Proceedings of the National Academy of Sciences of the United States of America
-
Proc. Natl. Acad. Sci. U.S.A. · Dec 2019
Bottleneck and selection in the germline and maternal age influence transmission of mitochondrial DNA in human pedigrees.
Heteroplasmy-the presence of multiple mitochondrial DNA (mtDNA) haplotypes in an individual-can lead to numerous mitochondrial diseases. The presentation of such diseases depends on the frequency of the heteroplasmic variant in tissues, which, in turn, depends on the dynamics of mtDNA transmissions during germline and somatic development. Thus, understanding and predicting these dynamics between generations and within individuals is medically relevant. ⋯ We show that heteroplasmic variants at intermediate frequencies can segregate for many generations in the human population, despite the strong germline bottleneck. We show that selection acts during germline development to keep the frequency of putatively deleterious variants from rising. Our findings have important applications for clinical genetics and genetic counseling.
-
Proc. Natl. Acad. Sci. U.S.A. · Sep 2019
Comprehensive genomic profiling of glioblastoma tumors, BTICs, and xenografts reveals stability and adaptation to growth environments.
Glioblastoma multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor-initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain undetermined. ⋯ Using data generated from whole-genome sequencing of 201 samples and RNA sequencing of 118 samples, we show that BTICs and xenografts resemble their parental tumor at the genomic level but differ at the mRNA expression and epigenomic levels, likely due to the different growth environment for each sample type. These findings suggest that a comprehensive genomic understanding of in vitro and in vivo GBM model systems is crucial for interpreting data from drug screens, and can help control for biases introduced by cell-culture conditions and the microenvironment in mouse models. We also found that lack of MGMT expression in pretreated GBM is linked to hypermutation, which in turn contributes to increased genomic heterogeneity and requires new strategies for GBM treatment.
-
Proc. Natl. Acad. Sci. U.S.A. · Aug 2019
Reconciling modern machine-learning practice and the classical bias-variance trade-off.
Breakthroughs in machine learning are rapidly changing science and society, yet our fundamental understanding of this technology has lagged far behind. Indeed, one of the central tenets of the field, the bias-variance trade-off, appears to be at odds with the observed behavior of methods used in modern machine-learning practice. The bias-variance trade-off implies that a model should balance underfitting and overfitting: Rich enough to express underlying structure in data and simple enough to avoid fitting spurious patterns. ⋯ This "double-descent" curve subsumes the textbook U-shaped bias-variance trade-off curve by showing how increasing model capacity beyond the point of interpolation results in improved performance. We provide evidence for the existence and ubiquity of double descent for a wide spectrum of models and datasets, and we posit a mechanism for its emergence. This connection between the performance and the structure of machine-learning models delineates the limits of classical analyses and has implications for both the theory and the practice of machine learning.
-
Proc. Natl. Acad. Sci. U.S.A. · Aug 2019
Effects of policy-driven hypothetical air pollutant interventions on childhood asthma incidence in southern California.
Childhood asthma is a major public health concern and has significant adverse impacts on the lives of the children and their families, and on society. There is an emerging link between air pollution, which is ubiquitous in our environment, particularly in urban centers, and incident childhood asthma. Here, using data from 3 successive cohorts recruited from the same 9 communities in southern California over a span of 20 y (1993 to 2014), we estimated asthma incidence using G-computation under hypothetical air pollution exposure scenarios targeting nitrogen dioxide (NO2) and particulate matter <2.5 μm (PM2.5) in separate interventions. ⋯ For example, compliance with a hypothetical standard of 20 ppb NO2 was estimated to result in 20% lower childhood asthma incidence (95% CI, -27% to -11%) compared with the exposure that actually occurred. The findings for hypothetical PM2.5 interventions, although statistically significant, were smaller in magnitude compared with results for the hypothetical NO2 interventions. Our results suggest a large potential public health benefit of air pollutant reduction in reduced incidence of childhood asthma.
-
Proc. Natl. Acad. Sci. U.S.A. · Jul 2019
AAV2/9-mediated overexpression of MIF inhibits SOD1 misfolding, delays disease onset, and extends survival in mouse models of ALS.
Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by the loss of upper and lower motor neurons. Transgenic mice that overexpress mutant SOD1 develop paralysis and accumulate misfolded SOD1 onto the cytoplasmic faces of intracellular organelles, including mitochondria and endoplasmic reticulum (ER). Recently, macrophage migration inhibitory factor (MIF) was shown to directly inhibit mutant SOD1 misfolding and binding to intracellular membranes. ⋯ Furthermore, mutant SOD1G93A and loxSOD1G37R mice injected with AAV2/9-MIF demonstrated a significant delay in disease onset and prolonged survival compared with their AAV2/9-GFP-injected or noninjected littermates. Moreover, these mice accumulated reduced amounts of misfolded SOD1 in their spinal cords, with no observed effect on glial overactivation as a result of MIF up-regulation. Our findings indicate that MIF plays a significant role in SOD1 folding and misfolding mechanisms and strengthen the hypothesis that MIF acts as a chaperone for misfolded SOD1 in vivo and may have further implications regarding the therapeutic potential role of up-regulation of MIF in modulating the specific accumulation of misfolded SOD1.