Phenotypic cell-to-cell variability within clonal populations may be a manifestation of 'gene expression noise', or it may reflect stable phenotypic variants. Such 'non-genetic cell individuality' can arise from the slow fluctuations of protein levels in mammalian cells. These fluctuations produce persistent cell individuality, thereby rendering a clonal population heterogeneous. However, it remains unknown whether this heterogeneity may account for the stochasticity of cell fate decisions in stem cells. Here we show that in clonal populations of mouse haematopoietic progenitor cells, spontaneous 'outlier' cells with either extremely high or low expression levels of the stem cell marker Sca-1 (also known as Ly6a; ref. 9) reconstitute the parental distribution of Sca-1 but do so only after more than one week. This slow relaxation is described by a gaussian mixture model that incorporates noise-driven transitions between discrete subpopulations, suggesting hidden multi-stability within one cell type. Despite clonality, the Sca-1 outliers had distinct transcriptomes. Although their unique gene expression profiles eventually reverted to that of the median cells, revealing an attractor state, they lasted long enough to confer a greatly different proclivity for choosing either the erythroid or the myeloid lineage. Preference in lineage choice was associated with increased expression of lineage-specific transcription factors, such as a >200-fold increase in Gata1 (ref. 10) among the erythroid-prone cells, or a >15-fold increased PU.1 (Sfpi1) (ref. 11) expression among myeloid-prone cells. Thus, clonal heterogeneity of gene expression level is not due to independent noise in the expression of individual genes, but reflects metastable states of a slowly fluctuating transcriptome that is distinct in individual cells and may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision.

Clonal populations of mammalian cells are inherently heterogeneous. They contain cells that display non-genetic variability resulting from gene expression noise and the fact that gene networks have multiple stable states. These stable, heritable variants within one cell type can exhibit different levels of responsiveness to environmental conditions. Hence, they could in principle serve as a temporary substrate for natural selection in the absence of mutations. We suggest that such ubiquitous but non-genetic variability can contribute to the somatic evolution of cancer cells, hence accelerating tumour progression independently of genetic mutations.

Summary Background Each year,1.1 million babies die from prematurity, andmany survivors are disabled. Worldwide, 15 million babies are preterm(<37 weeks’ gestation),withtwo decades of increasing ratesinalmost all countries with reliable data. Improved care of babies has reduced mortality in high-income countries, although effective interventions have yet to be scaled-up in most low-income countries. A 50% reduction goal for preterm-specific mortality by 2025 has been set in the “Born Too Soon” report. However, for preterm birth prevention,understanding of drivers and potential impact of preventive interventions is limited. We examine trends and estimate the potential reduction in preterm birthsforvery high human development index (VHHDI) countries if current evidence-based interventions were widely implemented. This analysis is to inform a “Born Too Soon” rate reduction target. Methods Countries were assessed for inclusion based on availability and quality ofpreterm prevalence data (2000-2010), and trend analyses with projections undertaken. We analysed drivers of rate increases in the USA, 1998-2004. For 39 VHHDI countrieswith >10,000 births, country-by-country analyses were performed based on target population, incremental coverage increase,and intervention efficacy. Cost savings were estimated based on reported costs for preterm care in the USAadjusted usingWorld Bank purchasing power parity. Findings From 2010, even if all VHHDI countries achieved annual preterm birth rate reductions of the best performers, (Sweden and Netherlands), 2000-2010 or 2005-2010(Lithuania, Estonia)), rates would experience a relative reduction of<5% by 2015 on average across the 39 countries.Our analysis of preterm birth rise 1998-2004 in USA suggests half the change is unexplained, but important drivers includeinductions/cesareandelivery and ART.For all 39 VHHDI countries, five interventionsmodeling at high coveragepredicted 5%preterm birth rate relative reduction from 9.59 to 9.07% of live births:smoking cessation (0.01 rate reduction), decreasing multiple embryo transfers during assisted reproductive technologies (0.06), cervical cerclage (0.15), progesterone supplementation (0.01), and reduction of non-medically indicated labour induction or caesarean delivery (0.29).These translate to 58,000 preterm births averted and total annual economic cost savings of ~US$ 3 billion. Interpretation Even with optimal coverage of current interventions, many being complex to implement, the estimated potential reduction in preterm birth is tiny. Hence we recommenda conservative target of 5% preterm birth rate relative reductionby 2015. Our findings highlight the urgent need for discovery research into underlying mechanisms of preterm birth, and developmentof innovative interventions. Furthermore, the highest preterm birth rates occur in low-income settings where the causes of prematurity may differand have simpler solutions, such as birth spacing and treatment of infections in pregnancy. Urgent focus on these settings also is critical t...