Fresh Pond Research Institute

Cambridge, MA, United States

Fresh Pond Research Institute

Cambridge, MA, United States
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Orzack S.H.,Fresh Pond Research Institute | Stubblefield J.W.,Fresh Pond Research Institute | Akmaev V.R.,Genzyme | Akmaev V.R.,Berg Inc | And 6 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

We describe the trajectory of the human sex ratio from conception to birth by analyzing data from (i) 3- to 6-d-old embryos, (ii) induced abortions, (iii) chorionic villus sampling, (iv) amniocentesis, and (v) fetal deaths and live births. Our dataset is the most comprehensive and largest ever assembled to estimate the sex ratio at conception and the sex ratio trajectory and is the first, to our knowledge, to include all of these types of data. Our estimate of the sex ratio at conception is 0.5 (proportion male), which contradicts the common claim that the sex ratio at conception is malebiased. The sex ratio among abnormal embryos is male-biased, and the sex ratio among normal embryos is female-biased. These biases are associated with the abnormal/normal state of the sex chromosomes and of chromosomes 15 and 17. The sex ratio may decrease in the first week or so after conception (due to excess male mortality); it then increases for at least 10-15 wk (due to excess female mortality), levels off after ∼20 wk, and declines slowly from 28 to 35 wk (due to excess malemortality). Total female mortality during pregnancy exceeds total male mortality. The unbiased sex ratio at conception, the increase in the sex ratio during the first trimester, and total mortality during pregnancy being greater for females are fundamental insights into early human development. © 2015, National Academy of Sciences. All rights reserved.


Hong W.S.,Yale University | Shpak M.,NeuroTexas Institute | Shpak M.,University of Texas at Austin | Shpak M.,Fresh Pond Research Institute | Townsend J.P.,Yale University
Cancer Research | Year: 2015

Determining the evolutionary history of metastases is a key problem in cancer biology. Several recent studies have presented inferences regarding the origin of metastases based on phylogenies of cancer lineages. Many of these studies have concluded that the observed monophyly of metastatic subclones favored metastasis-to-metastasis spread ("a metastatic cascade" rather than parallel metastases from the primary tumor). In this article, we argue that identifying a monophyletic clade of metastatic subclones does not provide sufficient evidence to unequivocally establish a history of metastatic cascades. In the absence of a complete phylogeny of the subclones within the primary tumor, a scenario of parallel metastatic events from the primary tumor is an equally plausible interpretation. Future phylogenetic studies on the origin of metastases should obtain a complete phylogeny of subclones within the primary tumor. This complete phylogeny may be obtainable by ultra-deep sequencing and phasing of large sections or by targeted sequencing of many small, spatially heterogeneous sections, followed by phylogenetic reconstruction using well-established molecular evolutionary models. In addition to resolving the evolutionary history of metastases, a complete phylogeny of subclones within the primary tumor facilitates the identification of driver mutations by application of phylogeny-based tests of natural selection. © 2015 AACR.


Orzack S.H.,Fresh Pond Research Institute | Steiner U.K.,Stanford University | Tuljapurkar S.,Stanford University | Thompson P.,University of Aberdeen
Oikos | Year: 2011

Understanding the static and dynamic expression of life history traits is a prerequisite for the development of a causal theory of the evolution of aging and of life histories. We analyzed the statics and dynamics of reproduction and survival in a wild population of the northern fulmar, Fulmarus glacialis (Procellaridae). Survival rate is most influenced by year as compared to age and cohort. When temporal variation is ignored, survival rate increases slowly with age and then declines more rapidly at late ages. Survival rate contingent upon reproductive 'stratum' (producing an egg, hatching an egg, fledging a hatchling) also exhibits this pattern. Survival and reproduction have a positive static association in that survival rate increases as the apparent energy allocated to reproduction increases (as indexed by stratum). There is a broad distribution of realized lifetime reproductive success, which could be due to 'fixed' heterogeneity, with some individuals always having low survival and reproduction and others always having high survival and reproduction, or be due to 'dynamic' heterogeneity, with all individuals having the same expected reproductive and survival rates. Analysis of stochastic stratum dynamics indicates that individuals do not remain long in any given stratum and suggest that the variation among individuals with respect to lifetime reproductive success is due to dynamic heterogeneity. The probability of producing an egg increases with age for both sexes, whereas the probability of producing a fledgling initially declines with age and then increases. These results underscore the necessity of understanding the static and dynamic expression of demographic traits when making a causal claim about their evolution. © 2011 The Authors. Oikos © 2011 Nordic Society Oikos.


Steiner U.K.,Stanford University | Tuljapurkar S.,Stanford University | Orzack S.H.,Fresh Pond Research Institute
Journal of Animal Ecology | Year: 2010

1. Understanding the evolution of life histories requires an assessment of the process that generates variation in life histories. Within-population heterogeneity of life histories can be dynamically generated by stochastic variation of reproduction and survival or be generated by individual differences that are fixed at birth. 2. We show for the kittiwake that dynamic heterogeneity is a sufficient explanation of observed variation of life histories. 3. The total heterogeneity in life histories has a small contribution fromreproductive stage dynamics and a large contribution from survival differences. We quantify the diversity in life histories by metrics computed fromthe generating stochastic process. 4. We show how dynamic heterogeneity can be used as a null model and also how it can lead to positive associations between reproduction and survival across the life span. 5. We believe our approach to identifying the nature of among-individual heterogeneity yields important insights into the forces that generate within-population variation of life-history traits. It provides an alternative to claims that fixed individual differences are a major determinant of heterogeneity in life histories. ©2009 The Authors. Journal compilation ©2009 British Ecological Society.


Orzack S.H.,Fresh Pond Research Institute
Biology and Philosophy | Year: 2014

The Formal Darwinism Project is an attempt to use mathematical theory to prove the claim that fitness maximization is the outcome of evolution in nature. Grafen's (2014, p. 12) conclusion from this project is that "....there is a very general expectation of something close to fitness maximisation, which will convert into fitness-maximisation unless there are particular kinds of circumstances-and further, that fitness is the same quantity for all genetic architectures." Grafen's claim appears to mean to him that natural populations are expected to contain individuals whose traits are optimal, i.e., any given trait outperforms all reasonable alternatives. I describe why Grafen's attempt can never provide a meaningful expectation as to the ubiquity of optimal traits in nature. This is so because it is based upon a misconception of the relationship between theory and empirical analysis. Even if one could use theory in the way Grafen proposes, I describe how his theory is causally incomplete. Finally, I describe how Grafen's conceptual framework is ambiguous. The Formal Darwinism Project has been inspired by "On The Origin of Species" by Darwin. The great lesson of this book was Darwin's demonstration of the necessary dialog between theory and data, with each influencing and being influenced by the other. Grafen's Formal Darwinism Project, an attempt to create understanding of nature by removing data from this dialog, reflects a failure to understand Darwin's great lesson. © 2014 Springer Science+Business Media Dordrecht.


Orzack S.H.,Fresh Pond Research Institute
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2012

Biologists in search of answers to real-world issues such as the ecological consequences of global warming, the design of species' conservation plans, understanding landscape dynamics and understanding gene expression make decisions constantly that are based on a 'philosophical' stance as to how to create and test explanations of an observed phenomenon. For better or for worse, some kind of philosophy is an integral part of the doing of biology. Given this, it is more important than ever to undertake a practical assessment of what philosophy does mean and should mean to biologists. Here, I address three questions: should biologists pay any attention to 'philosophy'; should biologists pay any attention to 'philosophy of biology'; and should biologists pay any attention to the philosophy of biology literature on modelling? I describe why the last question is easily answered affirmatively, with the proviso that the practical benefits to be gained by biologists from this literature will be directly proportional to the extent to which biologists understand 'philosophy' to be a part of biology, not apart from biology. © 2011 The Royal Society.


Stubblefield J.W.,Fresh Pond Research Institute | Orzack S.H.,Fresh Pond Research Institute
Theoretical Population Biology | Year: 2013

In some vertebrates, offspring help their parents produce additional offspring. Often individuals of one sex are more likely to become "helpers at the nest". We analyze how such sex-biased offspring helping can influence sex-ratio evolution. It is essential to account for age-structure because the sex ratios of early broods influence how much help is available for later broods; previous authors have not correctly accounted for this fact. When each female produces the same sex ratio in all broods (as assumed in all previous analyses of sex-biased helping), the optimal investment strategy is biased towards the more-helpful sex. When a female has facultative control over the sex ratio in each brood and each helper of a given sex increases the resource available for offspring production by a fixed amount, the optimal strategy is to produce only the more-helpful sex in early broods and only the less-helpful sex in later broods. When there are nonlinear returns from helping, i.e., each helper increases the amount of resource available for reproduction by an amount dependent upon the number of helpers, the optimal strategy is to maximize resource accrual from helping in early broods (which may involve the production of both sexes) and then switch to the exclusive production of the less-helpful sex in later broods. The population sex ratio is biased towards the more-helpful sex regardless of whether the sex ratio is fixed or age-dependent. When fitness returns from helping exhibit environmental patchiness, females are selected to produce only males on some patches and only females on others, and the population sex ratio may be biased in either direction. We discuss our results in light of empirical information on offspring helping, and we show via meta-analysis that there is no support for the claim of Griffin et al. [Griffin,A.S., Sheldon,B.C., West,S.A., 2005. Cooperative breeders adjust offspring sex ratios to produce helpful helpers. Amer. Nat. 166, 628-632] that parents produce more of the helpful sex when that sex is rare or absent. © 2012 Elsevier Inc.


Havens J.A.,University of Arkansas | Orzack S.H.,Fresh Pond Research Institute | Etges W.J.,University of Arkansas
Journal of Evolutionary Biology | Year: 2011

We describe indirect genetic benefits of mate choice in two allopatric populations of cactophilic Drosophila mojavensis. By manipulating mate choice opportunity, we show that greater mate choice among sexually mature adults leads to shorter offspring egg-to-adult development times; the extent of this reduction was influenced by population origin and by host plant environment. We performed multiple-choice mating trials with individually marked flies to investigate whether differential male mating success was a consequence of female choice, male interaction, or both. We demonstrate that male copulation frequency was not random and instead, was determined by female choice. Virgin females in these trials were no less discriminating than females that had been previously exposed to males. These results suggest that there are indirect benefits of female mate choice that are population and environment specific, consistent with the hypothesis of ecologically influenced 'good genes' sexual selection. © 2011 The Authors. Journal of Evolutionary Biology © 2011 European Society For Evolutionary Biology.


Shpak M.,NeuroTexas Institute | Shpak M.,University of Texas at Austin | Hall A.W.,Fresh Pond Research Institute | Goldberg M.M.,University of Texas at Austin | And 5 more authors.
Genomics | Year: 2014

In this paper we use eQTL mapping to identify associations between gene dysregulation and single nucleotide polymorphism (SNP) genotypes in glioblastoma multiforme (GBM). A set of 532,954 SNPs was evaluated as predictors of the expression levels of 22,279 expression probes. We identified SNPs associated with fold change in expression level rather than raw expression levels in the tumor. Following adjustment for false discovery rate, the complete set of probes yielded 9257 significant associations (p<. 0.05). We found 18 eQTLs that were missense mutations. Many of the eQTLs in the non-coding regions of a gene, or linked to nearby genes, had large numbers of significant associations (e.g. 321 for RNASE3, 101 for BNC2). Functional enrichment analysis revealed that the expression probes in significant associations were involved in signal transduction, transcription regulation, membrane function, and cell cycle regulation. These results suggest several loci that may serve as hubs in gene regulatory pathways associated with GBM. © 2014 Elsevier Inc.


Steinsaltz D.,University of Oxford | Orzack S.H.,Fresh Pond Research Institute
Paleobiology | Year: 2011

We describe statistical methods to formulate and validate statements about survival rates given a small number of individuals. These methods allow one to estimate the age-specific survival rate and assess its uncertainty, to assess whether the survival rates during some age range differ from the survival rates during another age range, and to assess whether the survivorship curve has a particular shape. We illustrate these methods by applying them to a sample of 22 Albertosaurus sarcophagus individuals. We show that this sample is too small to provide any confidence in the claim that this species had a "convex" survivorship curve arising from age-specific survival rates that decreased monotonically with age. However, we show that a sample of 50 to 100 individuals has reasonable statistical power to support such a claim. There is evidence for the much weaker claim that average survival rates for ages 2 to 15 were higher than survival rates for later ages. Finally, we describe one way to account for size-dependent fossilization rates and show that a plausible positively-size-dependent fossilization rate results in a substantially non-convex survivorship curve for A. sarcophagus. © 2011 The Paleontological Society. All rights reserved.

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