Genetic mapping of novel modifiers for ApcMin induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice

Abstract Background Familial adenomatous polyposis is an inherited genetic disease, characterized by colorectal polyps. It is caused by inactivating mutations in the Adenomatous polyposis coli (Apc) gene. Mice carrying a nonsense mutation in the Apc gene at R850, which is designated ApcMin/+ (Multiple intestinal neoplasia), develop intestinal adenomas. Several genetic modifier loci of Min (Mom) were previously mapped, but so far, most of the underlying genes have not been identified. To identify novel modifier loci associated with ApcMin/+, we performed quantitative trait loci (QTL) analysis for polyp development using 49 F1 crosses between different Collaborative Cross (CC) lines and C57BL/6 J-ApcMin/+mice. The CC population is a genetic reference panel of recombinant inbred lines, each line independently descended from eight genetically diverse founder strains. C57BL/6 J-ApcMin/+ males were mated with females from 49 CC lines. F1 offspring were terminated at 23 weeks and polyp counts from three sub-regions (SB1–3) of small intestinal and colon were recorded. Results The number of polyps in all these sub-regions and colon varied significantly between the different CC lines. At 95% genome-wide significance, we mapped nine novel QTL for variation in polyp number, with distinct QTL associated with each intestinal sub-region. QTL confidence intervals varied in width between 2.63–17.79 Mb. We extracted all genes in the mapped QTL at 90 and 95% CI levels using the BioInfoMiner online platform to extract, significantly enriched pathways and key linker genes, that act as regulatory and orchestrators of the phenotypic landscape associated with the ApcMin/+ mutation. Conclusions Genomic structure of the CC lines has allowed us to identify novel modifiers and confirmed some of the previously mapped modifiers. Key genes involved mainly in metabolic and immunological processes were identified. Future steps in this analysis will be to identify regulatory elements – and possible epistatic effects – located in the mapped QTL.

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A comparison of population types used for QTL mapping in Arabidopsis thaliana

Plant Genetic Resources ◽

10.1017/s1479262111000086 ◽

2011 ◽

Vol 9 (2) ◽

pp. 185-188 ◽

Cited By ~ 15

Author(s):

Joost J. B. Keurentjes ◽

Glenda Willems ◽

Fred van Eeuwijk ◽

Magnus Nordborg ◽

Maarten Koornneef

Keyword(s):

Qtl Mapping ◽

Recombinant Inbred Lines ◽

Genomic Structure ◽

Natural Populations ◽

Low Frequency ◽

Advantages And Disadvantages ◽

Genome Wide ◽

Different Types ◽

Mapping Populations

In Arabidopsis, a variety of mapping populations have been used for the detection of quantitative trait loci (QTLs) responsible for natural variation. In this study, we present an overview of the advantages and disadvantages of the different types of populations used. To do this, we compare the results of both experimental and natural populations for the commonly analysed trait flowering time. It is expected that genome wide association (GWA) mapping will be an increasingly important tool for QTL mapping because of the high allelic richness and mapping resolution in natural populations. In Arabidopsis, GWA mapping becomes ever more facilitated by the increasing availability of re-sequenced genomes of many accessions. However, specifically designed mapping populations such as recombinant inbred lines and near isogenic lines will remain important. The high QTL detection power of such experimental populations can identify spurious GWA associations, and their unique genomic structure is superior for investigating the role of low-frequency alleles. Future QTL studies will therefore benefit from a combined approach of GWA and classical linkage analysis.

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FAT4 Identified as a Potential Modifier of Orofacial Cleft Laterality

10.1101/2021.03.16.21253740 ◽

2021 ◽

Author(s):

Sarah W. Curtis ◽

Daniel Chang ◽

Miranda R. Sun ◽

Michael P. Epstein ◽

Jeffrey C. Murray ◽

...

Keyword(s):

Cleft Lip ◽

Genetic Factors ◽

Cleft Lip And Palate ◽

Genetic Modifier ◽

Upper Lip ◽

Orofacial Clefts ◽

Specific Domain ◽

Genome Wide ◽

Left And Right ◽

Genome Wide Significance

AbstractOrofacial clefts (OFCs) are common (1 in 700 births) congenital malformations that include cleft lip (CL) and cleft lip and palate (CLP). These OFC subtypes are also heterogeneous themselves, with the cleft lip occurring on the left, right, or both sides of the upper lip. Unilateral CL and CLP have a 2:1 bias towards left-sided clefts, suggesting a nonrandom process. Here, we performed a study of left- and right-sided clefts within the CL and CLP subtypes to better understand the genetic factors controlling cleft laterality. We conducted genome-wide modifier analyses by comparing cases that had right unilateral CL (RCL; N=130), left unilateral CL (LCL; N=216), right unilateral CLP (RCLP; N=416), or left unilateral CLP (LCLP; N=638), and identified a candidate region on 4q28, 400 kb downstream from FAT4, that approached genome-wide significance for LCL vs. RCL (p = 8.4×10−8). Consistent with its potential involvement as a genetic modifier of cleft lip, we found that Fat4 exhibits a specific domain of expression in the mesenchyme of the medial nasal processes that form the median upper lip. Overall, these results suggest that the epidemiological similarities in left-to right-sided clefts in CL and CLP are not reflected in the genetic association results.

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DNABERT: pre-trained Bidirectional Encoder Representations from Transformers model for DNA-language in genome

Bioinformatics ◽

10.1093/bioinformatics/btab083 ◽

2021 ◽

Author(s):

Yanrong Ji ◽

Zhihan Zhou ◽

Han Liu ◽

Ramana V Davuluri

Keyword(s):

Dna Sequences ◽

Regulatory Elements ◽

Ease Of Use ◽

Fine Tuning ◽

Supplementary Information ◽

Sequence Motifs ◽

Semantic Relationship ◽

Accurate Identification ◽

Conserved Sequence ◽

Genome Wide

Abstract Motivation Deciphering the language of non-coding DNA is one of the fundamental problems in genome research. Gene regulatory code is highly complex due to the existence of polysemy and distant semantic relationship, which previous informatics methods often fail to capture especially in data-scarce scenarios. Results To address this challenge, we developed a novel pre-trained bidirectional encoder representation, named DNABERT, to capture global and transferrable understanding of genomic DNA sequences based on up and downstream nucleotide contexts. We compared DNABERT to the most widely used programs for genome-wide regulatory elements prediction and demonstrate its ease of use, accuracy and efficiency. We show that the single pre-trained transformers model can simultaneously achieve state-of-the-art performance on prediction of promoters, splice sites and transcription factor binding sites, after easy fine-tuning using small task-specific labeled data. Further, DNABERT enables direct visualization of nucleotide-level importance and semantic relationship within input sequences for better interpretability and accurate identification of conserved sequence motifs and functional genetic variant candidates. Finally, we demonstrate that pre-trained DNABERT with human genome can even be readily applied to other organisms with exceptional performance. We anticipate that the pre-trained DNABERT model can be fined tuned to many other sequence analyses tasks. Availability and implementation The source code, pretrained and finetuned model for DNABERT are available at GitHub (https://github.com/jerryji1993/DNABERT). Supplementary information Supplementary data are available at Bioinformatics online.

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A genome-wide map of regulatory elements in zebrafish

Lab Animal ◽

10.1038/s41684-020-00695-7 ◽

2020 ◽

Vol 50 (1) ◽

pp. 17-17

Author(s):

Alexandra Le Bras

Keyword(s):

Regulatory Elements ◽

Genome Wide ◽

A Genome

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Epigenomic Analysis of RAD51 ChIP-seq Data Reveals cis-regulatory Elements Associated with Autophagy in Cancer Cell Lines

Cancers ◽

10.3390/cancers13112547 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2547

Author(s):

Keunsoo Kang ◽

Yoonjung Choi ◽

Hyeonjin Moon ◽

Chaelin You ◽

Minjin Seo ◽

...

Keyword(s):

Gene Regulation ◽

Homologous Recombination ◽

Cell Lines ◽

Regulatory Elements ◽

Binding Motif ◽

Genome Wide ◽

E Box ◽

Autophagy Pathway ◽

Mcf 7

RAD51 is a recombinase that plays a pivotal role in homologous recombination. Although the role of RAD51 in homologous recombination has been extensively studied, it is unclear whether RAD51 can be involved in gene regulation as a co-factor. In this study, we found evidence that RAD51 may contribute to the regulation of genes involved in the autophagy pathway with E-box proteins such as USF1, USF2, and/or MITF in GM12878, HepG2, K562, and MCF-7 cell lines. The canonical USF binding motif (CACGTG) was significantly identified at RAD51-bound cis-regulatory elements in all four cell lines. In addition, genome-wide USF1, USF2, and/or MITF-binding regions significantly coincided with the RAD51-associated cis-regulatory elements in the same cell line. Interestingly, the promoters of genes associated with the autophagy pathway, such as ATG3 and ATG5, were significantly occupied by RAD51 and regulated by RAD51 in HepG2 and MCF-7 cell lines. Taken together, these results unveiled a novel role of RAD51 and provided evidence that RAD51-associated cis-regulatory elements could possibly be involved in regulating autophagy-related genes with E-box binding proteins.

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Genome-wide identification and expression analysis of Raffinose synthetase family in cotton

BMC Bioinformatics ◽

10.1186/s12859-021-04276-4 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Ruifeng Cui ◽

Xiaoge Wang ◽

Waqar Afzal Malik ◽

Xuke Lu ◽

Xiugui Chen ◽

...

Keyword(s):

Abiotic Stress ◽

Expression Patterns ◽

Regulatory Elements ◽

Plant Leaves ◽

Motif Analysis ◽

Expression Levels ◽

Genome Wide ◽

Salt And Drought Stress ◽

Key Genes ◽

Stress Gene

Abstract Background The Raffinose synthetase (RAFS) genes superfamily is critical for the synthesis of raffinose, which accumulates in plant leaves under abiotic stress. However, it remains unclear whether RAFS contributes to resistance to abiotic stress in plants, specifically in the Gossypium species. Results In this study, we identified 74 RAFS genes from G. hirsutum, G. barbadense, G. arboreum and G. raimondii by using a series of bioinformatic methods. Phylogenetic analysis showed that the RAFS gene family in the four Gossypium species could be divided into four major clades; the relatively uniform distribution of the gene number in each species ranged from 12 to 25 based on species ploidy, most likely resulting from an ancient whole-genome polyploidization. Gene motif analysis showed that the RAFS gene structure was relatively conservative. Promoter analysis for cis-regulatory elements showed that some RAFS genes might be regulated by gibberellins and abscisic acid, which might influence their expression levels. Moreover, we further examined the functions of RAFS under cold, heat, salt and drought stress conditions, based on the expression profile and co-expression network of RAFS genes in Gossypium species. Transcriptome analysis suggested that RAFS genes in clade III are highly expressed in organs such as seed, root, cotyledon, ovule and fiber, and under abiotic stress in particular, indicating the involvement of genes belonging to clade III in resistance to abiotic stress. Gene co-expressed network analysis showed that GhRFS2A-GhRFS6A, GhRFS6D, GhRFS7D and GhRFS8A-GhRFS11A were key genes, with high expression levels under salt, drought, cold and heat stress. Conclusion The findings may provide insights into the evolutionary relationships and expression patterns of RAFS genes in Gossypium species and a theoretical basis for the identification of stress resistance materials in cotton.

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Genome-wide search and structural and functional analyses for late embryogenesis-abundant (LEA) gene family in poplar

BMC Plant Biology ◽

10.1186/s12870-021-02872-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zihan Cheng ◽

Xuemei Zhang ◽

Wenjing Yao ◽

Kai Zhao ◽

Lin Liu ◽

...

Keyword(s):

Gene Family ◽

Higher Plants ◽

Abiotic Stress Tolerance ◽

Gene Families ◽

Regulatory Elements ◽

Late Embryogenesis Abundant ◽

Genome Wide ◽

Lea Gene ◽

Late Embryogenesis ◽

Genome Wide Search

Abstract Background The Late Embryogenesis-Abundant (LEA) gene families, which play significant roles in regulation of tolerance to abiotic stresses, widely exist in higher plants. Poplar is a tree species that has important ecological and economic values. But systematic studies on the gene family have not been reported yet in poplar. Results On the basis of genome-wide search, we identified 88 LEA genes from Populus trichocarpa and renamed them as PtrLEA. The PtrLEA genes have fewer introns, and their promoters contain more cis-regulatory elements related to abiotic stress tolerance. Our results from comparative genomics indicated that the PtrLEA genes are conserved and homologous to related genes in other species, such as Eucalyptus robusta, Solanum lycopersicum and Arabidopsis. Using RNA-Seq data collected from poplar under two conditions (with and without salt treatment), we detected 24, 22 and 19 differentially expressed genes (DEGs) in roots, stems and leaves, respectively. Then we performed spatiotemporal expression analysis of the four up-regulated DEGs shared by the tissues, constructed gene co-expression-based networks, and investigated gene function annotations. Conclusion Lines of evidence indicated that the PtrLEA genes play significant roles in poplar growth and development, as well as in responses to salt stress.

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A Genome-Wide Analysis of Pathogenesis-Related Protein-1 (PR-1) Genes from Piper nigrum Reveals Its Critical Role during Phytophthora capsici Infection

Genes ◽

10.3390/genes12071007 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1007

Author(s):

Divya Kattupalli ◽

Asha Sreenivasan ◽

Eppurathu Vasudevan Soniya

Keyword(s):

Phytophthora Capsici ◽

Regulatory Elements ◽

Piper Nigrum ◽

Binding Motif ◽

Altered Expression ◽

Genome Wide ◽

A Genome ◽

Pathogenesis Related Protein ◽

Pathogenesis Related

Black pepper (Piper nigrum L.) is a prominent spice that is an indispensable ingredient in cuisine and traditional medicine. Phytophthora capsici, the causative agent of footrot disease, causes a drastic constraint in P. nigrum cultivation and productivity. To counterattack various biotic and abiotic stresses, plants employ a broad array of mechanisms that includes the accumulation of pathogenesis-related (PR) proteins. Through a genome-wide survey, eleven PR-1 genes that belong to a CAP superfamily protein with a caveolin-binding motif (CBM) and a CAP-derived peptide (CAPE) were identified from P. nigrum. Despite the critical functional domains, PnPR-1 homologs differ in their signal peptide motifs and core amino acid composition in the functional protein domains. The conserved motifs of PnPR-1 proteins were identified using MEME. Most of the PnPR-1 proteins were basic in nature. Secondary and 3D structure analyses of the PnPR-1 proteins were also predicted, which may be linked to a functional role in P. nigrum. The GO and KEGG functional annotations predicted their function in the defense responses of plant-pathogen interactions. Furthermore, a transcriptome-assisted FPKM analysis revealed PnPR-1 genes mapped to the P. nigrum-P. capsici interaction pathway. An altered expression pattern was detected for PnPR-1 transcripts among which a significant upregulation was noted for basic PnPR-1 genes such as CL10113.C1 and Unigene17664. The drastic variation in the transcript levels of CL10113.C1 was further validated through qRT-PCR and it showed a significant upregulation in infected leaf samples compared with the control. A subsequent analysis revealed the structural details, phylogenetic relationships, conserved sequence motifs and critical cis-regulatory elements of PnPR-1 genes. This is the first genome-wide study that identified the role of PR-1 genes during P. nigrum-P. capsici interactions. The detailed in silico experimental analysis revealed the vital role of PnPR-1 genes in regulating the first layer of defense towards a P. capsici infection in Panniyur-1 plants.

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Transcriptional Regulation of RUNX1: An Informatics Analysis

Genes ◽

10.3390/genes12081175 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1175

Author(s):

Amarni L. Thomas ◽

Judith Marsman ◽

Jisha Antony ◽

William Schierding ◽

Justin M. O’Sullivan ◽

...

Keyword(s):

Association Studies ◽

Regulatory Elements ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Runx1 Gene ◽

Gene Regulatory Elements ◽

Important Regulator ◽

Aml1 Gene ◽

Regulatory Landscape

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

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Genomic basis of striking fin shapes and colours in the fighting fish

Molecular Biology and Evolution ◽

10.1093/molbev/msab110 ◽

2021 ◽

Author(s):

Le Wang ◽

Fei Sun ◽

Zi Yi Wan ◽

Baoqing Ye ◽

Yanfei Wen ◽

...

Keyword(s):

Evolutionary Biology ◽

Association Studies ◽

Regulatory Element ◽

Regulatory Elements ◽

Major Effect ◽

Betta Splendens ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Phenotypic Variations ◽

Genomic Basis

Abstract Resolving the genomic basis underlying phenotypic variations is a question of great importance in evolutionary biology. However, understanding how genotypes determine the phenotypes is still challenging. Centuries of artificial selective breeding for beauty and aggression resulted in a plethora of colors, long fin varieties, and hyper-aggressive behavior in the air-breathing Siamese fighting fish (Betta splendens), supplying an excellent system for studying the genomic basis of phenotypic variations. Combining whole genome sequencing, QTL mapping, genome-wide association studies and genome editing, we investigated the genomic basis of huge morphological variation in fins and striking differences in coloration in the fighting fish. Results revealed that the double tail, elephant ear, albino and fin spot mutants each were determined by single major-effect loci. The elephant ear phenotype was likely related to differential expression of a potassium ion channel gene, kcnh8. The albinotic phenotype was likely linked to a cis-regulatory element acting on the mitfa gene and the double tail mutant was suggested to be caused by a deletion in a zic1/zic4 co-enhancer. Our data highlight that major loci and cis-regulatory elements play important roles in bringing about phenotypic innovations and establish Bettas as new powerful model to study the genomic basis of evolved changes.

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