scholarly journals Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression

Circulation ◽  
2021 ◽  
Author(s):  
Anthony M. Gacita ◽  
Dominic E. Fullenkamp ◽  
Joyce Ohiri ◽  
Tess Pottinger ◽  
Megan J. Puckelwartz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Transcriptional Start Site ◽  
Integrated Approach ◽  
Genomic Variation ◽  
Regulatory Control ◽  
Binding Motif ◽  
Human Cardiomyocytes ◽  
Inherited Cardiomyopathy ◽  
A Genome

Background: Inherited cardiomyopathy associates with a range of phenotype, mediated by genetic and non-genetic factors. Non-inherited cardiomyopathy also displays varying progression and outcomes. Expression of cardiomyopathy genes is under the regulatory control of promoters and enhancers, and human genetic variation in promoters and enhancers may contribute to this variability. Methods: We superimposed epigenomic profiling from hearts and cardiomyocytes, including promoter-capture chromatin conformation information, to identify enhancers for two cardiomyopathy genes, MYH7 and LMNA . Enhancer function was validated in human cardiomyocytes derived from induced pluripotent stem cells. We also conducted a genome-wide search to ascertain genomic variation in enhancers positioned to alter cardiac expression and correlated one of these variants to cardiomyopathy progression using biobank data. Results: Multiple enhancers were identified and validated for LMNA and MYH7 , including a key enhancer that regulates the switch from MYH6 expression to MYH7 expression. Deletion of this enhancer resulted in a dose-dependent increase in MYH6 and faster contractile rate in engineered heart tissues. We searched for genomic variation in enhancer sequences across the genome, with focus on nucleotide changes that create or interrupt transcription factor binding sites. rs875908 disrupts a TBX5 binding motif and maps to an enhancer region 2KB from the transcriptional start site of MYH7 . Gene editing to remove the enhancer harboring this variant markedly reduced MYH7 expression in human cardiomyocytes. Using biobank-derived data, rs875908 associated with longitudinal echocardiographic features with cardiomyopathy. Conclusions: Enhancers regulate cardiomyopathy gene expression, and genomic variation within these enhancer regions associates with cardiomyopathic progression over time. This integrated approach identified noncoding modifiers of cardiomyopathy and is applicable to other cardiac genes.

scholarly journals Genomic variation in the American pika: signatures of geographic isolation and implications for conservation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kelly B. Klingler ◽  
Joshua P. Jahner ◽  
Thomas L. Parchman ◽  
Chris Ray ◽  
Mary M. Peacock
Keyword(s):  
Genetic Variation ◽  
Genetic Structure ◽  
Sierra Nevada ◽  
Spatial Genetic Structure ◽  
Spatial Scales ◽  
Thermal Sensitivity ◽  
Genomic Variation ◽  
Genome Wide ◽  
A Genome ◽  
American Pika

Abstract Background Distributional responses by alpine taxa to repeated, glacial-interglacial cycles throughout the last two million years have significantly influenced the spatial genetic structure of populations. These effects have been exacerbated for the American pika (Ochotona princeps), a small alpine lagomorph constrained by thermal sensitivity and a limited dispersal capacity. As a species of conservation concern, long-term lack of gene flow has important consequences for landscape genetic structure and levels of diversity within populations. Here, we use reduced representation sequencing (ddRADseq) to provide a genome-wide perspective on patterns of genetic variation across pika populations representing distinct subspecies. To investigate how landscape and environmental features shape genetic variation, we collected genetic samples from distinct geographic regions as well as across finer spatial scales in two geographically proximate mountain ranges of eastern Nevada. Results Our genome-wide analyses corroborate range-wide, mitochondrial subspecific designations and reveal pronounced fine-scale population structure between the Ruby Mountains and East Humboldt Range of eastern Nevada. Populations in Nevada were characterized by low genetic diversity (π = 0.0006–0.0009; θW = 0.0005–0.0007) relative to populations in California (π = 0.0014–0.0019; θW = 0.0011–0.0017) and the Rocky Mountains (π = 0.0025–0.0027; θW = 0.0021–0.0024), indicating substantial genetic drift in these isolated populations. Tajima’s D was positive for all sites (D = 0.240–0.811), consistent with recent contraction in population sizes range-wide. Conclusions Substantial influences of geography, elevation and climate variables on genetic differentiation were also detected and may interact with the regional effects of anthropogenic climate change to force the loss of unique genetic lineages through continued population extirpations in the Great Basin and Sierra Nevada.

scholarly journals Chromosome-level assembly of the Atlantic silverside genome reveals extreme levels of sequence diversity and structural genetic variation

2020 ◽  
Author(s):  
Anna Tigano ◽  
Arne Jacobs ◽  
Aryn P. Wilder ◽  
Ankita Nand ◽  
Ye Zhan ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Structural Variation ◽  
Demographic History ◽  
Genome Structure ◽  
Genomic Variation ◽  
Adaptive Divergence ◽  
Effective Population ◽  
Atlantic Silverside ◽  
A Genome ◽  
Chromosome Level

AbstractThe levels and distribution of standing genetic variation in a genome can provide a wealth of insights about the adaptive potential, demographic history, and genome structure of a population or species. As structural variants are increasingly associated with traits important for adaptation and speciation, investigating both sequence and structural variation is essential for wholly tapping this potential. Using a combination of shotgun sequencing, 10X Genomics linked reads and proximity-ligation data (Chicago and Hi-C), we produced and annotated a chromosome-level genome assembly for the Atlantic silverside (Menidia menidia) - an established ecological model for studying the phenotypic effects of natural and artificial selection - and examined patterns of genomic variation across two individuals sampled from different populations with divergent local adaptations. Levels of diversity varied substantially across each chromosome, consistently being highly elevated near the ends (presumably near telomeric regions) and dipping to near zero around putative centromeres. Overall, our estimate of the genome-wide average heterozygosity in the Atlantic silverside is the highest reported for a fish, or any vertebrate, to date (1.32-1.76% depending on inference method and sample). Furthermore, we also found extreme levels of structural variation, affecting ~23% of the total genome sequence, including multiple large inversions (> 1 Mb and up to 12.6 Mb) associated with previously identified haploblocks showing strong differentiation between locally adapted populations. These extreme levels of standing genetic variation are likely associated with large effective population sizes and may help explain the remarkable adaptive divergence among populations of the Atlantic silverside.

scholarly journals Genomic variation in the American pika: signatures of geographic isolation and implications for conservation

2020 ◽  
Author(s):  
Kelly Brie Klingler ◽  
Joshua P Jahner ◽  
Thomas L Parchman ◽  
Chris Ray ◽  
Mary Peacock
Keyword(s):  
Genetic Variation ◽  
Genetic Structure ◽  
Sierra Nevada ◽  
Spatial Genetic Structure ◽  
Spatial Scales ◽  
Thermal Sensitivity ◽  
Genomic Variation ◽  
Genome Wide ◽  
A Genome ◽  
American Pika

Abstract Background: Distributional responses by alpine taxa to repeated, glacial-interglacial cycles throughout the last two million years have significantly influenced the spatial genetic structure of populations. These effects have been exacerbated for the American pika (Ochotona princeps), a small alpine lagomorph constrained by thermal sensitivity and a limited dispersal capacity. As a species of conservation concern, long-term lack of gene flow has important consequences for landscape genetic structure and levels of diversity within populations. Here, we use reduced representation sequencing (ddRADseq) to provide a genome-wide perspective on patterns of genetic variation across pika populations representing distinct subspecies. To investigate how landscape and environmental features shape genetic variation, we collected genetic samples from distinct geographic regions as well as across finer spatial scales in two geographically proximate mountain ranges of eastern Nevada. Results: Our genome-wide analyses corroborate range-wide, mitochondrial subspecific designations and reveal pronounced fine-scale population structure between the Ruby Mountains and East Humboldt Range of eastern Nevada. Populations in Nevada were characterized by low genetic diversity (𝜋=0.0006–0.0009; 𝜃W=0.0005–0.0007) relative to populations in California (𝜋=0.0014–0.0019; 𝜃W=0.0011–0.0017) and the Rocky Mountains (𝜋=0.0025–0.0027; 𝜃W=0.0021–0.0024), indicating substantial genetic drift in these isolated populations. Tajima’s D was positive for all sites (D=0.240-0.811), consistent with recent contraction in population sizes range-wide. Conclusions: Substantial influences of geography, elevation and climate variables on genetic differentiation were also detected and may interact with the regional effects of anthropogenic climate change to force the loss of unique genetic lineages through continued population extirpations in the Great Basin and Sierra Nevada.

scholarly journals Acquired variation outweighs inherited variation in whole genome analysis of methotrexate polyglutamate accumulation in leukemia

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4512-4520 ◽  
Author(s):  
Deborah French ◽  
Wenjian Yang ◽  
Cheng Cheng ◽  
Susana C. Raimondi ◽  
Charles G. Mullighan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Copy Number Variation ◽  
Cell Lines ◽  
Copy Number ◽  
Genomic Variation ◽  
Leukemia Cells ◽  
Whole Genome ◽  
Chromosome 18 ◽  
Number Variation

Abstract Methotrexate polyglutamates (MTXPGs) determine in vivo efficacy in acute lymphoblastic leukemia (ALL). MTXPG accumulation differs by leukemic subtypes, but genomic determinants of MTXPG variation in ALL remain unclear. We analyzed 3 types of whole genome variation: leukemia cell gene expression and somatic copy number variation, and inherited single nucleotide polymorphism (SNP) genotypes and determined their association with MTXPGs in leukemia cells. Seven genes (FHOD3, IMPA2, ME2, RASSF4, SLC39A6, SMAD2, and SMAD4) displayed all 3 types of genomic variation associated with MTXPGs (P < .05 for gene expression, P < .01 for copy number variation and SNPs): 6 on chromosome 18 and 1 on chromosome 10. Increased chromosome 18 (P = .002) or 10 (P = .036) copy number was associated with MTXPGs even after adjusting for ALL subtype. The expression of the top 7 genes in leukemia cells accounted for more variation in MTXPGs (46%) than did the expression of the top 7 genes in normal HapMap cell lines (20%). The top 7 inherited SNPs in patients accounted for approximately the same degree of variation (17%) in MTXPGs as did the top 7 SNP genotypes in HapMap cell lines (20%). We conclude that acquired genetic variation in leukemia cells has a stronger influence on MTXPG accumulation than inherited genetic variation.

Characterization of the DNA-binding motif of the arsenic-responsive transcription factor Yap8p

2008 ◽  
Vol 415 (3) ◽  
pp. 467-475 ◽  
Author(s):  
Yulia Ilina ◽  
Ewa Sloma ◽  
Ewa Maciaszczyk-Dziubinska ◽  
Marian Novotny ◽  
Michael Thorsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Mutational Analysis ◽  
Global Gene Expression ◽  
Binding Motif ◽  
Activator Protein 1 ◽  
Core Element ◽  
A Genome

Saccharomyces cerevisiae uses several mechanisms for arsenic detoxification including the arsenate reductase Acr2p and the arsenite efflux protein Acr3p. ACR2 and ACR3 are transcribed in opposite directions from the same promoter and expression of these genes is regulated by the AP-1 (activator protein 1)-like transcription factor Yap8p. Yap8p has been shown to permanently associate with this promoter and to stimulate ACR2/ACR3 expression in response to arsenic. In the present study we characterized the DNA sequence that is targeted by Yap8p. We show that Yap8p binds to a pseudo-palindromic TGATTAATAATCA sequence that is related to, but distinct from, the sequence recognized by other fungal AP-1 proteins. Probing the promoter by mutational analysis, we confirm the importance of the TTAATAA core element and pin-point nucleotides that flank this element as crucial for Yap8p binding and in vivo activation of ACR3 expression. A genome-wide search for this element combined with global gene expression analysis indicates that the principal function of Yap8p is to control expression of ACR2 and ACR3. We conclude that Yap8p and other yeast AP-1 proteins require distinct DNA-binding motifs to induce gene expression and propose that this fact contributed towards a separation of function between AP-1 proteins during evolution.

scholarly journals Genetic variation in a complex polyploid: unveiling the dynamic allelic features of sugarcane

2018 ◽  
Author(s):  
Danilo Augusto Sforça ◽  
Sonia Vautrin ◽  
Claudio Benicio Cardoso-Silva ◽  
Melina Cristina Mancini ◽  
María Victoria Romero da Cruz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Protein C ◽  
Orthologous Gene ◽  
Saccharum Spp ◽  
Map Construction ◽  
A Genome ◽  
Homeologous Chromosome ◽  
Polyploid Genome ◽  
Genetics And Genomics

AbstractBackgroundSugarcane (Saccharum spp.) is highly polyploid and aneuploid. Modern cultivars are derived from hybridization between S. officinarum and S. spontaneum. This combination results in a genome exhibiting variable ploidy among different loci, a huge genome size (approximately 10 Gb) and a high content of repetitive regions. Gene expression mechanisms are poorly understood in these cultivars. An approach using genomic, transcriptomic and genetic mapping can improve our knowledge of the behavior of genetics in sugarcane.ResultsThe hypothetical HP600 and centromere protein C (CENP-C) genes from sugarcane were used to elucidate the allelic expression and genomic and genetic behavior of this complex polyploid. The genomically side-by-side genes HP600 and CENP-C were found in two different homeologous chromosome groups with ploidies of eight and ten. The first region (Region01) was a Sorghum bicolor ortholog with all haplotypes of HP600 and CENP- C expressed, but HP600 exhibited an unbalanced haplotype expression. The second region (Region02) was a scrambled sugarcane sequence formed from different noncollinear genes containing duplications of HP600 and CENP-C (paralogs). This duplication occurred before the Saccharum genus formation and after the separation of sorghum and sugarcane, resulting in a nonexpressed HP600 pseudogene and a recombined fusion version of CENP-C and orthologous gene Sobic.003G299500 with at least two chimerical gene haplotypes expressed. The genetic map construction supported the difficulty of mapping markers located in duplicated regions of complex polyploid genomes.ConclusionAll these findings describe a low synteny region in sugarcane, formed by events occurring in all members of the Saccharum genus. Additionally, evidence of duplicated and truncate gene expression and the behavior of genetic markers in a duplicated region was found. Thus, we describe the complexity involved in sugarcane genetics and genomics and allelic dynamics, which can be useful for understanding the complex polyploid genome.

scholarly journals Genomic variation in the American pika: signatures of geographic isolation and implications for conservation

2021 ◽  
Author(s):  
Kelly Brie Klingler ◽  
Joshua P Jahner ◽  
Thomas L Parchman ◽  
Chris Ray ◽  
Mary Peacock
Keyword(s):  
Genetic Variation ◽  
Genetic Structure ◽  
Sierra Nevada ◽  
Spatial Genetic Structure ◽  
Spatial Scales ◽  
Thermal Sensitivity ◽  
Genomic Variation ◽  
Genome Wide ◽  
A Genome ◽  
American Pika

Abstract Background: Distributional responses by alpine taxa to repeated, glacial-interglacial cycles throughout the last two million years have significantly influenced the spatial genetic structure of populations. These effects have been exacerbated for the American pika (Ochotona princeps), a small alpine lagomorph constrained by thermal sensitivity and a limited dispersal capacity. As a species of conservation concern, long-term lack of gene flow has important consequences for landscape genetic structure and levels of diversity within populations. Here, we use reduced representation sequencing (ddRADseq) to provide a genome-wide perspective on patterns of genetic variation across pika populations representing distinct subspecies. To investigate how landscape and environmental features shape genetic variation, we collected genetic samples from distinct geographic regions as well as across finer spatial scales in two geographically proximate mountain ranges of eastern Nevada. Results: Our genome-wide analyses corroborate range-wide, mitochondrial subspecific designations and reveal pronounced fine-scale population structure between the Ruby Mountains and East Humboldt Range of eastern Nevada. Populations in Nevada were characterized by low genetic diversity (𝜋=0.0006–0.0009; 𝜃W=0.0005–0.0007) relative to populations in California (𝜋=0.0014–0.0019; 𝜃W=0.0011–0.0017) and the Rocky Mountains (𝜋=0.0025–0.0027; 𝜃W=0.0021–0.0024), indicating substantial genetic drift in these isolated populations. Tajima’s D was positive for all sites (D=0.240-0.811), consistent with recent contraction in population sizes range-wide. Conclusions: Substantial influences of geography, elevation and climate variables on genetic differentiation were also detected and may interact with the regional effects of anthropogenic climate change to force the loss of unique genetic lineages through continued population extirpations in the Great Basin and Sierra Nevada.

scholarly journals Genomic Variation in the American Pika: Signatures of Geographic Isolation and Implications for Conservation

2020 ◽  
Author(s):  
Kelly Brie Klingler ◽  
Joshua P Jahner ◽  
Thomas L Parchman ◽  
Chris Ray ◽  
Mary Peacock
Keyword(s):  
Genetic Variation ◽  
Genetic Structure ◽  
Sierra Nevada ◽  
Spatial Genetic Structure ◽  
Spatial Scales ◽  
Thermal Sensitivity ◽  
Genomic Variation ◽  
Genome Wide ◽  
A Genome ◽  
American Pika

Abstract Background: Distributional responses by alpine taxa to repeated, glacial-interglacial cycles throughout the last two million years have significantly influenced the spatial genetic structure of populations. These effects have been exacerbated for the American pika (Ochotona princeps), a small alpine lagomorph constrained by thermal sensitivity and a limited dispersal capacity. As a species of conservation concern, long-term lack of gene flow has important consequences for landscape genetic structure and levels of diversity within populations. Here, we use reduced representation sequencing (ddRADseq) to provide a genome-wide perspective on patterns of genetic variation across pika populations representing distinct subspecies. To investigate how landscape and environmental features shape genetic variation, we collected genetic samples from distinct geographic regions as well as across finer spatial scales in two geographically proximate mountain ranges of eastern Nevada. Results: Our genome-wide analyses corroborate range-wide, mitochondrial subspecific designations and reveal pronounced fine-scale population structure between the Ruby Mountains and East Humboldt Range of eastern Nevada. Populations in Nevada were characterized by low genetic diversity (𝜋=0.0006–0.0009; 𝜃W=0.0005–0.0007) relative to populations in California (𝜋=0.0014–0.0019; 𝜃W=0.0011–0.0017) and the Rocky Mountains (𝜋=0.0025–0.0027; 𝜃W=0.0021–0.0024), indicating substantial genetic drift in these isolated populations. Tajima’s D was positive for all sites (D=0.240-0.811), consistent with recent contraction in population sizes range-wide. Conclusions: Substantial influences of geography, elevation and climate variables on genetic differentiation were also detected and may interact with the regional effects of anthropogenic climate change to force the loss of unique genetic lineages through continued population extirpations in the Great Basin and Sierra Nevada.

Post-Transcriptional Regulation of Cardiac Sarcomere Protein Titin Through 3’ Untranslated Regions

2013 ◽  
Vol 9 ◽  
Author(s):  
Tara A Shrout
Keyword(s):  
Gene Expression ◽  
Transcriptional Control ◽  
Striated Muscle ◽  
Binding Capacity ◽  
Structural Features ◽  
Neonatal Rat ◽  
Regulatory Control ◽  
Untranslated Regions ◽  
Luciferase Reporter ◽  
Regulatory Effects

Titin is the largest known protein in the human body, and forms the backbone of all striated muscle sarcomeres. The elastic nature of titin is an important component of muscle compliance and functionality. A significant amount of energy is expended to synthesize titin, thus we postulate that titin gene expression is under strict regulatory control in order to conserve cellular resources. In general, gene expression is mediated in part by post-transcriptional control elements located within the 5’ and 3’ untranslated regions (UTRs) of mature mRNA. The 3’UTR in particular contains structural features that affect binding capacity to other RNA components, such as MicroRNA, which control mRNA localization, translation, and degradation. The degree and significance of the regulatory effects mediated by two determined variants of titin’s 3’ UTR were evaluated in Neonatal Rat Ventricular Myocyte and Human Embryonic Kidney cell lines. Recombinant plasmids to transfect these cells lines were engineered by insertion of the variant titin 3’UTR 431- and 1047-base pairs sequences into luciferase reporter vectors. Expression due to an unaltered reporter vector served as the control. Quantitative changes in luciferase activity due to the recombinants proportionally represented the effect titin’s respective 3’UTR conferred on downstream post-transcriptional expression relative to the control. The effect due to titin’s shorter 3’UTR sequence was inconclusive; however, results illustrated that titin’s longer 3’UTR sequence caused a 35 percent decrease in protein expression. Secondary structural analysis of the two sequences revealed differential folding patterns that affect the stability and degree of MicroRNA-binding within titin’s variant 3’UTR sequences.

Sign in / Sign up

Export Citation Format

Share Document