Unbiased association and expression studies identify novel genes for tooth development

AbstractPreviously reported co-occurrence of colorectal cancer (CRC) and tooth agenesis (TA) and the overlap in disease-associated gene variants suggest involvement of similar molecular pathways. In this study, we took an unbiased approach and tested genome-wide significant CRC-associated variants for association with isolated TA. Thirty single nucleotide variants (SNVs) in CRC-predisposing genes/loci were genotyped in a discovery dataset composed of 440 individuals with and without isolated TA. Genome-wide significant associations were found between TA and DUSP10 rs6687758 (P=1.25 × 10−9) and ATF1 rs11169552 (P=4.36 × 10−10), with strong association found with CASC8 rs10505477 (P=8.2 × 10−5). Additional CRC marker haplotypes were also significantly associated with TA (P<0.0002). Genotyping an independent dataset consisting of 52 cases with TA and 427 controls confirmed the association with CASC8.Atf1 and Dusp10 expression was detected in the mouse developing teeth from early bud stages to the formation of the complete tooth, suggesting a potential role for these genes and their encoded proteins in tooth development. Our findings suggest Atf1 and Dusp10 as new tooth development genes, while having a role in colorectal cancer. While their individual contributions in tooth development remain to be elucidated, these genes may be considered additional candidates to be tested in future human genetic studies.

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Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

Journal of Personalized Medicine ◽

10.3390/jpm11010033 ◽

2021 ◽

Vol 11 (1) ◽

pp. 33

Author(s):

Nayoung Han ◽

Jung Mi Oh ◽

In-Wha Kim

Keyword(s):

Copy Number ◽

Genome Wide Association Study ◽

Copy Number Gain ◽

Copy Number Variations ◽

Gene Gain ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Haplotype Blocks ◽

Genome Wide ◽

Control And Prevention

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.

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Prediction of genome-wide effects of single nucleotide variants on transcription factor binding

Scientific Reports ◽

10.1038/s41598-020-74793-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sebastian Carrasco Pro ◽

Katia Bulekova ◽

Brian Gregor ◽

Adam Labadorf ◽

Juan Ignacio Fuxman Bass

Keyword(s):

Binding Sites ◽

Cancer Type ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Regulatory Regions ◽

Genome Wide ◽

Transcriptional Regulatory ◽

Gene Regulatory ◽

The Impact ◽

The Relationship

Abstract Single nucleotide variants (SNVs) located in transcriptional regulatory regions can result in gene expression changes that lead to adaptive or detrimental phenotypic outcomes. Here, we predict gain or loss of binding sites for 741 transcription factors (TFs) across the human genome. We calculated ‘gainability’ and ‘disruptability’ scores for each TF that represent the likelihood of binding sites being created or disrupted, respectively. We found that functional cis-eQTL SNVs are more likely to alter TF binding sites than rare SNVs in the human population. In addition, we show that cancer somatic mutations have different effects on TF binding sites from different TF families on a cancer-type basis. Finally, we discuss the relationship between these results and cancer mutational signatures. Altogether, we provide a blueprint to study the impact of SNVs derived from genetic variation or disease association on TF binding to gene regulatory regions.

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Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival

Nature Communications ◽

10.1038/s41467-020-17386-z ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Syed H. Zaidi ◽

Tabitha A. Harrison ◽

Amanda I. Phipps ◽

Robert Steinfelder ◽

Quang M. Trinh ◽

...

Keyword(s):

Colorectal Cancer ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Impact On Survival

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Impact of Pre and Post Variant Filtration Strategies on Imputation

10.21203/rs.3.rs-128366/v1 ◽

2020 ◽

Author(s):

Celine Charon ◽

Rodrigue Allodji ◽

Vincent Meyer ◽

Jean-François Deleuze

Keyword(s):

Quality Control ◽

Rare Variants ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Direct Effects ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Genome Wide ◽

Conservative Post

Abstract Quality control methods for genome-wide association studies and fine mapping are commonly used for imputation, however, they result in loss of many single nucleotide polymorphisms (SNPs). To investigate the consequences of filtration on imputation, we studied the direct effects on the number of markers, their allele frequencies, imputation quality scores and post-filtration events. We pre-phrased 1,031 genotyped individuals from diverse ethnicities and compared the imputed variants to 1,089 NCBI recorded individuals for additional validation.Without variant pre-filtration based on quality control (QC), we observed no impairment in the imputation of SNPs that failed QC whereas with pre-filtration there was an overall loss of information. Significant differences between frequencies with and without pre-filtration were found only in the range of very rare (5E-04-1E-03) and rare variants (1E-03-5E-03) (p < 1E-04). Increasing the post-filtration imputation quality score from 0.3 to 0.8 reduced the number of single nucleotide variants (SNVs) <0.001 2.5 fold with or without QC pre-filtration and halved the number of very rare variants (5E-04). As a result, to maintain confidence and enough SNVs, we propose here a 2-step post-filtration approach to increase the number of very rare and rare variants compared to conservative post-filtration methods.

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HGG-41. STRUCTURAL VARIANT DRIVERS IN PEDIATRIC HIGH-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.322 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii351-iii351

Author(s):

Frank Dubois ◽

Ofer Shapira ◽

Noah Greenwald ◽

Travis Zack ◽

Jessica W Tsai ◽

...

Keyword(s):

Copy Number ◽

High Grade Glioma ◽

High Grade ◽

Structural Variants ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Effector Domains ◽

Topologically Associating Domains ◽

Genome Wide ◽

Pediatric High Grade Glioma

Abstract BACKGROUND Driver single nucleotide variants (SNV) and somatic copy number aberrations (SCNA) of pediatric high-grade glioma (pHGGs), including Diffuse Midline Gliomas (DMGs) are characterized. However, structural variants (SVs) in pHGGs and the mechanisms through which they contribute to glioma formation have not been systematically analyzed genome-wide. METHODS Using SvABA for SVs as well as the latest pipelines for SCNAs and SNVs we analyzed whole-genome sequencing from 174 patients. This includes 60 previously unpublished samples, 43 of which are DMGs. Signature analysis allowed us to define pHGG groups with shared SV characteristics. Significantly recurring SV breakpoints and juxtapositions were identified with algorithms we recently developed and the findings were correlated with RNAseq and H3K27ac ChIPseq. RESULTS The SV characteristics in pHGG showed three groups defined by either complex, intermediate or simple signature activities. These associated with distinct combinations of known driver oncogenes. Our statistical analysis revealed recurring SVs in the topologically associating domains of MYCN, MYC, EGFR, PDGFRA & MET. These correlated with increased mRNA expression and amplification of H3K27ac peaks. Complex recurring amplifications showed characteristics of extrachromosomal amplicons and were enriched in coding SVs splitting protein regulatory from effector domains. Integrative analysis of all SCNAs, SNVs & SVs revealed patterns of characteristic combinations between potential drivers and signatures. This included two distinct groups of H3K27M DMGs with either complex or simple signatures and different combinations of associated variants. CONCLUSION Recurrent SVs associate with signatures shaped by an underlying process, which can lead to distinct mechanisms to activate the same oncogene.

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Genome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers

Nature Communications ◽

10.1038/s41467-021-26600-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Qing-Lan Li ◽

Xiang Lin ◽

Ya-Li Yu ◽

Lin Chen ◽

Qi-Xin Hu ◽

...

Keyword(s):

Colorectal Cancer ◽

Colorectal Cancer Patient ◽

Nucleotide Polymorphisms ◽

Rna Seq ◽

Motif Analysis ◽

Single Nucleotide ◽

Super Enhancer ◽

Genome Wide ◽

Functional Factors ◽

Cancer Tissues

AbstractColorectal cancer is one of the most common cancers in the world. Although genomic mutations and single nucleotide polymorphisms have been extensively studied, the epigenomic status in colorectal cancer patient tissues remains elusive. Here, together with genomic and transcriptomic analysis, we use ChIP-Seq to profile active enhancers at the genome wide level in colorectal cancer paired patient tissues (tumor and adjacent tissues from the same patients). In total, we sequence 73 pairs of colorectal cancer tissues and generate 147 H3K27ac ChIP-Seq, 144 RNA-Seq, 147 whole genome sequencing and 86 H3K4me3 ChIP-Seq samples. Our analysis identifies 5590 gain and 1100 lost variant enhancer loci in colorectal cancer, and 334 gain and 121 lost variant super enhancer loci. Multiple key transcription factors in colorectal cancer are predicted with motif analysis and core regulatory circuitry analysis. Further experiments verify the function of the super enhancers governing PHF19 and TBC1D16 in regulating colorectal cancer tumorigenesis, and KLF3 is identified as an oncogenic transcription factor in colorectal cancer. Taken together, our work provides an important epigenomic resource and functional factors for epigenetic studies in colorectal cancer.

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Korean Genome Project: 1094 Korean personal genomes with clinical information

Science Advances ◽

10.1126/sciadv.aaz7835 ◽

2020 ◽

Vol 6 (22) ◽

pp. eaaz7835 ◽

Cited By ~ 2

Author(s):

Sungwon Jeon ◽

Youngjune Bhak ◽

Yeonsong Choi ◽

Yeonsu Jeon ◽

Seunghoon Kim ◽

...

Keyword(s):

Genome Wide Association Study ◽

Imputation Accuracy ◽

Clinical Information ◽

Genome Project ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome ◽

Whole Genomes ◽

Personal Genomes

We present the initial phase of the Korean Genome Project (Korea1K), including 1094 whole genomes (sequenced at an average depth of 31×), along with data of 79 quantitative clinical traits. We identified 39 million single-nucleotide variants and indels of which half were singleton or doubleton and detected Korean-specific patterns based on several types of genomic variations. A genome-wide association study illustrated the power of whole-genome sequences for analyzing clinical traits, identifying nine more significant candidate alleles than previously reported from the same linkage disequilibrium blocks. Also, Korea1K, as a reference, showed better imputation accuracy for Koreans than the 1KGP panel. As proof of utility, germline variants in cancer samples could be filtered out more effectively when the Korea1K variome was used as a panel of normals compared to non-Korean variome sets. Overall, this study shows that Korea1K can be a useful genotypic and phenotypic resource for clinical and ethnogenetic studies.

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Cytosine base editor 4 but not adenine base editor generates off-target mutations in mouse embryos

Communications Biology ◽

10.1038/s42003-019-0745-3 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 15

Author(s):

Hye Kyung Lee ◽

Harold E. Smith ◽

Chengyu Liu ◽

Michaela Willi ◽

Lothar Hennighausen

Keyword(s):

Point Mutations ◽

Mouse Embryos ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Base Editing ◽

Genome Wide ◽

Wide Range ◽

Family Based ◽

Correct Point ◽

Adenine Base

AbstractDeaminase base editing has emerged as a tool to install or correct point mutations in the genomes of living cells in a wide range of organisms. However, the genome-wide off-target effects introduced by base editors in the mammalian genome have been examined in only one study. Here, we have investigated the fidelity of cytosine base editor 4 (BE4) and adenine base editors (ABE) in mouse embryos using unbiased whole-genome sequencing of a family-based trio cohort. The same sgRNA was used for BE4 and ABE. We demonstrate that BE4-edited mice carry an excess of single-nucleotide variants and deletions compared to ABE-edited mice and controls. Therefore, an optimization of cytosine base editors is required to improve its fidelity. While the remarkable fidelity of ABE has implications for a wide range of applications, the occurrence of rare aberrant C-to-T conversions at specific target sites needs to be addressed.

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Association of HMGA2 Gene Variation with Height in Specific Pediatric Age Categories

Genomics Insights ◽

10.4137/gei.s944 ◽

2008 ◽

Vol 1 ◽

pp. GEI.S944 ◽

Cited By ~ 1

Author(s):

Struan F.A. Grant ◽

Mingyao Li ◽

Jonathan P. Bradfield ◽

Cecilia E. Kim ◽

Kiran Annaiah ◽

...

Keyword(s):

Old Age ◽

Strong Association ◽

Age Groups ◽

Age Group ◽

Pediatric Age ◽

Single Nucleotide ◽

Gene Variation ◽

Genome Wide ◽

A Genome ◽

Minor Alleles

Background Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs1042725, within the HMGA2 locus and height as a consequence of a genome wide association (GWA) study of this trait in adults; this observation was also reported in children aged 7–11 years old. Objective We examined in our Caucasian childhood cohort the effects of two strong surrogates for this SNP at this locus with height, rs8756 and rs7968902, with respect to the same pediatric age category but also in children grouped separately as younger and older. Methods Utilizing data from an ongoing GWA study in our cohort of 2,619 Caucasian children with measurements for height, we investigated the association of the previously reported variation at the HMGA2 locus with this height treated as a quantitative trait (age and sex corrected) in childhood in the 2–6 (n = 706), 7–11 (n = 617) and 12–18 (n = 1293) years old categories. Results The minor alleles of rs8756 and rs7968902 respectively (strong surrogates for rs1042725 i.e. r 2 = 0.873 and 0.761 in the CEU HapMap respectively) were significantly associated with height in the 7–11 years old age group ( P = 3.53 × 10–3 and 2.82 × 10–4, respectively) However in the 2–6 and 12–18 years old age groups, no association was observed. Conclusions We observe a strong association with height in same age group of 7–11 years old as has been previously reported. However, in the under 7s and the over 11s, no such association was observed.

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