithm. We then improve on that algorithm by integrating deconvolution with clonal phylogeny inference, using a mixed integer linear programming (MILP) model to incorporate a minimum evolution phylogenetic tree cost in the problem objective. We demonstrate the effectiveness of these methods on semi-simulated data of known ground truth, showing improved deconvolution accuracy relative to bulk data alone.

bioinformatics↗