Identifying the Genome-Wide Sequence Variations and Developing New Molecular Markers for Genetics Research by Re-Sequencing a Landrace Cultivar of Foxtail Millet

Dyslexia, a specific reading disability, is a common (up to 10% of children) and highly heritable (~70%) neurodevelopmental disorder. Behavioral and molecular genetic approaches are aimed towards dissecting its significant genetic component. In the proposed review, we will summarize advances in twin and molecular genetic research from the past 20 years. First, we will briefly outline the clinical and educational presentation and epidemiology of dyslexia. Next, we will summarize results from twin studies, followed by molecular genetic research (e.g., genome-wide association studies (GWASs)). In particular, we will highlight converging key insights from genetic research. (1) Dyslexia is a highly polygenic neurodevelopmental disorder with a complex genetic architecture. (2) Dyslexia categories share a large proportion of genetics with continuously distributed measures of reading skills, with shared genetic risks also seen across development. (3) Dyslexia genetic risks are shared with those implicated in many other neurodevelopmental disorders (e.g., developmental language disorder and dyscalculia). Finally, we will discuss the implications and future directions. As the diversity of genetic studies continues to increase through international collaborate efforts, we will highlight the challenges in advances of genetics discoveries in this field.

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Intra- and inter-specific variations of gene expression levels in yeast are largely neutral

10.1101/089995 ◽

2016 ◽

Cited By ~ 1

Author(s):

Jian-Rong Yang ◽

Calum Maclean ◽

Chungoo Park ◽

Huabin Zhao ◽

Jianzhi Zhang

Keyword(s):

Gene Expression ◽

Genome Sequence ◽

Large Fraction ◽

General Role ◽

Expression Levels ◽

Genome Wide ◽

Sequence Variations ◽

Expression Evolution ◽

Molecular Phenotypes ◽

Gene Expression Levels

ABSTRACTIt is commonly, although not universally, accepted that most intra- and inter-specific genome sequence variations are more or less neutral, whereas a large fraction of organism-level phenotypic variations are adaptive. Gene expression levels are molecular phenotypes that bridge the gap between genotypes and corresponding organism-level phenotypes. Yet, it is unknown whether natural variations in gene expression levels are mostly neutral or adaptive. Here we address this fundamental question by genome-wide profiling and comparison of gene expression levels in nine yeast strains belonging to three closely related Saccharomyces species and originating from five different ecological environments. We find that the transcriptome-based clustering of the nine strains approximates the genome sequence-based phylogeny irrespective of their ecological environments. Remarkably, only ∼0.5% of genes exhibit similar expression levels among strains from a common ecological environment, no greater than that among strains with comparable phylogenetic relationships but different environments. These and other observations strongly suggest that most intra- and inter-specific variations in yeast gene expression levels result from the accumulation of random mutations rather than environmental adaptations. This finding has profound implications for understanding the driving force of gene expression evolution, genetic basis of phenotypic adaptation, and general role of stochasticity in evolution.

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Genome-Wide CRISPR Screening in Acute Myeloid Leukemia Cells Identifies Genes in the PI3K/AKT/mTOR and MEK/ERK Pathways That Define Sensitivity to Trametinib

Blood ◽

10.1182/blood-2019-129117 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1395-1395

Author(s):

Tamilla Nechiporuk ◽

Alisa Damnernsawad ◽

Daniel Bottomly ◽

Quinlan Morrow ◽

Suyoun Choi ◽

...

Keyword(s):

Myeloid Leukemia ◽

Research Funding ◽

Molecular Pathways ◽

Refractory Disease ◽

Loss Of Function ◽

Ras Pathway ◽

Genetics Research ◽

Genome Wide ◽

Flt3 Inhibitors ◽

Acute Myeloid

Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a challenging disease to treat due to its heterogeneity and high level of relapsed/refractory disease. Exploration of molecular pathways that drive AML have implicated broad activation of the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pro-survival pathways in the pathogenesis of the disease. Among the most frequent genetic perturbations, direct mutation of N- or K-RAS as well as mutation of nearby pathway regulators (PTPN11, NF1) are identified in ~20% of patients with AML. An additional ~35% of AML patients exhibit mutations in FLT3 or KIT, upstream receptor tyrosine kinases known to activate the RAS pathway. Moreover, relapsed/refractory disease in response to novel molecularly targeted FLT3 inhibitors often results in RAS pathway mutations underpinning the connection between these molecular pathways in AML. These findings resulted in several preclinical studies and ongoing clinical trials testing the efficacies of MEK1/2 inhibitors in AML either as a single agent or in combination with FLT3 inhibitors. To elucidate pathways leading to changes in trametinib sensitivity and resistance in a FLT3-ITD genomic landscape, we performed a genome-wide CRISPR screen for trametinib sensitivity in MOLM13 AML cells, which carry a FLT3-ITD mutation. Results from both the genome-wide screen and independently generated cell lines with decreased sensitivity to trametinib indicated involvement of a diversity of genes and pathways, including the tumor-suppressor, PTEN (a negative regulator of PI3K/AKT/mTOR), AMBRA1 (an autophagy regulator via the mTOR pathway), and DUSP7 (a phosphatase negatively regulating downstream ERK activity). Cells engineered to have loss-of-function for these genes as well as cells cultured for resistance to trametinib showed perturbed signaling in downstream PI3K/AKT/mTOR and MEK/ERK signaling cascades. Our work identified genes whose loss of function in the disease-implicated pathways confer trametinib resistance in AML and provide a rationale for selecting combinatorial trametinib/FLT3 inhibitors treatment based on unique patient mutational and gene expression landscapes. Disclosures Tyner: Incyte: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Takeda: Research Funding; Takeda: Research Funding; Genentech: Research Funding; Constellation: Research Funding; Aptose: Research Funding; Genentech: Research Funding; Syros: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Array: Research Funding; Agios: Research Funding; Agios: Research Funding; Aptose: Research Funding; Array: Research Funding; AstraZeneca: Research Funding; Constellation: Research Funding; Petra: Research Funding; Syros: Research Funding; Petra: Research Funding.

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Genetics of Atrial Fibrillation in 2020

Circulation Research ◽

10.1161/circresaha.120.316575 ◽

2020 ◽

Vol 127 (1) ◽

pp. 21-33 ◽

Cited By ~ 4

Author(s):

Carolina Roselli ◽

Michiel Rienstra ◽

Patrick T. Ellinor

Keyword(s):

Atrial Fibrillation ◽

Complex Disease ◽

Association Studies ◽

Heart Rhythm ◽

Genome Wide Association Studies ◽

Future Directions ◽

Genetics Research ◽

Genome Wide ◽

Increased Risk ◽

Rhythm Disorder

Atrial fibrillation is a common heart rhythm disorder that leads to an increased risk for stroke and heart failure. Atrial fibrillation is a complex disease with both environmental and genetic risk factors that contribute to the arrhythmia. Over the last decade, rapid progress has been made in identifying the genetic basis for this common condition. In this review, we provide an overview of the primary types of genetic analyses performed for atrial fibrillation, including linkage studies, genome-wide association studies, and studies of rare coding variation. With these results in mind, we aim to highlighting the existing knowledge gaps and future directions for atrial fibrillation genetics research.

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Differential evolution in 3′UTRs leads to specific gene expression in Staphylococcus

Nucleic Acids Research ◽

10.1093/nar/gkaa047 ◽

2020 ◽

Vol 48 (5) ◽

pp. 2544-2563 ◽

Cited By ~ 2

Author(s):

Pilar Menendez-Gil ◽

Carlos J Caballero ◽

Arancha Catalan-Moreno ◽

Naiara Irurzun ◽

Inigo Barrio-Hernandez ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Regulation ◽

Bacterial Species ◽

Regulatory Elements ◽

Specific Gene ◽

Species Differentiation ◽

Orthologous Genes ◽

Genome Wide ◽

Sequence Variations ◽

Species Specific

Abstract The evolution of gene expression regulation has contributed to species differentiation. The 3′ untranslated regions (3′UTRs) of mRNAs include regulatory elements that modulate gene expression; however, our knowledge of their implications in the divergence of bacterial species is currently limited. In this study, we performed genome-wide comparative analyses of mRNAs encoding orthologous proteins from the genus Staphylococcus and found that mRNA conservation was lost mostly downstream of the coding sequence (CDS), indicating the presence of high sequence diversity in the 3′UTRs of orthologous genes. Transcriptomic mapping of different staphylococcal species confirmed that 3′UTRs were also variable in length. We constructed chimeric mRNAs carrying the 3′UTR of orthologous genes and demonstrated that 3′UTR sequence variations affect protein production. This suggested that species-specific functional 3′UTRs might be specifically selected during evolution. 3′UTR variations may occur through different processes, including gene rearrangements, local nucleotide changes, and the transposition of insertion sequences. By extending the conservation analyses to specific 3′UTRs, as well as the entire set of Escherichia coli and Bacillus subtilis mRNAs, we showed that 3′UTR variability is widespread in bacteria. In summary, our work unveils an evolutionary bias within 3′UTRs that results in species-specific non-coding sequences that may contribute to bacterial diversity.

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