Biology subjects

Cao, X.

Publications and source records attributed to Cao, X..

At least 217 records · Page 12Linked to original sources

bioRxiv2019

The Mammalian Cytosolic Thioredoxin Reductase Pathway Acts via a Membrane Protein to Reduce ER-localised Proteins

Folding of proteins entering the mammalian secretory pathway requires the insertion of the correct disulfide bonds. Disulfide formation involves both an oxidative pathway for their insertion and a reductive pathway to remove incorrectly formed disulfides. Reduction of these disulfides is critical for correct folding and degradation of misfolded proteins. Previously, we showed that the reductive pathway is driven by NADPH generated in the cytosol. Here, by reconstituting the pathway using purified proteins and ER microsomal membranes, we demonstrate that the thioredoxin reductase system provides the minimal cytosolic components required for reducing proteins within the ER lumen. In particular, saturation of the pathway and its protease sensitivity demonstrates the requirement for a membrane protein to shuttle electrons from the cytosol to the ER lumen. These results provide compelling evidence for the critical role of the cytosol in regulating ER redox homeostasis to ensure correct protein folding and to facilitate the degradation of misfolded ER proteins.

cell biology↗

bioRxiv2019

Dynamic brain network changes reflect neuroplasticity: molecular and cognitive evidence

Resting-state functional brain networks demonstrate dynamic changes on the scale of seconds. However, their genetic mechanisms and profound cognitive relevance remain less explored. We identified 459 Bonferroni-corrected genes, by associating temporal variability of regional functional connectivity patterns with Allen Brain gene expression profiles across the whole brain. These genes are partially verified in developing human brain gene expression in the BrainSpan Atlas, and are found to be involved in the enrichment of short- and long-term plasticity processes. The former process depends on synaptic plasticity, involving ion transmembrane transport, action potential propagation, and modulation. The latter process depends on structural plasticity, including axonal genesis, development, and guidance. Results from a longitudinal cognitive training study further revealed that baseline variability of the hippocampal network predicted cognitive ability changes after three months of training. Our genetic association results suggest that the short-term plasticity processes may account for the rapid changes of regional functional connectivity, while the underlying long-term plasticity processes explain why temporal variability can predict long-term learning outcomes. To our knowledge, this is the first demonstration that measuring the dynamic brain network can lead to a non-invasive quantification of neuroplasticity in humans.

neuroscience↗

bioRxiv2019

Oscillatory Viscoelastic Microfluidics for Efficient Focusing and Separation of Nanoscale Species

The ability to precisely control particle migration within microfluidic systems is essential for focusing, separating, counting and detecting a wide range of biological species. To date, viscoelastic microfluidic systems have primarily been applied to the focusing, separation and isolation of micron-sized species, with their use in nanoparticle manipulations being underdeveloped and underexplored, due to issues related to nanoparticle diffusivity and a need for extended channel lengths. To overcome such issues, we herein present sheathless oscillatory viscoelastic microfluidics as a method for focusing and separating both micron and sub-micron species. To highlight the efficacy of our approach, we segment our study into three size regimes, namely micron (where characteristic particle dimensions are above 1 m), sub-micron (where characteristic dimensions are between 1 m and 100 nm) and nano (where characteristic dimensions are below 100 nm) regimes. Based on the ability to successfully manipulate particles in all these regimes, we demonstrate the successful isolation of p-bodies from biofluids (in the micron regime), the focusing of {lambda}-DNA (in the sub-micron regime) and the focusing of extracellular vesicles (in the nano-regime). Finally, we characterize the physics underlying viscoelastic microflows using a dimensionless number that relates the lateral velocity (due to elastic effects) to the diffusion constant of the species within the viscoelastic carrier fluid. Based on the ability to precisely manipulate species in all three regimes, we expect that sheathless oscillatory viscoelastic microfluidics will provide for significant new opportunities in a range of biological and life science applications.

bioengineering↗

bioRxiv2019

Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment

Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29 - 14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni.\n\nAUTHOR SUMMARYIt has been argued that drug resistance is unlikely to spread rapidly in helminth parasites infecting humans. This is based, at least in part, on the premise that resistance mutations are rare or absent within populations prior to treatment, and take a long time to reach appreciable frequencies because helminth parasite generation time is long. This argument is critically dependent on the starting frequency of resistance alleles - if high levels of \"standing variation\" for resistance are present prior to deployment of treatment, resistance may spread rapidly. We examined frequencies of oxamniquine resistance alleles present in Schistosoma mansoni from Africa and the Middle East where oxamniquine has seen minimal use. We found that oxamniquine resistance alleles are widespread in the Old World, ranging from 4.29% in the Middle East to 14.91% in East African parasite populations. Furthermore, we show that resistance alleles from West African and the Caribbean schistosomes share a common origin, suggesting that these alleles travelled to the New World with S. mansoni during the transatlantic slave trade. Together, these results demonstrate extensive standing variation for oxamniquine resistance. Our results have important implications for both drug treatment policies and drug development efforts, and demonstrate the power of molecular surveillance approaches for guiding helminth control.

evolutionary biology↗

bioRxiv2019

Time-dependent Canonical Correlation Analysis for Multilevel Time Series

Canonical Correlation Analysis is a technique in multivariate data analysis for finding linear projections that maximize the correlation between two groups of variables. The correlations are typically defined without accounting for the serial correlations between observations, a typical setting for time series data. To understand the coupling dynamics and temporal variations between the two time-varying sources, we introduce the time-dependent canonical correlation analysis (TDCCA), a method for inferring time-dependent canonical vectors from multilevel time series data. A convex formulation of the problem is proposed, which leverages the singular value decomposition (SVD) characterization of all solutions of the CCA problem. We use simulated datasets to validate the proposed algorithm. Moreover, we propose a novel measure, canonical correlation variation as another way to assess the dynamic pattern of brain connections and we apply it to a real resting state fMRI dataset to study the aging effects on brain connectivity. Additionally, we explore our proposed method in a task-related fMRI to detect the temporal dynamics due to different motor tasks. We show that, compared to extant methods, the TDCCA-based approach not only detect temporal changes but also improves feature extraction. Together, this paper contributes broadly to new computational methodologies in understanding multilevel time series.

neuroscience↗

bioRxiv2019

Monitoring soil microorganisms with community-level physiological profiles using Biolog EcoPlatesTM in Chaohu lakeside wetland, east China

Under the circumstance of wetland degradation, we used Biolog EcoPlates method to investigate the impact of ecological restoration on the function of topsoil microbial communities by monitoring their metabolic diversity around Chaohu lakeside wetland. Four restoration patterns including reed shoaly land (RL), poplar plantation land (PL), abandoned shoaly grassland (GL) and cultivated flower land (FL) were selected. The result showed a rapid growth trend at the initial stage of incubation, following the fastest change rate at 72 h in both dormant and growing seasons, and the AWCD values of RL pattern was the highest at the detection points of each culture time, while the GL were the lowest. The calculation of diversity indicators also displayed significant lower McIntosh index in dormant season and Shannon-Wiener index in growing season in GL than in the others (P < 0.05). Carbohydrates and carboxylic acids were found to be the dominant substrates used in dormant season, whereas amino acids, polymers and phenolic acids were increasingly utilized by the microbial communities in growing season. We observed soil total potassium as the key factor that significantly affected the utilization efficiency of different carbon sources in both seasons (P < 0.05).

ecology↗

bioRxiv2019

Computational comparison of developmental cell lineage trees by alignments

The developmental cell lineage tree, which records every cell division event and the terminal developmental state of each single cell, is one of the most important traits of multicellular organisms, as well as key to many significant unresolved questions in biology. Recent technological breakthroughs are paving the way for direct determination of cell lineage trees, yet a general framework for the computational analysis of lineage trees, in particular an algorithm to compare two lineage trees, is still lacking. Based on previous findings that the same developmental program can be invoked by different cells on the lineage tree to produce highly similar subtrees, we designed Developmental Cell Lineage Tree Alignment (DELTA), an algorithm that exhaustively searches for lineage trees with phenotypic resemblance in lineal organization of terminal cells, meanwhile resolving detailed correspondence between individual cells. Using simulated and nematode lineage trees, we demonstrated DELTAs capability of revealing similarities of developmental programs by lineal resemblances. Moreover, DELTA successfully identifies gene deletion-triggered homeotic cell fate transformations, reveals functional relationship between mutants by quantifying their lineal similarities, and finds the evolutionary correspondence between cell types defined non-uniformly for different species. DELTA establishes novel foundation for comparative study of lineage trees, much like sequence alignment algorithm for biological sequences, and along with the increase of lineage tree data, will likely bring unique insights for the myriads of important questions surrounding cell lineage trees.

bioinformatics↗

bioRxiv2019

Protein secondary structure determines the temporal relationship between folding and disulfide formation

How and when disulfides form in proteins during their folding is a fundamental question in cell biology. Two models describe the relationship between disulfide formation and folding, the folded precursor model, in which formation of nascent structure occurs prior to the disulfides and the quasi-stochastic model where disulfides form prior to complete domain folding. Here we investigate oxidative folding within a cellular milieu of three structurally diverse substrates in order to understand the folding mechanisms required to achieve correct cysteine coupling. We use a eukaryotic translation system in which we can manipulate the redox conditions and produce stalled translation intermediates representative of different stages of translocation. We identify different disulfide bonded isomers by non-reducing SDS-PAGE. Using this approach, we determined whether each substrate followed a folding driven or disulfide driven mechanism. Our results demonstrate that the folding model is substrate-dependent with disulfides forming prior to complete domain folding in a cysteine-rich domain lacking secondary structure, whereas disulfide formation was absent in proteins with defined structural elements. In addition, we demonstrate the presence and rearrangement of non-native disulfides specifically in substrates following the quasi-stochastic model. These findings demonstrate why non-native disulfides are prevented from forming in proteins with well-defined secondary structure. Significance statementA third of human proteins contain structural elements called disulfide bonds that are often crucial for stability and function. Disulfides form between cysteines in the specialised environment of the endoplasmic reticulum (ER), during the complex process of protein folding. Many proteins contain multiple cysteines that can potentially form correct or incorrect cysteine pairings. To investigate how correct disulfide pairs are formed in a biological context, we developed an experimental approach to assess disulfide formation and rearrangement as proteins enter the ER. We found that a disulfide-dense protein domain with atypical secondary structure undergoes disulfide orchestrated folding as it enters the ER and is prone to incorrect disulfide formation. In contrast, proteins with defined secondary structure form folding dependent, native disulfides. These findings show how different mechanisms of disulfide formation can be rationalised from structural features of the folding domains.

biochemistry↗

bioRxiv2019

EpiAlignment: alignment with both DNA sequence and epigenomic data

Comparative epigenomics, by subjecting both epigenome and genome to interspecies comparison, has become a powerful approach to reveal regulatory features of the genome. Thus elucidated regulatory features surpassed the information derived from comparison of genomic sequences alone. Here, we present EpiAlignment, a web-based tool to align genomic regions with both DNA sequence and epigenomic data. EpiAlignment takes DNA sequence and epigenomic profiles derived by ChIP-seq, DNase-seq, or ATAC-seq from two species as input data, and outputs the best semi-global alignments. These alignments are based on EpiAlignment scores, computed by a dynamic programming algorithm that accounts for both sequence alignment and epigenome similarity. For timely response, the EpiAlignment web server automatically initiates up to 140 computing threads depending on the size of user input data. For users convenience, we have pre-compiled the comparable human and mouse epigenome datasets in matched cell types and tissues from the Roadmap Epigenomics and ENCODE consortia. Users can either upload their own data or select pre-compiled datasets as inputs for EpiAlignment analyses. Results are presented in graphical and tabular formats where the entries can be interactively expanded to visualize additional features of these aligned regions. EpiAlignment is available at https://epialign.ucsd.edu/.

bioinformatics↗

bioRxiv2019

Dissection of the cellular function of the ZBED6 transcription factor in mouse myoblast cells using gene editing, RNAseq and proteomics

The transcription factor ZBED6 acts as a repressor of Igf2 and affects directly or indirectly the transcriptional regulation of thousands of genes. Here, we use gene editing in mouse C2C12 myoblasts and show that ZBED6 regulates Igf2 exclusively through its binding site 5'-GGCTCG-3' in intron 1 of Igf2. Deletion of this motif (Igf2{Delta}GGCT) or complete ablation of Zbed6 leads to ~20-fold up-regulation of IGF2 protein. Quantitative proteomics revealed an activation of Ras signaling pathway in both Zbed6-/- and Igf2{Delta}GGCT myoblasts, and a significant enrichment of mitochondrial membrane proteins among proteins showing altered expression in Zbed6-/- myoblasts. Both Zbed6-/- and Igf2{Delta}GGCT myoblasts showed a faster growth rate and developed myotube hypertrophy. These cells exhibited an increased O2 consumption rate, due to IGF2 up-regulation. Transcriptome analysis revealed ~30% overlap between differentially expressed genes in Zbed6-/- and Igf2{Delta}GGCT myotubes, with an enrichment of up-regulated genes involved in muscle development. In contrast, ZBED6-overexpression in myoblasts led to cell apoptosis, cell cycle arrest, reduced mitochondrial activities and ceased myoblast differentiation. The similarities in growth and differentiation phenotypes observed in Zbed6-/- and Igf2{Delta}GGCT myoblasts demonstrates that ZBED6 affects mitochondrial activity and myogenesis largely through its regulation of IGF2 expression. This study suggests that the interaction between ZBED6-Igf2 may be a therapeutic target for human diseases where anabolism is impaired.

molecular biology↗

bioRxiv2019

Genotypic frequencies at equilibrium for polysomic inheritance under double-reduction

Polyploids are organisms whose genomes consist of more than two complete sets of chromosomes. Both autopolyploids and allopolyploids may display polysomic inheritance. A peculiarity of polysomic inheritance is multivalent formation during meiosis resulting in double-reduction, which occurs when sister chromatid fragments are segregated into the same gamete. Double-reduction can result in gametes carrying identical-by-descent alleles and slightly increasing homozygosity. This will cause the genotypic frequencies to deviate from expected values and will thus bias the results of standard population genetic analytical methods used in molecular ecology and selective breeding. In this study, we extend existing double-reduction models to account for any even level of ploidy, and derive the symbolic expressions for genotypic frequencies via two methods. Inbreeding coefficients and heterozygosity under double-reduction and inbreeding are also calculated. Numerical solutions obtained by computer simulations are compared with analytical solutions predicted by the model to validate the model.

genetics↗

bioRxiv2018

SmbHLH37 functions antagonistically with SmMYC2 in regulating jasmonate-mediated biosynthesis of phenolic acids in Salvia miltiorrhiza

Jasmonates (JAs) are integral to various defense responses and induce biosynthesis of many secondary metabolites. MYC2, a basic helix-loop-helix (bHLH) transcription factor (TF), acts as a transcriptional activator of JA signaling. MYC2 is repressed by the JASMONATE ZIM-domain (JAZ) proteins in the absence of JA, but de-repressed by the protein complex SCFCOI1 on perception of JA. We previously reported that overexpression of SmMYC2 promotes the production of salvianolic acid B (Sal B) in Salvia miltiorrhiza. However, the responsible molecular mechanism is unclear. Here, we showed that SmMYC2 binds to and activates the promoters of its target genes SmTAT1, SmPAL1, and SmCYP98A14 to activate Sal B accumulations. SmbHLH37, a novel bHLH gene significantly up-regulated by constitutive expression of SmMYC2, was isolated from S. miltiorrhiza for detailed functional characterization. SmbHLH37 forms a homodimer and interacts with SmJAZ3/8. Overexpression of SmbHLH37 substantially decreased yields of Sal B. SmbHLH37 binds to the promoters of its target genes SmTAT1 and SmPAL1 and blocks their expression to suppress the pathway for Sal B biosynthesis. These results indicate that SmbHLH37 negatively regulates JA signaling and functions antagonistically with SmMYC2 in regulating Sal B biosynthesis in S. miltiorrhiza.

plant biology↗

bioRxiv2018

Wheat avenin-like protein and its significant Fusarium Head Blight resistant functions

Wheat Avenin-like proteins (TaALP) are atypical storage proteins belonging to the Prolamin superfamily. Previous studies on ALPs have focused on the proteins positive effects on dough strength, whilst no correlation has been made between TaALPs and the plant immune system. Here, we performed genome-wide characterization of ALP encoding genes in bread wheat. In silico analyses indicated the presence of critical peptides in TaALPs that are active in the plant immune system. Pathogenesis-related nucleotide motifs were also identified in the putative promoter regions of TaALP encoding genes. RT-PCR was performed on TaALP and previously characterised pathogenesis resistance genes in developing wheat caryopses under control and Fusarium graminearum infection conditions. The results showed that TaALP and NMT genes were upregulated upon F. graminearum inoculation. mRNA insitu hybridization showed that TaALP genes were expressed in the embryo, aleurone and sub-aleurone layer cells. Seven TaALP genes were cloned for the expression of recombinant proteins in Escherichia coli, which displayed significant inhibitory function on F. graminearum under anti-fungal tests. In addition, FHB index association analyses showed that allelic variations of two ALP genes on chromosome 7A were significantly correlated with FHB symptoms. Over-expression of an ALP gene on chromosome 7A showed an enhanced resistance to FHB. Yeast two Hybridization results revealed that ALPs have potential proteases inhibiting effect on metacaspases and beta-glucosidases. A vital infection process related pathogen protein, F. graminearum Beta-glucosidase was found to interact with ALPs. Our study is the first to report a class of wheat storage protein or gluten protein with biochemical functions. Due to its abundance in the grain and the important multi-functions, the results obtained in the current study are expected to have a significant impact on wheat research and industry.

molecular biology↗

bioRxiv2018

Effects of the anesthetic MS-222 on silver pomfret (Pampus argenteus) juveniles under aquaculture treatment stresses

The silver pomfret (Pampus argenteus) is a major economically important marine fish in China. However, P. argenteus is sensitive to many stress factors and susceptible to injury. This problem could be resolved using anesthesia. We determined the lowest effective dose (LED) of tricaine methanesulfonate (MS-222) and assessed the longest safe deep anesthesia time and effect after aquaculture treatment stresses. P. argenteus juveniles were exposed to six concentrations of MS-222 (10, 25, 50, 75, 100, and 125 mg L-1); LED was established at 75 mg L-1. The juveniles were exposed to different deep anesthesia times (4, 7, 10, 12, and 15 min) at 75 mg L-1; the longest safe deep anesthesia time under LED was 10 min. Finally, the juveniles were randomly divided into four groups: control group (CG), draining group (DG, drain), anesthetic group (AG, drain + MS-222 + aquaculture treatment); and non-anesthetic group (NAG, drain + aquaculture treatment). Plasma cortisol levels in the NAG, AG, DG, and CG groups were 38.739 {+/-} 1.065 (highest), 25.083 {+/-} 0.587, 28.644 {+/-} 0.612, and 22.620 {+/-} 0.836 ng mL-1 (lowest). The AG group showed significant differences in superoxide dismutase, catalase, and malondialdehyde activities, except for glutathione. HSP70, HSP90, GR1, and GR2 mRNA levels in the NAG group increased sharply in response to stressors. GR1 and GR2 mRNA levels in the AG group also increased significantly, whereas HSP70 and HSP90 mRNA levels showed no significant differences. Thus, MS-222 can reduce oxidative damage, stress reaction, and resistance to aquaculture treatment stresses in P. argenteus.

animal behavior and cognition↗

bioRxiv2018

Nitric oxide synthase-mediated early nitric oxide-burst alleviates drought-induced oxidative damage in ammonium supplied-rice roots

Ammonium (NH4+) can enhance rice drought tolerance in comparison to nitrate (NO3-). The mechanism underpinning this relationship was investigated based on the time-dependent nitric oxide (NO) production and its protective role in oxidative stress of NH4+-/NO3--supplied rice under drought. An early burst of NO was induced by drought 3h after root NH4+ treatment but not after NO3- treatment. Root oxidative damage induced by drought was significantly higher in NO3- than in NH4+-treatment due to its reactive oxygen species accumulation. Inducing NO production by applying NO donor 3h after NO3- treatment alleviated the oxidative damage, while inhibiting the early NO burst increased root oxidative damage in NH4+ treatment. Application of nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) completely suppressed NO synthesis in roots 3h after NH4+ treatment and aggravated drought-induced oxidative damage, indicating the aggravation of oxidative damage might have resulted from changes in NOS-mediated early NO burst. Drought also increased root antioxidant enzymes activities, which were further induced by NO donor but repressed by NO scavenger and NOS inhibitor in NH4+-treated roots. Thus, the NOS-mediated early NO burst plays an important role in alleviating oxidative damage induced by drought by enhancing antioxidant defenses in NH4+-supplied rice roots.\n\nHighlightNOS-mediated early NO burst plays an important role in alleviating oxidative damage induced by water stress, by enhancing the antioxidant defenses in roots supplemented with NH4+

physiology↗

bioRxiv2018

Balance of Mechanical Forces Drives Endothelial Gap Formation and May Facilitate Cancer and Immune-Cell Extravasation

The formation of gaps in the endothelium is a crucial process underlying both cancer and immune cell extravasation, contributing to the functioning of the immune system during infection, the unfavorable development of chronic inflammation and tumor metastasis. Here, we present a stochastic-mechanical multiscale model of an endothelial cell monolayer and show that the dynamic nature of the endothelium leads to spontaneous gap formation, even without intervention from the transmigrating cells. These gaps preferentially appear at the vertices between three endothelial cells, as opposed to the border between two cells. We quantify the frequency and lifetime of these gaps, and validate our predictions experimentally. Interestingly, we find experimentally that cancer cells also preferentially extravasate at vertices, even when they first arrest on borders. This suggests that extravasating cells, rather than initially signaling to the endothelium, might exploit the autonomously forming gaps in the endothelium to initiate transmigration.

bioengineering↗

bioRxiv2018

Sirt7 regulates circadian phase coherence of hepatic circadian clock via a body temperature/Hsp70-Sirt7-Cry1 axis

The biological clock is generated in the hypothalamic suprachiasmatic nucleus (SCN), which synchronizes peripheral oscillators to coordinate physiological and behavioral activities throughout the body. Disturbance of circadian phase coherence between the central and peripheral could disrupt rhythms and thus cause diseases and aging. Here, we identified hepatic Sirt7 as an early element responsive to light, which ensures the phase coherence in mouse liver. Loss of Sirt7 leads to advanced liver circadian phase; restricted feeding in daytime entrains hepatic clock more rapidly in Sirt7-/- mice compared to wild-types. Molecularly, a light-driven body temperature (BT) oscillation induces rhythmic expression of Hsp70, which binds to and promotes the ubiquitination and proteasomal degradation of Sirt7. Sirt7 rhythmically deacetylates Cry1 on K565/579 and promotes Fbxl3-mediated degradation, thus coupling hepatic clock to the central pacemaker. Together, our data identify a novel BT/Hsp70-Sirt7-Cry1 axis, which transmits biological timing cues from the central to the peripheral and ensures circadian phase coherence in livers.

molecular biology↗

bioRxiv2018

Development of a joint evolutionary model for the genome and the epigenome

BackgroundInterspecies epigenome comparisons yielded functional information that cannot be revealed by genome comparison alone, begging for theoretical advances that enable principled analysis approaches. Whereas probabilistic genome evolution models provided theoretical foundation to comparative genomics studies, it remains challenging to extend DNA evolution models to epigenomes.\n\nResultsWe present an effort to develop ab initio evolution models for epigenomes, by explicitly expressing the joint probability of multispecies DNA sequences and histone modifications on homologous genomic regions. This joint probability is modeled as a mixture of four components representing four evolutionary hypotheses, namely dependence and independence of interspecies epigenomic variations to sequence mutations and to sequence insertions and deletions (indels). For model fitting, we implemented a maximum likelihood method by coupling downhill simplex algorithm with dynamic programming. Based on likelihood comparisons, the model can be used to infer whether interspecies epigenomic variations depend on mutation or indels in local genomic sequences. We applied this model to analyze DNase hypersensitive regions and spermatid H3K4me3 ChIP-seq data from human and rhesus macaque. Approximately 5.5% of homologous regions in the genomes exhibited H3K4me3 modification in either species, among which approximately 67% homologous regions exhibited sequence-dependent interspecies H3K4me3 variations. Mutations accounted for less sequence-dependent H3K4me3 variations than indels. Among transposon-mediated indels, ERV1 insertions and L1 insertions were most strongly associated with H3K4me3 gains and losses, respectively.\n\nConclusionThis work initiates a class of probabilistic evolution models that jointly model the genomes and the epigenomes, thus helps to bring evolutionary principles to comparative epigenomic studies.

bioinformatics↗