Sequence Fusion Algorithm of Tumor Gene Sequencing and Alignment Based on Machine Learning

With the rapid development of DNA high-throughput testing technology, there is a high correlation between DNA sequence variation and human diseases, and detecting whether there is variation in DNA sequence has become a hot research topic at present. DNA sequence variation is relatively rare, and the establishment of DNA sequence sparse matrix, which can quickly detect and reason fusion variation point, has become an important work of tumor gene testing. Because there are differences between the current comparison software and mutation detection software in detecting the same sample, there are errors between the results of derivative sequence comparison and the detection of mutation. In this paper, SNP and InDel detection methods based on machine learning and sparse matrix detection are proposed, and VarScan 2, Genome Analysis Toolkit (GATK), BCFtools, and FreeBayes are compared. In the research of SNP and InDel detection with intelligent reasoning, the experimental results show that the detection accuracy and recall rate are better when the depth is increasing. The reasoning fusion method proposed in this paper has certain advantages in comparison effect and discovery in SNP and InDel and has good effect on swelling and pain gene detection.

Factors Driving DNA Methylation Variation in Human Blood

Epigenetic changes are required for normal development and health, and can also underlie disease states; yet, the nature and respective contribution of factors that drive epigenetic variation in humans remain to be fully characterized. Here, we assessed how the blood DNA methylome of 958 adults is affected by genetic variation, aging, sex and 139 diverse environmental exposures, and investigated whether these effects are direct or mediated by changes in cellular composition, measured by deep immunophenotyping. We show that cellular heterogeneity and DNA sequence variation are the strongest predictors of DNA methylation levels. We identify latent cytomegalovirus infection as a major driver of DNA methylation variation and delineate three distinct effects of aging on DNA methylation, including increased dispersion consistent with epigenetic drift. Our rich dataset provides a unique resource for the design and interpretation of epigenetic studies and highlight critical factors in medical epigenomics studies.

Phenotypic plasticity explains apparent reverse evolution of fat synthesis in parasitic wasps

Numerous cases of evolutionary trait loss and regain have been reported over the years. Here, we argue that such reverse evolution can also become apparent when trait expression is plastic in response to the environment. We tested this idea for the loss and regain of fat synthesis in parasitic wasps. We first show experimentally that the wasp Leptopilina heterotoma switches lipogenesis on in a fat-poor environment, and completely off in a fat-rich environment. Plasticity suggests that this species did not regain fat synthesis, but that it can be switched off in some environmental settings. We then compared DNA sequence variation and protein domains of several more distantly related parasitoid species thought to have lost lipogenesis, and found no evidence for non-functionality of key lipogenesis genes. This suggests that other parasitoids may also show plasticity of fat synthesis. Last, we used individual-based simulations to show that a switch for plastic expression can remain functional in the genome for thousands of generations, even if it is only used sporadically. The evolution of plasticity could thus also explain other examples of apparent reverse evolution.

Mutational processes in cancer preferentially affect binding of particular transcription factors

Protein binding microarrays provide comprehensive information about the DNA binding specificities of transcription factors (TFs), and can be used to quantitatively predict the effects of DNA sequence variation on TF binding. There has also been substantial progress in dissecting the patterns of mutations, i.e., the "mutational signatures", generated by different mutational processes. By combining these two layers of information we can investigate whether certain mutational processes tend to preferentially affect binding of particular classes of TFs. Such preferential alterations of binding might predispose to particular oncogenic pathways. We developed and implemented a method, termed "Signature-QBiC", that integrates protein binding microarray data with the signatures of mutational processes, with the aim of predicting which TFs’ binding profiles are preferentially perturbed by particular mutational processes. We used Signature-QBiC to predict the effects of 47 signatures of mutational processes on 582 human TFs. Pathway analysis showed that binding of TFs involved in NOTCH1 signaling is strongly affected by the signatures of several mutational processes, including exposure to ultraviolet radiation. Additionally, toll-like-receptor signaling pathways are also vulnerable to disruption by this exposure. This study provides a novel overview of the effects of mutational processes on TF binding and the potential of these processes to activate oncogenic pathways through mutating TF binding sites.

Copper Ions Induce DNA Sequence Variation in Zygotic Embryo Culture-Derived Barley Regenerants

In vitro tissue culture could be exploited to study cellular mechanisms that induce sequence variation. Altering the metal ion composition of tissue culture medium affects biochemical pathways involved in tissue culture-induced variation. Copper ions are involved in the mitochondrial respiratory chain and Yang cycle. Copper ions may participate in oxidative mutations, which may contribute to DNA sequence variation. Silver ions compete with copper ions to bind to the complex IV subunit of the respiratory chain, thus affecting the Yang cycle and DNA methylation. The mechanisms underlying somaclonal variation are unknown. In this study, we evaluated embryo-derived barley regenerants obtained from a single double-haploid plant via embryo culture under varying copper and silver ion concentrations and different durations of in vitro culture. Morphological variation among regenerants and the donor plant was not evaluated. Methylation-sensitive Amplified Fragment Length Polymorphism analysis of DNA samples showed DNA methylation pattern variation in CG and CHG (H = A, C, or T) sequence contexts. Furthermore, modification of in vitro culture conditions explained DNA sequence variation, demethylation, and de novo methylation in the CHG context, as indicated by analysis of variance. Linear regression indicated that DNA sequence variation was related to de novo DNA methylation in the CHG context. Mediation analysis showed the role of copper ions as a mediator of sequence variation in the CHG context. No other contexts showed a significant sequence variation in mediation analysis. Silver ions did not act as a mediator between any methylation contexts and sequence variation. Thus, incorporating copper ions in the induction medium should be treated with caution.

Epimutations driven by small RNAs arise frequently but have limited duration in a metazoan organism

Epigenetic regulation involves changes in gene expression independent of DNA sequence variation that are inherited through cell division (Holliday, 2006). In addition to a fundamental role in cell differentiation, some epigenetic changes can also be transmitted transgenerationally through meiosis (Heard and Martienssen, 2014). Epigenetic alterations (“epimutations”) could thus contribute to heritable variation within populations and be subject to evolutionary processes such as natural selection and drift (Burggren, 2016). However, this suggestion is controversial, partly because unlike classical mutations involving DNA sequence changes, key parameters such as the rate at which epimutations arise and their persistence are unknown. Here, we perform the first genome-wide study of epimutations in a metazoan organism. We use experimental evolution to characterise the rate, spectrum and stability of epimutations driven by small silencing RNAs in the model nematode C. elegans. We show that epimutations arise spontaneously at a rate ∼25 times greater than DNA sequence changes and typically have short half-lives of 2-3 generations. Nevertheless, some epimutations last at least 10 generations. Epimutations thus may contribute to evolutionary processes over a short timescale but are unlikely to bring about long-term divergence without further DNA sequence changes.