Faculty Opinions recommendation of The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia.

2013 ◽  
Author(s):  
Gary Donohoe ◽  
Sinead Kelly
Keyword(s):  
Phenotypic Heterogeneity ◽  
Genome Wide

scholarly journals Cis-Regulatory Logic Produces Gene-Expression Noise Describing Phenotypic Heterogeneity in Bacteria

2021 ◽  
Vol 12 ◽  
Author(s):  
Debajyoti Chowdhury ◽  
Chao Wang ◽  
Aiping Lu ◽  
Hailong Zhu
Keyword(s):  
Gene Expression ◽  
Phenotypic Variability ◽  
Regulatory Elements ◽  
Phenotypic Heterogeneity ◽  
Animal Cells ◽  
Gene Expression Noise ◽  
Expression Noise ◽  
Promoter Architecture ◽  
Genome Wide ◽  
Rational Construction

Gene transcriptional process is random. It occurs in bursts and follows single-molecular kinetics. Intermittent bursts are measured based on their frequency and size. They influence temporal fluctuations in the abundance of total mRNA and proteins by generating distinct transcriptional variations referred to as “noise”. Noisy expression induces uncertainty because the association between transcriptional variation and the extent of gene expression fluctuation is ambiguous. The promoter architecture and remote interference of different cis-regulatory elements are the crucial determinants of noise, which is reflected in phenotypic heterogeneity. An alternative perspective considers that cellular parameters dictating genome-wide transcriptional kinetics follow a universal pattern. Research on noise and systematic perturbations of promoter sequences reinforces that both gene-specific and genome-wide regulation occur across species ranging from bacteria and yeast to animal cells. Thus, deciphering gene-expression noise is essential across different genomics applications. Amidst the mounting conflict, it is imperative to reconsider the scope, progression, and rational construction of diversified viewpoints underlying the origin of the noise. Here, we have established an indication connecting noise, gene expression variations, and bacterial phenotypic variability. This review will enhance the understanding of gene-expression noise in various scientific contexts and applications.

scholarly journals The PAX1 locus at 20p11 is a modifier for bilateral cleft lip only

2020 ◽  
Author(s):  
Sarah W. Curtis ◽  
Daniel Chang ◽  
Myoung Keun Lee ◽  
John R. Shaffer ◽  
Karlijne Indencleef ◽  
...  
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Cleft Lip ◽  
Mixed Model ◽  
Cleft Lip And Palate ◽  
Phenotypic Heterogeneity ◽  
Mixed Model Approach ◽  
Genome Wide ◽  
A Genome ◽  
Model Approach

AbstractNonsyndromic orofacial clefts (OFCs) are the most common craniofacial birth defect in humans and, like many complex traits, OFCs are phenotypically and etiologically heterogenous. The phenotypic heterogeneity of OFCs extends beyond the structures affected by the cleft (e.g., cleft lip (CL) and cleft lip and palate (CLP) to other features, such as the severity of the cleft. Here, we focus on bilateral and unilateral clefts as one dimension of OFC severity. Unilateral clefts are more frequent than bilateral clefts for both CL and CLP, but the genetic architecture of these subtypes is not well understood, and it is not known if genetic variants predispose for the formation of one subtype over another. Therefore, we tested for subtype-specific genetic associations in 44 bilateral CL (BCL) cases, 434 unilateral CL (UCL) cases, 530 bilateral CLP cases (BCLP), 1123 unilateral CLP (UCLP) cases, and unrelated controls (N = 1626), using the mixed-model approach implemented in GENESIS. While no novel loci were found in subtype-specific analyses comparing cases to controls, the genetic architecture of UCL was distinct compared to BCL, with 43.8% of suggestive loci (p < 1.0×10−5) having non-overlapping confidence intervals between the two subtypes. To further understand the genetic risk factors for severity differences, we then performed a genome-wide scan for modifiers using a similar mixed-model approach and found one genome-wide significant modifier locus on 20p11 (p = 7.53×10−9), 300kb downstream of PAX1, associated with higher odds of BCL compared to UCL, which also replicated in an independent cohort (p = 0.0018) and showed no effect in BCLP (p>0.05). We further found that SNPs at this locus were associated with normal human nasal shape. Taken together, these results suggest bilateral and unilateral clefts may have differences in their genetic architecture, especially between CL and CLP. Moreover, our results suggest BCL, the rarest form of OFC, may be genetically distinct from the other OFC subtypes. This expands our understanding of genetic modifiers for subtypes of OFCs and further elucidates the genetic mechanisms behind the phenotypic heterogeneity in OFCs.

The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia

2013 ◽  
Vol 18 (4) ◽  
pp. 443-450 ◽  
Author(s):  
T A Lett ◽  
M M Chakavarty ◽  
D Felsky ◽  
E J Brandl ◽  
A K Tiwari ◽  
...  
Keyword(s):  
Phenotypic Heterogeneity ◽  
Genome Wide

Family-based exome-sequencing approach identifies rare susceptibility variants for lithium-responsive bipolar disorder

Genome ◽  
2013 ◽  
Vol 56 (10) ◽  
pp. 634-640 ◽  
Author(s):  
Cristiana Cruceanu ◽  
Amirthagowri Ambalavanan ◽  
Dan Spiegelman ◽  
Julie Gauthier ◽  
Ronald G. Lafrenière ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Rare Variants ◽  
Association Studies ◽  
Phenotypic Heterogeneity ◽  
Exome Capture ◽  
Genome Wide Association Studies ◽  
Complex Disorder ◽  
Genome Wide ◽  
High Throughput Dna Sequencing ◽  
Family Based

Bipolar disorder (BD) is a psychiatric condition characterized by the occurrence of at least two episodes of clinically disturbed mood including mania and depression. A vast literature describing BD studies suggests that a strong genetic contribution likely underlies this condition; heritability is estimated to be as high as 80%. Many studies have identified BD susceptibility loci, but because of the genetic and phenotypic heterogeneity observed across individuals, very few loci were subsequently replicated. Research in BD genetics to date has consisted of classical linkage or genome-wide association studies, which have identified candidate genes hypothesized to present common susceptibility variants. Although the observation of such common variants is informative, they can only explain a small fraction of the predicted BD heritability, suggesting a considerable contribution would come from rare and highly penetrant variants. We are seeking to identify such rare variants, and to increase the likelihood of being successful, we aimed to reduce the phenotypic heterogeneity factor by focusing on a well-defined subphenotype of BD: excellent response to lithium monotherapy. Our group has previously shown positive response to lithium therapy clusters in families and has a consistent clinical presentation with minimal comorbidity. To identify such rare variants, we are using a targeted exome capture and high-throughput DNA sequencing approach, and analyzing the entire coding sequences of BD affected individuals from multigenerational families. We are prioritizing rare variants with a frequency of less than 1% in the population that segregate with affected status within each family, as well as being potentially highly penetrant (e.g., protein truncating, missense, or frameshift) or functionally relevant (e.g., 3′UTR, 5′UTR, or splicing). By focusing on rare variants in a familial cohort, we hope to explain a significant portion of the missing heritability in BD, as well as to narrow our current insight on the key biochemical pathways implicated in this complex disorder.

scholarly journals Erratum: The genome-wide supported microRNA-137 variant predicts phenotypic heterogeneity within schizophrenia

2013 ◽  
Vol 18 (10) ◽  
pp. 1146-1146 ◽  
Author(s):  
T A Lett ◽  
M M Chakravarty ◽  
D Felsky ◽  
E J Brandl ◽  
A K Tiwari ◽  
...  
Keyword(s):  
Phenotypic Heterogeneity ◽  
Genome Wide
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