Genomic prediction based on selective linkage disequilibrium pruning of low-coverage whole-genome sequence variants in a pure Duroc population.

BACKGROUND: Although the accumulation of whole-genome sequencing (WGS) data has accelerated the identification of mutations underlying complex traits, its impact on the accuracy of genomic predictions is limited. Reliable genotyping data and pre-selected beneficial loci can be used to improve prediction accuracy. Previously, we reported a low-coverage sequencing genotyping method that yielded 11.3 million highly accurate single-nucleotide polymorphisms (SNPs) in pigs. Here, we introduce a method termed selective linkage disequilibrium pruning (SLDP), which refines the set of SNPs that show a large gain during prediction of complex traits using whole-genome SNP data. RESULTS: We used the SLDP method to identify and select markers among millions of SNPs based on genome-wide association study (GWAS) prior information. We evaluated the performance of SLDP with respect to three real traits and six simulated traits with varying genetic architectures using two representative models (genomic best linear unbiased prediction and BayesR) on samples from 3579 Duroc boars. SLDP was determined by testing 180 combinations of two core parameters (GWAS P-value thresholds and linkage disequilibrium r2). The parameters for each trait were optimized in the training population by five fold cross-validation and then tested in the validation population. Similar to previous GWAS prior-based methods, the performance of SLDP was mainly affected by the genetic architecture of the traits analyzed. Specifically, SLDP performed better for traits controlled by major quantitative trait loci (QTL) or a small number of quantitative trait nucleotides (QTN). Compared with two commercial SNP chips, genotyping-by-sequencing data, and an unselected whole-genome SNP panel, the SLDP strategy led to significant improvements in prediction accuracy, which ranged from 0.84 to 3.22% for real traits controlled by major or moderate QTL and from 1.23 to 11.47% for simulated traits controlled by a small number of QTN. CONCLUSIONS: The SLDP marker selection method can be incorporated into mainstream prediction models to yield accuracy improvements for traits with a relatively simple genetic architecture, however, it has no significant advantage for traits not controlled by major QTL. The main factors that affect its performance are the genetic architecture of traits and the reliability of GWAS prior information. Our findings can facilitate the application of WGS-based genomic selection.

Methods to detect and characterize introgression.

Introgression, also known as introgressive hybridization, refers to the process that genetic components from the gene pool of one population transfer to the other via constant backcrossing. Introgression is widespread in nature, which plays important roles in increasing genetic diversity and improving adaptability to the environment, and in turn, influences the evolutionary progress of animals, plants and humans. Being as an important evolutionary event, researchers pay great attention to the detection of introgression, the introgression direction, the introgression timing, the pattern of introgression and so on. With the rapid development of high-throughput sequencing technologies, methods to detect and characterize introgression based on genome-wide data are continuously developed. In this review, we summarize a series of methods for introgression detection, and introduce the design principles and applications of these methods. We also discuss the maintenance and selection of gene segments after introgression. This review provides a relatively comprehensive reference for the studies on introgression.

The transmission of human mitochondrial DNA in four-generation pedigrees.

Most of the pathogenic variants in mitochondrial DNA (mtDNA) exist in a heteroplasmic state (coexistence of mutant and wild-type mtDNA). Understanding how mtDNA is transmitted is crucial for predicting mitochondrial disease risk. Previous studies were based mainly on two-generation pedigree data, which are limited by the randomness in a single transmission. In this study, we analyzed the transmission of heteroplasmies in 16 four-generation families. First, we found that 57.8% of the variants in the great grandmother were transmitted to the fourth generation. The direction and magnitude of the frequency change during transmission appeared to be random. Moreover, no consistent correlation was identified between the frequency changes among the continuous transmissions, suggesting that most variants were functionally neutral or mildly deleterious and thus not subject to strong natural selection. Additionally, we found that the frequency of one nonsynonymous variant (m.15773G>A) showed a consistent increase in one family, suggesting that this variant may confer a fitness advantage to the mitochondrion/cell. We also estimated the effective bottleneck size during transmission to be 21-71. In summary, our study demonstrates the advantages of multigeneration data for studying the transmission of mtDNA for shedding new light on the dynamics of the mutation frequency in successive generations.

Denoising method for a lidar bathymetry system based on a low-rank recovery of non-local data structures.

The lidar bathymetry system (LBS) echo is often contaminated by mixed noise, which severely affects the accuracy of measuring sea depth. The denoising algorithm based on a single echo cannot deal with the decline of the signal-to-noise ratio and impulse noise caused by sea waves and abrupt terrain changes. Therefore, we propose a new denoising method for LBS based on non-local structure extraction and the low-rank recovery model. First, the high-frequency noise is eliminated based on the multiple echo in a small neighborhood, and then the matrix is constructed based on the processing results in a larger range. Then, we make full use of the structural similarity between LBS echoes by transforming the echo denoising issues into low-rank matrix restoration to further eliminate the noise. The experimental results show that this method can effectively preserve the seafloor signal and eliminate the mixed noise.

Genome-wide analysis suggests multiple domestication events of Chinese local pigs.

Chinese local pigs have abundant phenotypes as a result of different cultures and habits of Chinese populations, geographic constraints and the long history of pig domestication. A comprehensive investigation of local Chinese pigs will benefit biodiversity research and future breeding practices. However, their classification and demographic history are not yet clear. We studied 91 Chinese local pigs from 14 breeds and 15 Chinese wild boars to reveal the dispersal of Chinese pigs, genetic groups and the demographic history. Based on spatial feature analyses, we believe that the geographic landscape played an important role in the dispersal of local pigs. According to genetic studies, Chinese pigs are divided into three groups where each group appears to have a distinct background. The nucleotide diversity, observed heterozygosity, runs of homozygosity and inbreeding coefficient varied among the groups and widespread migration also existed between the groups. Furthermore, demographic models have been constructed to explain the evolutionary relationship between the groups using the approximate Bayesian computation approach. These suggested that Chinese local pigs are inherited from an extinct Sus scrofa population from ~22 000 years ago. Then, the three groups diverged from ancestors ~16 000, ~11 000 and ~8700 years ago respectively. This study advances our understanding of the genetic variation and demographic history of Chinese local pigs.

Genome­wide association study and genomic prediction for growth traits in yellow-plumage chicken using genotyping-by-sequencing.

BACKGROUND: Growth traits are of great importance for poultry breeding and production and have been the topic of extensive investigation, with many quantitative trait loci (QTL) detected. However, due to their complex genetic background, few causative genes have been confirmed and the underlying molecular mechanisms remain unclear, thus limiting our understanding of QTL and their potential use for the genetic improvement of poultry. Therefore, deciphering the genetic architecture is a promising avenue for optimising genomic prediction strategies and exploiting genomic information for commercial breeding. The objectives of this study were to: (1) conduct a genome-wide association study to identify key genetic factors and explore the polygenicity of chicken growth traits; (2) investigate the efficiency of genomic prediction in broilers; and (3) evaluate genomic predictions that harness genomic features. RESULTS: We identified five significant QTL, including one on chromosome 4 with major effects and four on chromosomes 1, 2, 17, and 27 with minor effects, accounting for 14.5 to 34.1% and 0.2 to 2.6% of the genomic additive genetic variance, respectively, and 23.3 to 46.7% and 0.6 to 4.5% of the observed predictive accuracy of breeding values, respectively. Further analysis showed that the QTL with minor effects collectively had a considerable influence, reflecting the polygenicity of the genetic background. The accuracy of genomic best linear unbiased predictions (BLUP) was improved by 22.0 to 70.3% compared to that of the conventional pedigree-based BLUP model. The genomic feature BLUP model further improved the observed prediction accuracy by 13.8 to 15.2% compared to the genomic BLUP model. CONCLUSIONS: A major QTL and four minor QTL were identified for growth traits; the remaining variance was due to QTL effects that were too small to be detected. The genomic BLUP and genomic feature BLUP models yielded considerably higher prediction accuracy compared to the pedigree-based BLUP model. This study revealed the polygenicity of growth traits in yellow-plumage chickens and demonstrated that the predictive ability can be greatly improved by using genomic information and related features.

Silencing of retrotransposon-derived imprinted gene RTL1 is the main cause for postimplantational failures in mammalian cloning.

Substantial rates of fetal loss plague all in vitro procedures involving embryo manipulations, including human-assisted reproduction, and are especially problematic for mammalian cloning where over 90% of reconstructed nuclear transfer embryos are typically lost during pregnancy. However, the epigenetic mechanism of these pregnancy failures has not been well described. Here we performed methylome and transcriptome analyses of pig induced pluripotent stem cells and associated cloned embryos, and revealed that aberrant silencing of imprinted genes, in particular the retrotransposon-derived RTL1 gene, is the principal epigenetic cause of pregnancy failure. Remarkably, restoration of RTL1 expression in pig induced pluripotent stem cells rescued fetal loss. Furthermore, in other mammals, including humans, low RTL1 levels appear to be the main epigenetic cause of pregnancy failure.

Local Stability of McKean-Vlasov Equations Arising from Heterogeneous Gibbs Systems Using Limit of Relative Entropies.

A family of heterogeneous mean-field systems with jumps is analyzed. These systems are constructed as a Gibbs measure on block graphs. When the total number of particles goes to infinity, the law of large numbers is shown to hold in a multi-class context, resulting in the weak convergence of the empirical vector towards the solution of a McKean-Vlasov system of equations. We then investigate the local stability of the limiting McKean-Vlasov system through the construction of a local Lyapunov function. We first compute the limit of adequately scaled relative entropy functions associated with the explicit stationary distribution of the N-particles system. Using a Laplace principle for empirical vectors, we show that the limit takes an explicit form. Then we demonstrate that this limit satisfies a descent property, which, combined with some mild assumptions shows that it is indeed a local Lyapunov function.

Quantification of circadian rhythm in mitochondrial DNA copy number in whole blood, and identification of factors that influence it.

Mitochondrial DNA (mtDNA), the genetic material in mitochondria, encodes key genes related to the respiratory chain and ATP production. To accurate quantification mtDNA content in whole blood is important for various disease states. Absolute quantitative Real-time PCR and platelet contamination erase method were used for mtDNA copy number analysis in whole blood. In the quantitative study of mtDNA content, it was found that whole blood mtDNA copy number showed a fluctuating rhythm during a 24-h period due to dynamic changes in white blood cells combined with platelets. However, when isolated white blood cells were used, or absolute whole blood mtDNA was calculated, the circadian rhythm pattern of mtDNA disappeared. In this study, a feasible method that can accurately quantify mitochondrial DNA in small blood samples was established, and it was found that two factors which greatly influenced mtDNA copy number were sampling time and platelets in blood.

Weyl Prior and Bayesian Statistics.

When using Bayesian inference, one needs to choose a prior distribution for parameters. The well-known Jeffreys prior is based on the Riemann metric tensor on a statistical manifold. Takeuchi and Amari defined the α -parallel prior, which generalized the Jeffreys prior by exploiting a higher-order geometric object, known as a Chentsov-Amari tensor. In this paper, we propose a new prior based on the Weyl structure on a statistical manifold. It turns out that our prior is a special case of the α -parallel prior with the parameter α equaling - n , where n is the dimension of the underlying statistical manifold and the minus sign is a result of conventions used in the definition of α -connections. This makes the choice for the parameter α more canonical. We calculated the Weyl prior for univariate Gaussian and multivariate Gaussian distribution. The Weyl prior of the univariate Gaussian turns out to be the uniform prior.

Effectiveness of Intensive Endoscopic Screening for Esophageal Cancer in China: A Community-Based Study.

Evidence is required to evaluate the effectiveness of population-level endoscopic screening for esophageal cancer (EC). In this study, 5,632 permanent residents aged 25-65 years from 6 villages in Hua County, Henan Province, China, were defined as the screening cohort and were offered intensive endoscopic screening. Residents of all 914 remaining villages in Hua County were included as the control cohort, and age-sex standardization was used to calculate the expected numbers of EC and upper gastrointestinal (GI) tract cancer cases and deaths in the screening cohort. The effectiveness of screening was assessed by comparing observed numbers of cases and deaths with expected numbers after 9-year follow-up of these screened subjects (2007-2016). In the screening cohort, 23 upper GI cancers (including 16 ECs) and 10 upper GI cancer deaths (including 5 EC deaths) were identified, and 47% (standardized incidence ratio = 0.53, 95% confidence interval (CI): 0.33, 0.87) and 66% (standardized mortality ratio = 0.34, 95% CI: 0.14, 0.81) reductions in cumulative EC incidence and mortality were found. For upper GI cancers, incidence and mortality were lowered by 43% (standardized incidence ratio = 0.57, 95% CI: 0.38, 0.86) and 53% (standardized mortality ratio = 0.47, 95% CI: 0.25, 0.88), respectively. This study showed that upper GI tract endoscopy is an effective population-level screening test for EC in high-risk regions.

A Complex Structural Variation on Chromosome 27 Leads to the Ectopic Expression of HOXB8 and the Muffs and Beard Phenotype in Chickens.

Muffs and beard (Mb) is a phenotype in chickens where groups of elongated feathers gather from both sides of the face (muffs) and below the beak (beard). It is an autosomal, incomplete dominant phenotype encoded by the Muffs and beard (Mb) locus. Here we use genome-wide association (GWA) analysis, linkage analysis, Identity-by-Descent (IBD) mapping, array-CGH, genome re-sequencing and expression analysis to show that the Mb allele causing the Mb phenotype is a derived allele where a complex structural variation (SV) on GGA27 leads to an altered expression of the gene HOXB8. This Mb allele was shown to be completely associated with the Mb phenotype in nine other independent Mb chicken breeds. The Mb allele differs from the wild-type mb allele by three duplications, one in tandem and two that are translocated to that of the tandem repeat around 1.70 Mb on GGA27. The duplications contain total seven annotated genes and their expression was tested during distinct stages of Mb morphogenesis. A continuous high ectopic expression of HOXB8 was found in the facial skin of Mb chickens, strongly suggesting that HOXB8 directs this regional feather-development. In conclusion, our results provide an interesting example of how genomic structural rearrangements alter the regulation of genes leading to novel phenotypes. Further, it again illustrates the value of utilizing derived phenotypes in domestic animals to dissect the genetic basis of developmental traits, herein providing novel insights into the likely role of HOXB8 in feather development and differentiation.

An Analog-Front ROIC with On-Chip Non-Uniformity Compensation for Diode-Based Infrared Image Sensors.

This paper proposes a CMOS front-end readout-integrated circuit (ROIC) with on-chip non-uniformity compensation technique for a diode-based uncooled infrared image sensor. Two techniques are adopted to achieve on-chip non-uniformity compensation: a reference dummy metal line is introduced to alleviate the dominant non-uniformity with IR-drop presented in large pixel array, and a current splitting architecture-based variable current source for diode bias is proposed to compensate other residual non-uniformity. A differential integrator is chosen as the main amplifier of readout circuit for its superior noise performance. For low power design, a pulse-powered row buffer is designed in this work. The proposed ROIC for 384 × 288 diode-based detector array is fabricated with a 0.35- µ m CMOS process. It occupies an area of 4.4 mm × 15 mm, and the power consumption is 180 mW. The measured result shows that with the proposed on-chip non-uniformity compensation, the output voltage variation is greatly reduced from 2.5 V to 60 mV.

Robust Noise Suppression Technique for a LADAR System via Eigenvalue-Based Adaptive Filtering.

The laser detection and ranging system (LADAR) is widely used in various fields that require 3D measurement, detection, and modeling. In order to improve the system stability and ranging accuracy, it is necessary to obtain the complete waveform of pulses that contain target information. Due to the inevitable noise, there are distinct deviations between the actual and expected waveforms, so noise suppression is essential. To achieve the best effect, the filters' parameters that are usually set as empirical values should be adaptively adjusted according to the different noise levels. Therefore, we propose a novel noise suppression method for the LADAR system via eigenvalue-based adaptive filtering. Firstly, an efficient noise level estimation method is developed. The distributions of the eigenvalues of the sample covariance matrix are analyzed statistically after one-dimensional echo data are transformed into matrix format. Based on the boundedness and asymptotic properties of the noise eigenvalue spectrum, an estimation method for noise variances in high dimensional settings is proposed. Secondly, based on the estimated noise level, an adaptive guided filtering algorithm is designed within the gradient domain. The optimized parameters of the guided filtering are set according to an estimated noise level. Through simulation analysis and testing experiments on echo waves, it is proven that our algorithm can suppress the noise reliably and has advantages over the existing relevant methods.

Examining the Reproducibility of 6 Published Studies in Public Health Services and Systems Research.

OBJECTIVE: Research replication, or repeating a study de novo, is the scientific standard for building evidence and identifying spurious results. While replication is ideal, it is often expensive and time consuming. Reproducibility, or reanalysis of data to verify published findings, is one proposed minimum alternative standard. While a lack of research reproducibility has been identified as a serious and prevalent problem in biomedical research and a few other fields, little work has been done to examine the reproducibility of public health research. We examined reproducibility in 6 studies from the public health services and systems research subfield of public health research. DESIGN: Following the methods described in each of the 6 papers, we computed the descriptive and inferential statistics for each study. We compared our results with the original study results and examined the percentage differences in descriptive statistics and differences in effect size, significance, and precision of inferential statistics. All project work was completed in 2017. RESULTS: We found consistency between original and reproduced results for each paper in at least 1 of the 4 areas examined. However, we also found some inconsistency. We identified incorrect transcription of results and omitting detail about data management and analyses as the primary contributors to the inconsistencies. RECOMMENDATIONS: Increasing reproducibility, or reanalysis of data to verify published results, can improve the quality of science. Researchers, journals, employers, and funders can all play a role in improving the reproducibility of science through several strategies including publishing data and statistical code, using guidelines to write clear and complete methods sections, conducting reproducibility reviews, and incentivizing reproducible science.

Transcriptional Gene Silencing Maintained by OTS1 SUMO Protease Requires a DNA-Dependent Polymerase V-Dependent Pathway.

The expression of genes with aberrant structure is prevented at both the transcriptional and posttranscriptional regulation levels. Aberrant gene silencing at the posttranscriptional level is well studied; however, it is not well understood how aberrant genes are silenced at the transcriptional level. In this study, through genetic screening a transgenic report line that harbors an aberrant gene (35S-LUC, lacking 3'-untranslated region [3'-UTR]) and lacks luciferase (LUC) activity, we identify that the small ubiquitin-like modifier (SUMO) protease OTS1 gene is required for maintaining the silence of the reporter 35S-LUC and an endogenous mutator-like element MULE-F19G14 at the transcriptional level, which requires DNA-dependent RNA polymerase (Pol) V and DDR complex, but not Pol IV. The increased transcripts in ots1 mutants are terminated by the 3'-UTRs of downstream genes. In addition to ots1 mutations, mutations in several known or putative SUMO proteases and two SUMO E3 ligases, SIZ1 and MMS21, have similar effects on this silencing regulation. Taken together, our results reveal that the enzymes involved in the SUMOylation process restrain aberrant gene transcription by using a downstream gene 3'-UTR, and this regulation requires a functional Pol V-dependent pathway in Arabidopsis (Arabidopsis thaliana).

Post-transcriptional Regulation of Keratinocyte Progenitor Cell Expansion, Differentiation and Hair Follicle Regression by miR-22.

Hair follicles (HF) undergo precisely regulated recurrent cycles of growth, cessation, and rest. The transitions from anagen (growth), to catagen (regression), to telogen (rest) involve a physiological involution of the HF. This process is likely coordinated by a variety of mechanisms including apoptosis and loss of growth factor signaling. However, the precise molecular mechanisms underlying follicle involution after hair keratinocyte differentiation and hair shaft assembly remain poorly understood. Here we demonstrate that a highly conserved microRNA, miR-22 is markedly upregulated during catagen and peaks in telogen. Using gain- and loss-of-function approaches in vivo, we find that miR-22 overexpression leads to hair loss by promoting anagen-to-catagen transition of the HF, and that deletion of miR-22 delays entry to catagen and accelerates the transition from telogen to anagen. Ectopic activation of miR-22 results in hair loss due to the repression a hair keratinocyte differentiation program and keratinocyte progenitor expansion, as well as promotion of apoptosis. At the molecular level, we demonstrate that miR-22 directly represses numerous transcription factors upstream of phenotypic keratin genes, including Dlx3, Foxn1, and Hoxc13. We conclude that miR-22 is a critical post-transcriptional regulator of the hair cycle and may represent a novel target for therapeutic modulation of hair growth.

Fringing Electric Field Sensors for Anti-Attack at System-Level Protection.

Information system security has been in the spotlight of individuals and governments in recent years. Integrated Circuits (ICs) function as the basic element of communication and information spreading, therefore they have become an important target for attackers. From this perspective, system-level protection to keep chips from being attacked is of vital importance. This paper proposes a novel method based on a fringing electric field (FEF) sensor to detect whether chips are dismantled from a printed circuit board (PCB) as system-level protection. The proposed method overcomes the shortcomings of existing techniques that can be only used in specific fields. After detecting a chip being dismantled from PCB, some protective measures like deleting key data can be implemented to be against attacking. Fringing electric field sensors are analyzed through simulation. By optimizing sensor's patterns, areas and geometrical parameters, the methods that maximize sensitivity of fringing electric field sensors are put forward and illustrated. The simulation is also reproduced by an experiment to ensure that the method is feasible and reliable. The results of experiments are inspiring in that they prove that the sensor can work well for protection of chips and has the advantage of universal applicability, low cost and high reliability.

A cis-regulatory mutation of PDSS2 causes silky-feather in chickens.

Silky-feather has been selected and fixed in some breeds due to its unique appearance. This phenotype is caused by a single recessive gene (hookless, h). Here we map the silky-feather locus to chromosome 3 by linkage analysis and subsequently fine-map it to an 18.9 kb interval using the identical by descent (IBD) method. Further analysis reveals that a C to G transversion located upstream of the prenyl (decaprenyl) diphosphate synthase, subunit 2 (PDSS2) gene is causing silky-feather. All silky-feather birds are homozygous for the G allele. The silky-feather mutation significantly decreases the expression of PDSS2 during feather development in vivo. Consistent with the regulatory effect, the C to G transversion is shown to remarkably reduce PDSS2 promoter activity in vitro. We report a new example of feather structure variation associated with a spontaneous mutation and provide new insight into the PDSS2 function.

A de novo silencer causes elimination of MITF-M expression and profound hearing loss in pigs.

BACKGROUND: Genesis of novel gene regulatory modules is largely responsible for morphological and functional evolution. De novo generation of novel cis-regulatory elements (CREs) is much rarer than genomic events that alter existing CREs such as transposition, promoter switching or co-option. Only one case of de novo generation has been reported to date, in fish and without involvement of phenotype alteration. Yet, this event likely occurs in other animals and helps drive genetic/phenotypic variation. RESULTS: Using a porcine model of spontaneous hearing loss not previously characterized we performed gene mapping and mutation screening to determine the genetic foundation of the phenotype. We identified a mutation in the non-regulatory region of the melanocyte-specific promoter of microphthalmia-associated transcription factor (MITF) gene that generated a novel silencer. The consequent elimination of expression of the MITF-M isoform led to early degeneration of the intermediate cells of the cochlear stria vascularis and profound hearing loss, as well as depigmentation, all of which resemble the typical phenotype of Waardenburg syndrome in humans. The mutation exclusively affected MITF-M and no other isoforms. The essential function of Mitf-m in hearing development was further validated using a knock-out mouse model. CONCLUSIONS: Elimination of the MITF-M isoform alone is sufficient to cause deafness and depigmentation. To our knowledge, this study provides the first evidence of a de novo CRE in mammals that produces a systemic functional effect.