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

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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Systematic identification of human SNPs affecting regulatory element activity

10.1101/460402 ◽

2018 ◽

Cited By ~ 2

Author(s):

Joris van Arensbergen ◽

Ludo Pagie ◽

Vincent FitzPatrick ◽

Marcel de Haas ◽

Marijke Baltissen ◽

...

Keyword(s):

Association Studies ◽

Regulatory Element ◽

Regulatory Elements ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

A Cell ◽

Element Activity ◽

Systematic Identification

AbstractMost of the millions of single-nucleotide polymorphisms (SNPs) in the human genome are non-coding, and many overlap with putative regulatory elements. Genome-wide association studies have linked many of these SNPs to human traits or to gene expression levels, but rarely with sufficient resolution to identify the causal SNPs. Functional screens based on reporter assays have previously been of insufficient throughput to test the vast space of SNPs for possible effects on enhancer and promoter activity. Here, we have leveraged the throughput of the SuRE reporter technology to survey a total of 5.9 million SNPs, including 57% of the known common SNPs. We identified more than 30 thousand SNPs that alter the activity of putative regulatory elements, often in a cell-type specific manner. These data indicate that a large proportion of human non-coding SNPs may affect gene regulation. Integration of these SuRE data with genome-wide association studies may help pinpoint SNPs that underlie human traits.

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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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Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy

10.1101/2020.04.23.20076208 ◽

2020 ◽

Author(s):

Katherina C. Chua ◽

Chenling Xiong ◽

Carol Ho ◽

Taisei Mushiroda ◽

Chen Jiang ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Association Studies ◽

Meta Analysis ◽

Regulatory Elements ◽

Hazard Ratio ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Sensory Peripheral Neuropathy ◽

Genome Wide ◽

Microtubule Targeting Agents

AbstractMicrotubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), βCALGB40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 - 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

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Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

10.1101/2020.03.02.973735 ◽

2020 ◽

Author(s):

Nadja Makki ◽

Jingjing Zhao ◽

Zhaoyang Liu ◽

Walter L. Eckalbar ◽

Aki Ushiki ◽

...

Keyword(s):

Adolescent Idiopathic Scoliosis ◽

Connective Tissue ◽

Idiopathic Scoliosis ◽

Association Studies ◽

Regulatory Elements ◽

Intervertebral Discs ◽

Genome Wide Association Studies ◽

Specific Expression ◽

Enhancer Activity ◽

Genome Wide

AbstractAdolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ∼3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in noncoding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral discs (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and ChIP-seq against H3K27ac in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.

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Addressing the Missing Heritability Problem With the Help of Regulatory Features

Evolutionary Bioinformatics ◽

10.1177/1176934319860861 ◽

2019 ◽

Vol 15 ◽

pp. 117693431986086

Author(s):

Shan-Shan Dong ◽

Yan Guo ◽

Tie-Lin Yang

Keyword(s):

Target Genes ◽

Association Studies ◽

Complex Diseases ◽

Regulatory Elements ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Susceptibility Loci ◽

Missing Heritability ◽

Genome Wide ◽

Missing Heritability Problem

Genome-wide association studies (GWASs) have successfully identified thousands of susceptibility loci for human complex diseases. However, missing heritability is still a challenging problem. Considering most GWAS loci are located in regulatory elements, we recently developed a pipeline named functional disease-associated single-nucleotide polymorphisms (SNPs) prediction (FDSP), to predict novel susceptibility loci for complex diseases based on the interpretation of regulatory features and published GWAS results with machine learning. When applied to type 2 diabetes and hypertension, the predicted susceptibility loci by FDSP were proved to be capable of explaining additional heritability. In addition, potential target genes of the predicted positive SNPs were significantly enriched in disease-related pathways. Our results suggested that taking regulatory features into consideration might be a useful way to address the missing heritability problem. We hope FDSP could offer help for the identification of novel susceptibility loci for complex diseases.

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Whole genome sequencing identifies common and rare structural variants contributing to hematologic traits in the NHLBI TOPMed program

10.1101/2021.12.16.21267871 ◽

2021 ◽

Author(s):

Marsha M. Wheeler ◽

Adrienne M Stilp ◽

Shuquan Rao ◽

Bjarni V Halldorsson ◽

Doruk V Beyter ◽

...

Keyword(s):

Blood Cell ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Association Studies ◽

Regulatory Elements ◽

Chromatin Domain ◽

Genome Wide Association Studies ◽

Whole Genome ◽

Structural Variants ◽

Genome Wide

Genome-wide association studies (GWAS) have identified thousands of single nucleotide variants and small indels that contribute to the genetic architecture of hematologic traits. While structural variants (SVs) are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of SVs to quantitative blood cell trait variation is unknown. Here we utilized SVs detected from whole genome sequencing (WGS) in ancestrally diverse participants of the NHLBI TOPMed program (N=50,675). Using single variant tests, we assessed the association of common and rare SVs with red cell-, white cell-, and platelet-related quantitative traits. The results show 33 independent SVs (23 common and 10 rare) reaching genome-wide significance. The majority of significant association signals (N=27) replicated in independent datasets from deCODE genetics and the UK BioBank. Moreover, most trait-associated SVs (N=24) are within 1Mb of previously-reported GWAS loci. SV analyses additionally discovered an association between a complex structural variant on 17p11.2 and white blood cell-related phenotypes. Based on functional annotation, the majority of significant SVs are located in non-coding regions (N=26) and predicted to impact regulatory elements and/or local chromatin domain boundaries in blood cells. We predict that several trait-associated SVs represent the causal variant. This is supported by genome-editing experiments which provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

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Integration of methylation QTL and enhancer–target gene maps with schizophrenia GWAS summary results identifies novel genes

Bioinformatics ◽

10.1093/bioinformatics/btz161 ◽

2019 ◽

Vol 35 (19) ◽

pp. 3576-3583 ◽

Cited By ~ 7

Author(s):

Chong Wu ◽

Wei Pan

Keyword(s):

Quantitative Trait ◽

Large Scale ◽

Target Gene ◽

Association Studies ◽

Regulatory Elements ◽

Supplementary Information ◽

Genome Wide Association Studies ◽

Novel Genes ◽

Gene Pairs ◽

Genome Wide

Abstract Motivation Most trait-associated genetic variants identified in genome-wide association studies (GWASs) are located in non-coding regions of the genome and thought to act through their regulatory roles. Results To account for enriched association signals in DNA regulatory elements, we propose a novel and general gene-based association testing strategy that integrates enhancer-target gene pairs and methylation quantitative trait locus data with GWAS summary results; it aims to both boost statistical power for new discoveries and enhance mechanistic interpretability of any new discovery. By reanalyzing two large-scale schizophrenia GWAS summary datasets, we demonstrate that the proposed method could identify some significant and novel genes (containing no genome-wide significant SNPs nearby) that would have been missed by other competing approaches, including the standard and some integrative gene-based association methods, such as one incorporating enhancer-target gene pairs and one integrating expression quantitative trait loci. Availability and implementation Software: wuchong.org/egmethyl.html Supplementary information Supplementary data are available at Bioinformatics online.

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Pan-Cancer Study Detects Novel Genetic Risk Variants and Shared Genetic Basis in Two Large Cohorts

10.1101/635367 ◽

2019 ◽

Cited By ~ 3

Author(s):

Sara R. Rashkin ◽

Rebecca E. Graff ◽

Linda Kachuri ◽

Khanh K. Thai ◽

Stacey E. Alexeeff ◽

...

Keyword(s):

Genetic Basis ◽

Association Studies ◽

Large Population ◽

Regulatory Elements ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Risk Variants ◽

Genome Wide ◽

Pan Cancer ◽

Shared Genetic

AbstractDeciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. However, no studies have investigated pan-cancer pleiotropy within single, well-defined populations unselected for phenotype. We undertook novel genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (413,870 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detected 21 novel genome-wide significant risk variants. In addition, numerous cancer sites exhibited clear heritability. Investigations of pleiotropy identified 12 cancer pairs exhibiting either positive or negative genetic correlations and 43 pleiotropic loci. We identified 158 pleiotropic variants, many of which were enriched for regulatory elements and influenced cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

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Antipsychotic-induced epigenomic reorganization in frontal cortex samples from individuals with schizophrenia

10.1101/2021.07.14.452426 ◽

2021 ◽

Author(s):

Bohan Zhu ◽

Richard I Ainsworth ◽

Zengmiao Wang ◽

Salvador Sierra ◽

Chengyu Deng ◽

...

Keyword(s):

Frontal Cortex ◽

Histone Modifications ◽

Association Studies ◽

Regulatory Elements ◽

Postmortem Brain ◽

Antipsychotic Treatment ◽

Genome Wide Association Studies ◽

Epigenetic Marks ◽

Genome Wide ◽

The Impact

Genome wide association studies have revealed >150 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, no study so far has profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects or the effect of antipsychotic treatment on such epigenetic marks. Here we show the first comprehensive epigenomic characterization of the frontal cortex of 29 individuals with schizophrenia and 29 matched controls, including histone modifications associated with active promoters and enhancers H3K4me3 and H3K27ac along with RNA expression in neuronal and glial nuclei. Schizophrenia subjects exhibited thousands of cell type-specific epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, RGS4 and HTR2A. Comparing untreated and treated schizophrenia subjects with controls, our findings provide entirely new insights into differentially modified genes associated with unexpected pathways that are potential markers of antipsychotic treatment. Additionally, we show that the effect of age on the epigenomic landscape is more pronounced in frontal cortex samples of antipsychotic-treated schizophrenia subjects. Together, our data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark the impact of age and antipsychotic treatment on chromatin organization.

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Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

10.1101/2021.05.10.443466 ◽

2021 ◽

Author(s):

Sylvan C Baca ◽

Cassandra Singler ◽

Soumya Zacharia ◽

Ji-Heui Seo ◽

Tunc Morova ◽

...

Keyword(s):

Prostate Cancer ◽

Steady State ◽

Binding Sites ◽

Association Studies ◽

Prostate Cancer Risk ◽

Regulatory Elements ◽

Genome Wide Association Studies ◽

Genetic Determinants ◽

Genome Wide ◽

Context Dependent

Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.

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