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The study is now published online in Scientific Reports, a journal from the Nature Publishing Group. Liggins Institute molecular biologist, Dr Justin O'Sullivan, says the findings on how crowded genes behave are important for our understanding of development and disease. The researchers developed 3D digital models of how the DNA is folded inside the nucleus of a yeast cell, and then mapped how genes encoded in the DNA are clustered inside the nucleus. They found that the regions of DNA that control replication are crowded together. By mutating certain genes they could change the pattern of crowding and thus the timing of replication. They also found that those genes that were turned on – or expressed – were physically separated from those that were turned off. "The more we understand about what's happening to the genes encoded in the DNA inside the cell nucleus, the easier it is to understand how that DNA structure responds to the environment outside the cell," Dr O'Sullivan says. "So these findings add to our understanding of epigenetics - the chemical process in which the environment modifies the DNA, switching the genes responsible for certain developmental processes on or off. "Our next step is to investigate whether the development of common diseases is influenced by the way genes with mutations are crowded together and communicate with one another," he says. The researchers used a 3D digital model to examine the folding of the DNA inside the yeast cell nucleus. They verified the model using measurements from live yeast cells. Explore further: Mapping the 3-D structure of DNA More information: T. Pichugina et al. A diffusion model for the coordination of DNA replication in Schizosaccharomyces pombe, Scientific Reports (2016). DOI: 10.1038/srep18757

Miller C.A.,Washington University in St. Louis | White B.S.,Washington University in St. Louis | White B.S.,University of Washington | Dees N.D.,Washington University in St. Louis | And 21 more authors.
PLoS Computational Biology | Year: 2014

The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal, with subpopulations of neoplastic cells harboring distinct mutations. A fine resolution view of this clonal architecture provides insight into tumor heterogeneity, evolution, and treatment response, all of which may have clinical implications. Single tumor analysis already contributes to understanding these phenomena. However, cryptic subclones are frequently revealed by additional patient samples (e.g., collected at relapse or following treatment), indicating that accurately characterizing a tumor requires analyzing multiple samples from the same patient. To address this need, we present SciClone, a computational method that identifies the number and genetic composition of subclones by analyzing the variant allele frequencies of somatic mutations. We use it to detect subclones in acute myeloid leukemia and breast cancer samples that, though present at disease onset, are not evident from a single primary tumor sample. By doing so, we can track tumor evolution and identify the spatial origins of cells resisting therapy. © 2014 Miller et al. Source

Sadler L.C.,University of Auckland | McKinlay C.J.D.,The New School | McKinlay C.J.D.,Liggins Institute | McCowan L.M.E.,The New School
American Journal of Obstetrics and Gynecology | Year: 2016

Background The recently published INTERGROWTH-21st Project international population standard for newborn size is intended for global use, but its ability to identify small infants at risk of adverse outcomes in a general obstetric population has not been reported. Objective The objective of the study was to compare adverse neonatal outcomes among small-for-gestational-age (SGA) infants between the INTERGROWTH-21st standard and a customized birthweight standard (accounting for maternal characteristics of height, weight, parity, and ethnicity). We hypothesized that in a multiethnic general obstetric population in Auckland, New Zealand, a customized birthweight standard would better identify SGA infants at-risk of neonatal morbidity/mortality and stillbirth than the INTERGROWTH-21st standard. Study Design Using prospectively gathered maternity data from a general obstetric population in Auckland, New Zealand, from 2006 to 2013 (n = 53,484 births at ≥ 33 weeks), infants were classified as SGA (birthweight < 10th centile) by INTERGROWTH-21st and customized standards. Infants were further categorized as SGA by both criteria, INTERGROWTH-21st only, customized only, or not SGA (met neither criteria). Composite adverse neonatal outcome was defined as neonatal death, neonatal intensive care admission > 48 hours, or ventilation > 4 hours or 5-minute Apgar score < 7. Relative risks for primary outcomes were estimated using modified Poisson regression, with the non-SGA group as the referent. Results Incidence of SGA was 4.5% by INTERGROWTH-21st and 11.6% by customized standard. Compared with those not SGA, infants identified as small for gestational age by both criteria had the highest risk of adverse neonatal outcome (relative risk [RR], 4.1, 95% confidence interval [CI], 3.7-4.6) and stillbirth (RR, 8.3, 95% CI, 5.1-13.4). Infants SGA by customized standard only (n = 4015) had an increased risk of adverse neonatal outcome (RR, 2.0, 95% CI, 1.8-2.2) and stillbirth (RR, 3.0, 95% CI, 1.7-5.3). Few infants were identified as SGA by INTERGROWTH-21st only (n = 172), and risks of adverse neonatal outcome and stillbirth were not increased. Findings were unchanged when analyses were limited to term infants (n = 50,739). The INTERGROWTH-21st standard identified more Indian (12.8%) and Asian (5.8%) but fewer European (3.0%) and Pacific (2.9%) infants as SGA (P <.01). Customized criteria identified more than 3 times as many SGA infants among Maori (14.5%), Pacific (13.5%), and European (11.2%) infants and twice as many among Asian (10.3%) infants (P<0.01) compared with INTERGROWTH-21st criteria. The majority of SGA infants by INTERGROWTH-21st only were born to Indian and Asian mothers (95.4%). Conclusions In our general obstetric population, birthweight customization identified more SGA infants at risk of perinatal mortality and morbidity compared with the INTERGROWTH-21st standard. The INTERGROWTH-21st standard failed to detect many at-risk SGA infants, particularly among ethnic groups with larger maternal size while disproportionately identifying higher rates of SGA among those with smaller maternal size. Local validation is needed prior to implementation of the INTERGROWTH-21st standard to avoid misclassification of infant birth size. © 2016 Elsevier Inc. All rights reserved. Source

Smith G.C.,The New School | Konycheva G.,The New School | Dziadek M.A.,The New School | Ravelich S.R.,The New School | And 6 more authors.
Journal of Nutrigenetics and Nutrigenomics | Year: 2011

Background/Aims: Early-life methyl-donor deficiency is implicated in growth restriction and later-life development of type 2 diabetes mellitus. We ascertained whether dietary methyl-donor deficiency in the mother during pregnancy or during postweaning growth in the rat would impair glucose homeostasis, insulin secretion and pancreatic endocrine development in young adults. Methods: Effects of maternal methyl deficiency (90% deficiency in methionine, folate and choline) were compared with those of postweaning methyl deficiency and with control diets for effects on growth, impaired glucose tolerance, insulin secretion and pancreas development in offspring. Studies focussed on male offspring, which have been shown more susceptible to early-life influences on later disease development. Results: Prenatal methyl deficiency delayed delivery, restricted birthweight by 22%, reduced litter size by 33% and increased offspring mortality to 23% shortly after birth. It reduced relative endocrine pancreatic mass in adult male offspring to 46% of endocrine mass in controls, but only mildly impaired their glucose tolerance and insulin secretion. In contrast, postweaning methyl deficiency restricted growth of male rats and reduced relative pancreatic endocrine mass (-40%), but improved their glucose tolerance, despite decreased insulin secretion. Conclusion: It is clear that the global undernutrition (UN) during pregnancy in rodents alters glucose metabolism in adult offspring. It has been hypothesised that alterations in epigenetic mechanisms may underlie this phenotype. However, removing all methyl donors during pregnancy, which are essential for epigenetic processes in development, did not cause any alteration in glucose metabolism in offspring as seen in the global UN model. © 2011 S. Karger AG, Basel. Source

Bloomfield F.H.,Liggins Institute | Bloomfield F.H.,Gravida National Center for Growth and Development | Jaquiery A.L.,Liggins Institute | Jaquiery A.L.,University of Auckland | And 3 more authors.
Nestle Nutrition Institute Workshop Series | Year: 2013

Fetal growth is largely regulated by nutritional supply. The placenta is responsible for fetal nutrient supply for much of pregnancy, but in early pregnancy nutrition is histiotrophic. Both placental size and efficiency, and fetal growth, may be affected by maternal nutritional state before and during very early pregnancy. In contrast, manipulating maternal nutrition during later stages of pregnancy has a smaller than expected effect on fetal growth. Maternal nutrition before and during early pregnancy also has a greater effect on gestation length than maternal nutrition later in pregnancy, suggesting that nutritional status may regulate both fetal growth trajectory and gestation length and that these two outcomes may be linked. Thus, determination of the nutritional factors regulating fetal growth, and potentially postnatal growth and body phenotype, may lie with the maternal nutritional status even before conception. Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel. Source

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