Faculty Bibliography
Searched for:
person:chakra01 or evrong01
Total Results:
565
A PIECE OF MY MIND. A Wild Rotation
PMID: 27533153
ISSN: 1538-3598
CID: 3332572
The Genome Project-Write
PMID: 27256881
ISSN: 1095-9203
CID: 2126732
Rare coding TTN variants are associated with electrocardiographic QT interval in the general population
We have shown previously that noncoding variants mapping around a specific set of 170 genes encoding cardiomyocyte intercalated disc (ID) proteins are more enriched for associations with QT interval than observed for genome-wide comparisons. At a false discovery rate (FDR) of 5%, we had identified 28 such ID protein-encoding genes. Here, we assessed whether coding variants at these 28 genes affect QT interval in the general population as well. We used exome sequencing in 4,469 European American (EA) and 1,880 African American (AA) ancestry individuals from the population-based ARIC (Atherosclerosis Risk In Communities) Study cohort to focus on rare (allele frequency <1%) potentially deleterious (nonsynonymous, stop-gain, splice) variants (n = 2,398 for EA; n = 1,693 for AA) and tested their effects on standardized QT interval residuals. We identified 27 nonsynonymous variants associated with QT interval (FDR 5%), 22 of which were in TTN. Taken together with the mapping of a QT interval GWAS locus near TTN, our observation of rare deleterious coding variants in TTN associated with QT interval show that TTN plays a role in regulation of cardiac electrical conductance and coupling, and is a risk factor for cardiac arrhythmias and sudden cardiac death.
PMCID:4913250
PMID: 27321809
ISSN: 2045-2322
CID: 2746612
Commentary: The central questions of human genetics: Richard Lewontin's 1968 senior lecture in Victor McKusick's Bar Harbor short course
PMID: 27582441
ISSN: 1464-3685
CID: 2746592
Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study [Correction]
[This corrects the article DOI: 10.1371/journal.pgen.1005378.].
PMCID:4927064
PMID: 27355579
ISSN: 1553-7404
CID: 2746602
Revealing rate-limiting steps in complex disease biology: The crucial importance of studying rare, extreme-phenotype families
The major challenge in complex disease genetics is to understand the fundamental features of this complexity and why functional alterations at multiple independent genes conspire to lead to an abnormal phenotype. We hypothesize that the various genes involved are all functionally united through gene regulatory networks (GRN), and that mutant phenotypes arise from the consequent perturbation of one or more rate-limiting steps that affect the function of the entire GRN. Understanding a complex phenotype thus entails unraveling the details of each GRN, namely, the transcription factors that bind to cis regulatory elements affected by sequence variants altering transcription of specific genes, and their mutual feedback relationships. These GRNs can be identified through their rate-limiting steps and are best uncovered by genomic analyses of rare, extreme phenotype families, thus providing a coherent molecular basis to complex traits and disorders.
PMID: 27062178
ISSN: 1521-1878
CID: 2746622
Resolving rates of mutation in the brain using single-neuron genomics
Whether somatic mutations contribute functional diversity to brain cells is a long-standing question. Single-neuron genomics enables direct measurement of somatic mutation rates in human brain and promises to answer this question. A recent study (Upton et al., 2015) reported high rates of somatic LINE-1 element (L1) retrotransposition in the hippocampus and cerebral cortex that would have major implications for normal brain function, and suggested that these events preferentially impact genes important for neuronal function. We identify aspects of the single-cell sequencing approach, bioinformatic analysis, and validation methods that led to thousands of artifacts being interpreted as somatic mutation events. Our reanalysis supports a mutation frequency of approximately 0.2 events per cell, which is about fifty-fold lower than reported, confirming that L1 elements mobilize in some human neurons but indicating that L1 mosaicism is not ubiquitous. Through consideration of the challenges identified, we provide a foundation and framework for designing single-cell genomics studies.
PMID: 26901440
ISSN: 2050-084x
CID: 3332562
Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk
BACKGROUND: Rare genetic variants influence blood pressure (BP). METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of approximately 170 000 common variants (minor allele frequency, >/=1%; statistical significance, P
PMCID:4771070
PMID: 26658788
ISSN: 1942-3268
CID: 2746652
Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa
PRPF31-associated retinitis pigmentosa presents a fascinating enigma: some mutation carriers are blind, while others are asymptomatic. We identify the major molecular cause of this incomplete penetrance through three cardinal features: (1) there is population variation in the number (3 or 4) of a minisatellite repeat element (MSR1) adjacent to the PRPF31 core promoter; (2) in vitro, 3-copies of the MSR1 element can repress gene transcription by 50 to 115-fold; (3) the higher-expressing 4-copy allele is not observed among symptomatic PRPF31 mutation carriers and correlates with the rate of asymptomatic carriers in different populations. Thus, a linked transcriptional modifier decreases PRPF31 gene expression that leads to haploinsufficiency. This result, taken with other identified risk alleles, allows precise genetic counseling for the first time. We also demonstrate that across the human genome, the presence of MSR1 repeats in the promoters or first introns of genes is associated with greater population variability in gene expression indicating that copy number variation of MSR1s is a generic controller of gene expression and promises to provide new insights into our understanding of gene expression regulation.
PMCID:4725990
PMID: 26781568
ISSN: 2045-2322
CID: 2746632
A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family [Case Report]
Mutations in the PIGN gene involved in the glycosylphoshatidylinositol (GPI) anchor biosynthesis pathway cause Multiple Congenital Anomalies-Hypotonia-Seizures syndrome 1 (MCAHS1). The syndrome manifests developmental delay, hypotonia, and epilepsy, combined with multiple congenital anomalies. We report on the identification of a homozygous novel c.755A>T (p.D252V) deleterious mutation in a patient with Israeli-Arab origin with MCAHS1. The mutated PIGN caused a significant decrease of the overall GPI-anchored proteins and CD24 expression. Our results, strongly support previously published data, that partial depletion of GPI-anchored proteins is sufficient to cause severe phenotypic expression.
PMCID:5635853
PMID: 26364997
ISSN: 1552-4833
CID: 2746672
