Graph tilings in incompatibility systems

Given two graphs $H$ and $G$, an \emph{$H$-tiling} of $G$ is a collection of vertex-disjoint copies of $H$ in $G$ and an \emph{$H$-factor} is an $H$-tiling that covers all vertices of $G$. K\"{u}hn and Osthus managed to characterize, up to an additive constant, the minimum degree threshold which forces an $H$-factor in a host graph $G$. In this paper we study a similar tiling problem in a system that is locally bounded. An \emph{incompatibility system} $\mathcal{F}$ over $G$ is a family $\mathcal{F}=\{F_v\}_{v\in V(G)}$ with $F_v\subseteq \{\{e,e'\}\in {E(G)\choose 2}: e\cap e'=\{v\}\}$. We say that two edges $e,e'\in E(G)$ are \emph{incompatible} if $\{e,e'\}\in F_v$ for some $v\in V(G)$, and otherwise \emph{compatible}. A subgraph $H$ of $G$ is \emph{compatible} if every pair of edges in $H$ are compatible. An incompatibility system $\mathcal{F}$ is \emph{$\Delta$-bounded} if for any vertex $v$ and any edge $e$ incident with $v$, there are at most $\Delta$ two-subsets in $F_v$ containing $e$. This notion was partly motivated by a concept of transition system introduced by Kotzig in 1968, and first formulated by Krivelevich, Lee and Sudakov to study the robustness of Hamiltonicity of Dirac graphs. We prove that for any $\alpha>0$ and any graph $H$ with $h$ vertices, there exists a constant $\mu>0$ such that for any sufficiently large $n$ with $n\in h\mathbb{N}$, if $G$ is an $n$-vertex graph with $\delta(G)\ge(1-\frac{1}{\chi^*(H)}+\alpha)n$ and $\mathcal{F}$ is a $\mu n$-bounded incompatibility system over $G$, then there exists a compatible $H$-factor in $G$, where the value $\chi^*(H)$ is either the chromatic number $\chi(H)$ or the critical chromatic number $\chi_{cr}(H)$ and we provide a dichotomy. Moreover, the error term $\alpha n$ is inevitable in general case

Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity.

Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations

Multiple breast cancer risk variants are associated with differential transcript isoform expression in tumors.

Genome-wide association studies have identified over 70 single-nucleotide polymorphisms (SNPs) associated with breast cancer. A subset of these SNPs are associated with quantitative expression of nearby genes, but the functional effects of the majority remain unknown. We hypothesized that some risk SNPs may regulate alternative splicing. Using RNA-sequencing data from breast tumors and germline genotypes from The Cancer Genome Atlas, we tested the association between each risk SNP genotype and exon-, exon-exon junction- or transcript-specific expression of nearby genes. Six SNPs were associated with differential transcript expression of seven nearby genes at FDR < 0.05 (BABAM1, DCLRE1B/PHTF1, PEX14, RAD51L1, SRGAP2D and STXBP4). We next developed a Bayesian approach to evaluate, for each SNP, the overlap between the signal of association with breast cancer and the signal of association with alternative splicing. At one locus (SRGAP2D), this method eliminated the possibility that the breast cancer risk and the alternate splicing event were due to the same causal SNP. Lastly, at two loci, we identified the likely causal SNP for the alternative splicing event, and at one, functionally validated the effect of that SNP on alternative splicing using a minigene reporter assay. Our results suggest that the regulation of differential transcript isoform expression is the functional mechanism of some breast cancer risk SNPs and that we can use these associations to identify causal SNPs, target genes and the specific transcripts that may mediate breast cancer risk

Online medical consultation in China: Evidence from obesity doctors

ObjectiveOnline medical consultation (OMC) is increasingly used in China, but there have been few in-depth studies of consultation arrangements and fee structures of online doctors in China. This research assessed the consultation arrangements and fee structure of OMC in China by undertaking a case study of obesity doctors from four representative OMC platforms.MethodsDetailed information, including fees, waiting time and doctor information, was collected from four obesity OMC platforms and analyzed using descriptive statistical analysis.ResultsThe obesity OMC platforms in China shared similarities in the use of big data and artificial intelligence (AI) but differed across service access, specific consultation arrangements and fees. Big data search and AI response technologies were used by most platforms to match users with doctors and reduce doctors' pressure. The descriptive statistical analysis showed that the higher the rank of the online doctor, the higher the online fee and the longer the wait time. Through a comparison with offline hospitals, we found online doctors' fees exceeded offline hospital doctors' fees by up to 90%.ConclusionsOMC platforms can gain competitive advantages over offline medical institutions through the following measures: make fuller use of big data and AI technologies to provide users with longer duration, lower cost and more efficient consultation services; provide better user experience than offline medical institutions; use big data and fee advantages to screen doctors to match users' consultation needs instead of screening by the rank of doctors only; and cooperate with commercial insurance providers to provide innovative health care packages

Assessment of differential gene expression in human peripheral nerve injury

BACKGROUND: Microarray technology is a powerful methodology for identifying differentially expressed genes. However, when thousands of genes in a microarray data set are evaluated simultaneously by fold changes and significance tests, the probability of detecting false positives rises sharply. In this first microarray study of brachial plexus injury, we applied and compared the performance of two recently proposed algorithms for tackling this multiple testing problem, Significance Analysis of Microarrays (SAM) and Westfall and Young step down adjusted p values, as well as t-statistics and Welch statistics, in specifying differential gene expression under different biological states. RESULTS: Using SAM based on t statistics, we identified 73 significant genes, which fall into different functional categories, such as cytokines / neurotrophin, myelin function and signal transduction. Interestingly, all but one gene were down-regulated in the patients. Using Welch statistics in conjunction with SAM, we identified an additional set of up-regulated genes, several of which are engaged in transcription and translation regulation. In contrast, the Westfall and Young algorithm identified only one gene using a conventional significance level of 0.05. CONCLUSION: In coping with multiple testing problems, Family-wise type I error rate (FWER) and false discovery rate (FDR) are different expressions of Type I error rates. The Westfall and Young algorithm controls FWER. In the context of this microarray study, it is, seemingly, too conservative. In contrast, SAM, by controlling FDR, provides a promising alternative. In this instance, genes selected by SAM were shown to be biologically meaningful

Population genomic analysis reveals that homoploid hybrid speciation can be a lengthy process

This work was supported by grants from National key research and development program (2017YFC0505203), National Natural Science Foundation of China (grant numbers 31590821, 31670665, 91731301), National Key Project for Basic Research (2014CB954100), CAS “Light of West China” Program and Graduate Student’s Research and Innovation Fund of Sichuan University (2018YJSY007).An increasing number of species are thought to have originated by homoploid hybrid speciation (HHS), but in only a handful of cases are details of the process known. A previous study indicated that Picea purpurea, a conifer in the Qinghai–Tibet Plateau (QTP), originated through HHS from P. likiangensis and P. wilsonii. To investigate this origin in more detail, we analysed transcriptome data for 114 individuals collected from 34 populations of the three Picea species from their core distributions in the QTP. Phylogenetic, principal component and admixture analyses of nuclear SNPs showed the species to be delimited genetically and that P. purpurea was admixed with approximately 60% of its ancestry derived from P. wilsonii and 40% from P. likiangensis. Coalescent simulations revealed the best‐fitting model of origin involved formation of an intermediate hybrid lineage between P. likiangensis and P. wilsonii approximately 6 million years ago (mya), which backcrossed to P. wilsonii to form P. purpurea approximately one mya. The intermediate hybrid lineage no longer exists and is referred to as a “ghost” lineage. Our study emphasizes the power of population genomic analysis combined with coalescent analysis for reconstructing the stages involved in the origin of a homoploid hybrid species over an extended period. In contrast to other studies, we show that these stages can in some instances span a relatively long period of evolutionary time.PostprintPeer reviewe

Whole-Genome Sequencing of Individuals from a Founder Population Identifies Candidate Genes for Asthma

Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS

Incorporating Alternative Polygenic Risk Scores into the BOADICEA Breast Cancer Risk Prediction Model

Background: The multifactorial risk prediction model BOADI-CEA enables identification of women at higher or lower risk of developing breast cancer. BOADICEA models genetic susceptibility in terms of the effects of rare variants in breast cancer susceptibility genes and a polygenic component, decomposed into an unmeasured and a measured component -the polygenic risk score (PRS). The current version was developed using a 313 SNP PRS. Here, we evaluated approaches to incorporating this PRS and alternative PRS in BOADICEA.Methods: The mean, SD, and proportion of the overall polygenic component explained by the PRS (a2) need to be estimated. a was estimated using logistic regression, where the age-specific log-OR is constrained to be a function of the age-dependent polygenic relative risk in BOADICEA; and using a retrospective likelihood (RL) approach that models, in addition, the unmeasured polygenic component.Results: Parameters were computed for 11 PRS, including 6 variations of the 313 SNP PRS used in clinical trials and imple-mentation studies. The logistic regression approach underestimates a, as compared with the RL estimates. The RL a estimates were very close to those obtained by assuming proportionality to the OR per 1 SD, with the constant of proportionality estimated using the 313 SNP PRS. Small variations in the SNPs included in the PRS can lead to large differences in the mean.Conclusions: BOADICEA can be readily adapted to different PRS in a manner that maintains consistency of the model.Impact : The methods described facilitate comprehensive breast cancer risk assessment