Department of Genome Sciences Faculty Papers

Permanent URI for this collectionhttps://digital.lib.washington.edu/handle/1773/15639

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Genomic analysis of nCoV spread. Situation report 2020-01-23.
(2020-01-23) Bedford, Trevor; Neher, Richard; Hadfield, James; Hodcroft, Emma; Ilcisin, Misja; Muller, Nicola
Using 24 public shared novel coronavirus (nCoV) genomes, we examined genetic diversity to infer date of common ancestor and rate of spread. We find: 24 sampled genomes are nearly identical, differing by 0-3 mutations This lack of genetic diversity has a parsimonious explanation that the outbreak descends either from a single introduction into the human population or a small number of animal to human transmissions of very similar viruses. This event most likely occurred in November or early December 2019. There has been ongoing human-to-human spread since this point resulting in observed cases. Using estimates of total case count from Imperial College London of several thousand cases, we infer a reproductive number between 1.5 and 3.5 indicating rapid growth in the Nov-Jan period.
Resolving multicopy duplications de novo using polyploid phasing
(Springer, 2017-05) Chaisson, Mark J; Mukherjee, Sudipto; Kannan, Sreeram; Eichler, Evan E
While the rise of single-molecule sequencing systems has enabled an unprecedented rise in the ability to assemble complex regions of the genome, long segmental duplications in the genome still remain a challenging frontier in assembly. Segmental duplications are at the same time both gene rich and prone to large structural rearrangements, making the resolution of their sequences important in medical and evolutionary studies. Duplicated sequences that are collapsed in mammalian de novo assemblies are rarely identical; after a sequence is duplicated, it begins to acquire paralog specific variants. In this paper, we study the problem of resolving the variations in multicopy long-segmental duplications by developing and utilizing algorithms for polyploid phasing. We develop two algorithms: the first one is targeted at maximizing the likelihood of observing the reads given the underlying haplotypes using discrete ma- trix completion. The second algorithm is based on correlation clustering and exploits an assumption, which is often satisfied in these duplications, that each paralog has a sizable number of paralog-specific variants. We develop a detailed simulation methodology, and demonstrate the superior performance of the proposed algorithms on an array of simulated datasets. We measure the likelihood score as well as reconstruction accuracy, i.e., what fraction of the reads are clustered correctly. In both the performance metrics, we find that our algorithms dominate existing algorithms on more than 93% of the datasets. While the discrete matrix completion performs better on likelihood score, the correlation clustering algorithm performs better on reconstruction accuracy due to the stronger regularization inherent in the algorithm. We also show that our correlation-clustering algorithm can reconstruct on an average 7:0 haplotypes in 10-copy duplication data-sets whereas existing algorithms reconstruct less than 1 copy on average.
The evolution and population diversity of human-specific segmental duplications
(Nature Ecology & Evolution, 2017-02-17) Dennis, Megan Y; Harshman, Lana; Nelson, Bradley J; Penn, Osnat; Cantsilieris, Stuart; Huddleston, John; Antonacci, Francesca; Penewit, Kelsi; Denman, Laura; Raja, Archana; Baker, Carl; Mark, Kenneth; Malig, Maika; Janke, Nicolette; Espinoza, Claudia; Stessman, Holly A; Nuttle, Xander; Hoekzema, Kendra; Graves, Tina A; Wilson, Richard K; Eichler, Evan E
Segmental duplications contribute significantly to the evolution, adaptation and diseaseassociated instability of the human genome. The largest and most identical duplications suffer from the poorest characterization, often corresponding to genome gaps and misassembly. Here we focus on creating a framework to understand the evolution, copy number variation and coding potential of human-specific segmental duplications (HSDs). We identify 218 HSDs (>5 kbp in length) based on analysis of 322 deeply sequenced ape and human genomes. We target 268 large-insert human bacterial artificial chromosomes, 85 of which have been incorporated into the most recent human reference build (GRCh38) correcting 24 large euchromatic gaps, and 269 nonhuman primate clones for finished sequencing in order to resolve the structure and evolution of the largest, most complex regions with protein-coding potential (n=80 genes/33 gene families). Our analyses indicate that these HSDs (28 duplications ranging in length from 11–677 kbp) are non-randomly organized (P<1x10-6), cluster in association with core duplicons (P<1x10-7) and the majority represent intrachromosomal events arranged predominantly in an interspersed inverted orientation (18/26; P=0.014). Phylogenetic reconstruction suggests different waves of HSD with the latest burst occurring <1.3 million years ago. These 16 duplications and 28 genes would be specific to the genus Homo, including three gene families absent in ancient Neanderthal and Denisova genomes. Of particular interest are the TCAF1/TCAF2 family, which is the most stratified of the Homo sapiens-specific duplications and has been implicated in the somatosensation of cold. Overall, copy number variation analysis (n=2,379 genomes), RNA sequence mapping (GTEx) and targeted resequencing of the protein-coding regions (n=3,275 controls) identify ten gene families where copy number never returns to the ancestral state, there is evidence of mRNA splicing and expression, and no common gene-disruptive mutation events are observed in the general population. We propose that this subset of genes, including functional paralogs ARHGAP11B and SRGAP2C, represents excellent candidates for the evolution of human-specific adaptive traits.
Evolutionary conservation of regulated longevity assurance mechanisms
(2007) McElwee, Joshua J.; Schuster, Eugene; Blanc, Eric; Piper, Matthew D.; Thomas, James H.; Patel, Dhaval S.; Selman, Colin; Withers, Dominic J.; Thorton, Janet M.; Partridge, Linda; Gems, David
Background: To what extent are the determinants of aging in animal species universal? Insulin/insulin-like growth factor (IGF)-1 signaling (IIS) is an evolutionarily conserved (public) regulator of longevity; yet it remains unclear whether the genes and biochemical processes through which IIS acts on aging are public or private (that is, lineage specific). To address this, we have applied a novel, multi-level cross-species comparative analysis to compare gene expression changes accompanying increased longevity in mutant nematodes, fruitflies and mice with reduced IIS. Results: Surprisingly, there is little evolutionary conservation at the level of individual, orthologous genes or paralogous genes under IIS regulation. However, a number of gene categories are significantly enriched for genes whose expression changes in long-lived animals of all three species. Down-regulated categories include protein biosynthesis-associated genes. Up-regulated categories include sugar catabolism, energy generation, glutathione-S-transferases (GSTs) and several other categories linked to cellular detoxification (that is, phase 1 and phase 2 metabolism of xenobiotic and endobiotic toxins). Protein biosynthesis and GST activity have recently been linked to aging and longevity assurance, respectively. Conclusion: These processes represent candidate, regulated mechanisms of longevity-control that are conserved across animal species. The longevity assurance mechanisms via which IIS acts appear to be lineage-specific at the gene level (private), but conserved at the process level (or semipublic). In the case of GSTs, and cellular detoxification generally, this suggests that the mechanisms of aging against which longevity assurance mechanisms act are, to some extent, lineage specific.
The Caenorhabditis chemoreceptor gene families
(2008) Thomas, James H.; Robertson, Hugh M.
Background: Chemoreceptor proteins mediate the first step in the transduction of environmental chemical stimuli, defining the breadth of detection and conferring stimulus specificity. Animal genomes contain families of genes encoding chemoreceptors that mediate taste, olfaction, and pheromone responses. The size and diversity of these families reflect the biology of chemoperception in specific species. Results: Based on manual curation and sequence comparisons among putative G-protein-coupled chemoreceptor genes in the nematode Caenorhabditis elegans, we identified approximately 1300 genes and 400 pseudogenes in the 19 largest gene families, most of which fall into larger superfamilies. In the related species C. briggsae and C. remanei, we identified most or all genes in each of the 19 families. For most families, C. elegans has the largest number of genes and C. briggsae the smallest number, suggesting changes in the importance of chemoperception among the species. Protein trees reveal family-specific and species-specific patterns of gene duplication and gene loss. The frequency of strict orthologs varies among the families, from just over 50% in two families to less than 5% in three families. Several families include large species-specific expansions, mostly in C. elegans and C. remanei. Conclusion: Chemoreceptor gene families in Caenorhabditis species are large and evolutionarily dynamic as a result of gene duplication and gene loss. These dynamics shape the chemoreceptor gene complements in Caenorhabditis species and define the receptor space available for chemosensory responses. To explain these patterns, we propose the gray pawn hypothesis: individual genes are of little significance, but the aggregate of a large number of diverse genes is required to cover a large phenotype space.
Multiple origins of resistance-conferring mutations in Plasmodium vivax dihydrofolate reductase
(2008) Hawkins, Vivian N.; Auliff, Alyson; Prajapati, Surendra Kumar; Rungsihirunrat, Kanchana; Hapuarachchi, Hapuarachchige C.; Maestre, Amanda; O'Neil, Michael T.; Cheng, Qin; Joshi, Hema; Nabangchang, Kesara; Sibley, Carol Hopkins
Background: In order to maximize the useful therapeutic life of antimalarial drugs, it is crucial to understand the mechanisms by which parasites resistant to antimalarial drugs are selected and spread in natural populations. Recent work has demonstrated that pyrimethamine-resistance conferring mutations in Plasmodium falciparum dihydrofolate reductase (dhfr) have arisen rarely de novo, but spread widely in Asia and Africa. The origin and spread of mutations in Plasmodium vivax dhfr were assessed by constructing haplotypes based on sequencing dhfr and its flanking regions. Methods: The P. vivax dhfr coding region, 792 bp upstream and 683 bp downstream were amplified and sequenced from 137 contemporary patient isolates from Colombia, India, Indonesia, Papua New Guinea, Sri Lanka, Thailand, and Vanuatu. A repeat motif located 2.6 kb upstream of dhfr was also sequenced from 75 of 137 patient isolates, and mutational relationships among the haplotypes were visualized using the programme Network. Results: Synonymous and non-synonymous single nucleotide polymorphisms (SNPs) within the dhfr coding region were identified, as was the well-documented in-frame insertion/deletion (indel). SNPs were also identified upstream and downstream of dhfr, with an indel and a highly polymorphic repeat region identified upstream of dhfr. The regions flanking dhfr were highly variable. The double mutant (58R/117N) dhfr allele has evolved from several origins, because the 58R is encoded by at least 3 different codons. The triple (58R/61M/117T) and quadruple (57L/61M/117T/173F, 57I/58R/61M/117T and 57L/58R/61M/117T) mutant alleles had at least three independent origins in Thailand, Indonesia, and Papua New Guinea/Vanuatu. Conclusion: It was found that the P. vivax dhfr coding region and its flanking intergenic regions are highly polymorphic and that mutations in P. vivax dhfr that confer antifolate resistance have arisen several times in the Asian region. This contrasts sharply with the selective sweep of rare antifolate resistant alleles observed in the P. falciparum populations in Asia and Africa. The finding of multiple origins of resistance-conferring mutations has important implications for drug policy.
World Antimalarial Resistance Network (WARN) IV: Clinical pharmacology
(2007) Barnes, Karen I.; Lindegardh, Niklas; Ogundahunsi, Olumide; Olliaro, Piero; Plowe, Christopher V.; Randrianarievelojosia, Milijaona; Gbotosho, Grace O.; Watkins, William M.; Sibley, Carol Hopkins; White, Nicholas J.
A World Antimalarial Resistance Network (WARN) database has the potential to improve the treatment of malaria, through informing current drug selection and use and providing a prompt warning of when treatment policies need changing. This manuscript outlines the contribution and structure of the clinical pharmacology component of this database. The determinants of treatment response are multi-factorial, but clearly providing adequate blood concentrations is pivotal to curing malaria. The ability of available antimalarial pharmacokinetic data to inform optimal dosing is constrained by the small number of patients studied, with even fewer (if any) studies conducted in the most vulnerable populations. There are even less data relating blood concentration data to the therapeutic response (pharmacodynamics). By pooling all available pharmacokinetic data, while paying careful attention to the analytical methodologies used, the limitations of small (and thus underpowered) individual studies may be overcome and factors that contribute to inter-individual variability in pharmacokinetic parameters defined. Key variables for pharmacokinetic studies are defined in terms of patient (or study subject) characteristics, the formulation and route of administration of the antimalarial studied, the sampling and assay methodology, and the approach taken to data analysis. Better defining these information needs and criteria of acceptability of pharmacokinetic-pharmacodynamic (PK-PD) studies should contribute to improving the quantity, relevance and quality of these studies. A better understanding of the pharmacokinetic properties of antimalarials and a more clear definition of what constitutes "therapeutic drug levels" would allow more precise use of the term "antimalarial resistance", as it would indicate when treatment failure is not caused by intrinsic parasite resistance but is instead the result of inadequate drug levels. The clinical pharmacology component of the WARN database can play a pivotal role in monitoring accurately for true antimalarial drug resistance and promptly correcting sub-optimal dosage regimens to prevent these contributing to the emergence and spread of antimalarial resistance.
World Antimalarial Resistance Network (WARN) III: Molecular markers for drug resistant malaria
(2007) Plowe, Christopher V.; Roper, Cally; Barnwell, John W.; Happi, Christian T.; Joshi, Hema H.; Mbacham, Wilfred; Meshnick, Steven R.; Mugittu, Kefas; Naidoo, Inbarani; Price, Ric N.; Shafer, Robert W.; Sibley, Carol Hopkins; Sutherland, Colin J.; Zimmerman, Peter A.; Rosenthal, Phillip J.
Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, more effective combination therapies presents an opportunity to create an open access database that brings together standardized data on molecular markers of drug resistant malaria from around the world. This paper presents a rationale for creating a global database of molecular markers for drug resistant malaria and for linking it to similar databases containing results from clinical trials of drug efficacy, in vitro studies of drug susceptibility, and pharmacokinetic studies of antimalarial drugs, in a World Antimalarial Resistance Network (WARN). This database will be a global resource, guiding the selection of first line drugs for treating uncomplicated malaria, for preventing malaria in travelers and for intermittent preventive treatment of malaria in pregnant women, infants and other vulnerable groups. Perhaps most important, a global database for molecular markers of drug resistant malaria will accelerate the identification and validation of markers for resistance to artemisinin-based combination therapies and, thereby, potentially prolong the useful therapeutic lives of these important new drugs.
World Antimalarial Resistance Network (WARN) II: In vitro antimalarial drug susceptibility
(2007) Bacon, David J.; Jambou, Ronan; Fandeur, Thierry; Le Bras, Jacques; Wongsrichanalai, Chansuda; Fukuda, Mark M.; Ringwald, Pascal; Sibley, Carol Hopkins; Kyle, Dennis E.
Intrinsic resistance of Plasmodium falciparum is clearly a major determinant of the clinical failure of antimalarial drugs. However, complex interactions between the host, the parasite and the drug obscure the ability to define parasite drug resistance in vivo. The in vitro antimalarial drug susceptibility assay determines ex-vivo growth of parasite in the presence of serial drug concentrations and, thus, eliminates host effects, such as drug metabolism and immunity. Although the sensitivity of the parasite to various antimalarials provided by such a test provides an important indicator of intrinsic parasite susceptibility, there are fundamental methodological issues that undermine comparison of in vitro susceptibility both between laboratories and within a single laboratory over time. A network of laboratories is proposed that will agree on the basic parameters of the in vitro test and associated measures of quality control. The aim of the network would be to establish baseline values of sensitivity to commonly used antimalarial agents from key regions of the world, and create a global database, linked to clinical, molecular and pharmacology databases, to support active surveillance to monitor temporal trends in parasite susceptibility. Such a network would facilitate the rapid detection of strains with novel antimalarial resistance profiles and investigate suitable alternative treatments with retained efficacy.
The rationale and plan for creating a World Antimalarial Resistance Network (WARN)
(2007) Sibley, Carol Hopkins; Barnes, Karen I.; Plowe, Christopher V.
Drug resistant malaria was a major factor contributing to the failure of a worldwide campaign to eradicate malaria in the last century, and now threatens the large investment being made by the global community in the rollout of effective new drug combinations to replace failed drugs. Four related papers in this issue of Malaria Journal make the case for creating the World Antimalarial Resistance Network (WARN), which will consist of four linked open-access global databases containing clinical, in vitro, molecular and pharmacological data, and networks of reference laboratories that will support these databases and related surveillance activities. WARN will serve as a public resource to guide antimalarial drug treatment and prevention policies and to help confirm and characterize the new emergence of new resistance to antimalarial drugs and to contain its spread.
A database of antimalarial drug resistance
(2006) Sibley, Carol Hopkins; Ringwald, Pascal
A large investment is required to develop, license and deploy a new antimalarial drug. Too often, that investment has been rapidly devalued by the selection of parasite populations resistant to the drug action. To understand the mechanisms of selection, detailed information on the patterns of drug use in a variety of environments, and the geographic and temporal patterns of resistance is needed. Currently, there is no publically-accessible central database that contains information on the levels of resistance to antimalaria drugs. This paper outlines the resources that are available and the steps that might be taken to create a dynamic, open access database that would include current and historical data on clinical efficacy, in vitro responses and molecular markers related to drug resistance in Plasmodium falciparum and Plasmodium vivax. The goal is to include historical and current data on resistance to commonly used drugs, like chloroquine and sulfadoxine-pyrimethamine, and on the many combinations that are now being tested in different settings. The database will be accessible to all on the Web. The information in such a database will inform optimal utilization of current drugs and sustain the longest possible therapeutic life of newly introduced drugs and combinations. The database will protect the valuable investment represented by the development and deployment of novel therapies for malaria.
Interaction of an atypical Plasmodium falciparum ETRAMP with human apolipoproteins
(2008) Vignali, Marissa; McKinlay, Anastasia; LaCount, Douglas J.; Chettier, Rakesh; Bell, Russell; Sahasrabudhe, Sudhir; Hughes, Robert E.; Fields, Stanley
Background: In order to establish a successful infection in the human host, the malaria parasite Plasmodium falciparum must establish interactions with a variety of human proteins on the surface of different cell types, as well as with proteins inside the host cells. To better understand this aspect of malaria pathogenesis, a study was conducted with the goal of identifying interactions between proteins of the parasite and those of its human host. Methods: A modified yeast two-hybrid methodology that preferentially selects protein fragments that can be expressed in yeast was used to conduct high-throughput screens with P. falciparum protein fragments against human liver and cerebellum libraries. The resulting dataset was analyzed to exclude interactions that are not likely to occur in the human host during infection. Results: An initial set of 2,200 interactions was curated to remove proteins that are unlikely to play a role in pathogenesis based on their annotation or localization, and proteins that behave promiscuously in the two-hybrid assay, resulting in a final dataset of 456 interactions. A cluster that implicates binding between P. falciparum PFE1590w/ETRAMP5, a putative parasitophorous vacuole membrane protein, and human apolipoproteins ApoA, ApoB and ApoE was selected for further analysis. Different isoforms of ApoE, which are associated with different outcomes of malaria infection, were shown to display differential interactions with PFE1590w. Conclusion: A dataset of interactions between proteins of P. falciparum and those of its human host was generated. The preferential interaction of the P. falciparum PFE1590w protein with the human ApoE e3 and ApoE e4 isoforms, but not the ApoE e2 isoform, supports the hypothesis that ApoE genotype affects risk of malaria infection. The dataset contains other interactions of potential relevance to disease that may identify possible vaccine candidates and drug targets.
Hominoid chromosomal rearrangements on 17q map to complex regions of segmental duplication
(2008) Cardone, Maria Francesca; Jiang, Zhaoshi; D'Addabbo, Pietro; Archidiacono, Nicoletta; Rocchi, Mariano; She, Xinwei; Eichler, Evan E.; Ventura, Mario.
Background: Chromosomal rearrangements, such as translocations and inversions, are recurrent phenomena during evolution, and both of them are involved in reproductive isolation and speciation. To better understand the molecular basis of chromosome rearrangements and their part in karyotype evolution, we have investigated the history of human chromosome 17 by comparative fluorescence in situ hybridization (FISH) and sequence analysis. Results: Human bacterial artificial chromosome/p1 artificial chromosome probes spanning the length of chromosome 17 were used in FISH experiments on great apes, Old World monkeys and New World monkeys to study the evolutionary history of this chromosome. We observed that the macaque marker order represents the ancestral organization. Human, chimpanzee and gorilla homologous chromosomes differ by a paracentric inversion that occurred specifically in the Homo sapiens/Pan troglodytes/Gorilla gorilla ancestor. Detailed analyses of the paracentric inversion revealed that the breakpoints mapped to two regions syntenic to human 17q12/21 and 17q23, both rich in segmental duplications. Conclusion: Sequence analyses of the human and macaque organization suggest that the duplication events occurred in the catarrhine ancestor with the duplication blocks continuing to duplicate or undergo gene conversion during evolution of the hominoid lineage. We propose that the presence of these duplicons has mediated the inversion in the H. sapiens/P. troglodytes/G. gorilla ancestor. Recently, the same duplication blocks have been shown to be polymorphic in the human population and to be involved in triggering microdeletion and duplication in human. These results further support a model where genomic architecture has a direct role in both rearrangement involved in karyotype evolution and genomic instability in human.
Independent centromere formation in a capricious, gene-free domain of chromosome 13q21 in Old World monkeys and pigs
(2006) Cardone, Maria Francesca; Alonso, Alicia; Pazienza, Michele; Ventura, Mario; Montermurro, Gabriella; Carbone, Lucia; De Jong, Pieter J.; Stanyon, Roscoe; D'Addabbo, Pietro; Archidiacono, Nicoletta; She, Xinwei; Eichler, Evan E.; Warburton, Peter E.; Rocchi, Mariano
Background: Evolutionary centromere repositioning and human analphoid neocentromeres occurring in clinical cases are, very likely, two stages of the same phenomenon whose properties still remain substantially obscure. Chromosome 13 is the chromosome with the highest number of neocentromeres. We reconstructed the mammalian evolutionary history of this chromosome and characterized two human neocentromeres at 13q21, in search of information that could improve our understanding of the relationship between evolutionarily new centromeres, inactivated centromeres, and clinical neocentromeres. Results: Chromosome 13 evolution was studied, using FISH experiments, across several diverse superordinal phylogenetic clades spanning >100 million years of evolution. The analysis revealed exceptional conservation among primates (hominoids, Old World monkeys, and New World monkeys), Carnivora (cat), Perissodactyla (horse), and Cetartiodactyla (pig). In contrast, the centromeres in both Old World monkeys and pig have apparently repositioned independently to a central location (13q21). We compared these results to the positions of two human 13q21 neocentromeres using chromatin immunoprecipitation and genomic microarrays. Conclusion: We show that a gene-desert region at 13q21 of approximately 3.9 Mb in size possesses an inherent potential to form evolutionarily new centromeres over, at least, approximately 95 million years of mammalian evolution. The striking absence of genes may represent an important property, making the region tolerant to the extensive pericentromeric reshuffling during subsequent evolution. Comparison of the pericentromeric organization of chromosome 13 in four Old World monkey species revealed many differences in sequence organization. The region contains clusters of duplicons showing peculiar features.
The genomic distribution of intraspecific and interspecific sequence divergence of human segmental duplications relative to human/chimpanzee chromosomal rearrangements
(2008) Marques-Bonet, Tom�s; Cheng, Ze; She, Xinwei; Eichler, Evan E.; Navarro, Arcadi
Background: It has been suggested that chromosomal rearrangements harbor the molecular footprint of the biological phenomena which they induce, in the form, for instance, of changes in the sequence divergence rates of linked genes. So far, all the studies of these potential associations have focused on the relationship between structural changes and the rates of evolution of singlecopy DNA and have tried to exclude segmental duplications (SDs). This is paradoxical, since SDs are one of the primary forces driving the evolution of structure and function in our genomes and have been linked not only with novel genes acquiring new functions, but also with overall higher DNA sequence divergence and major chromosomal rearrangements. Results: Here we take the opposite view and focus on SDs. We analyze several of the features of SDs, including the rates of intraspecific divergence between paralogous copies of human SDs and of interspecific divergence between human SDs and chimpanzee DNA. We study how divergence measures relate to chromosomal rearrangements, while considering other factors that affect evolutionary rates in single copy DNA. Conclusion: We find that interspecific SD divergence behaves similarly to divergence of singlecopy DNA. In contrast, old and recent paralogous copies of SDs do present different patterns of intraspecific divergence. Also, we show that some relatively recent SDs accumulate in regions that carry inversions in sister lineages.
On the number of founding germ cells in humans
(2005) Zheng, Chang-Jiang; Luebeck, E. Georg; Byers, Breck E.; Moolgavkar, Suresh H.
Background: The number of founding germ cells (FGCs) in mammals is of fundamental significance to the fidelity of gene transmission between generations, but estimates from various methods vary widely. In this paper we obtain a new estimate for the value in humans by using a mathematical model of germ cell development that depends on available oocyte counts for adult women. Results: The germline-development model derives from the assumption that oogonial proliferation in the embryonic stage starts with a founding cells at t = 0 and that the subsequent proliferation can be defined as a simple stochastic birth process. It follows that the population size X(t) at the end of germline expansion (around the 5th month of pregnancy in humans; t = 0.42 years) is a random variable with a negative binomial distribution. A formula based on the expectation and variance of this random variable yields a moment-based estimate of a that is insensitive to the progressive reduction in oocyte numbers due to their utilization and apoptosis at later stages of life. In addition, we describe an algorithm for computing the maximum likelihood estimation of the FGC population size (a), as well as the rates of oogonial division and loss to apoptosis. Utilizing both of these approaches to evaluate available oocyte-counting data, we have obtained an estimate of a = 2 - 3 for Homo sapiens. Conclusion: The estimated number of founding germ cells in humans corresponds well with values previously derived from chimerical or mosaic mouse data. These findings suggest that the large variation in oocyte numbers between individual women is consistent with a smaller founding germ cell population size than has been estimated by cytological analyses.

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