scholarly journals Converging evidence for differential regulatory control of APOEε4 on African versus European haplotypes

2021 ◽  
Author(s):  
Karen Nuytemans ◽  
Marina LipkinVasquez ◽  
Liyong Wang ◽  
Derek Van Booven ◽  
Anthony J Griswold ◽  
...  
Keyword(s):  
Regulatory Control ◽  
Regulatory Function ◽  
Enhancer Activity ◽  
Single Fragment ◽  
Reporter Assays ◽  
Different Populations ◽  
The Difference ◽  
Massively Parallel Reporter Assay ◽  
Intron 2 ◽  
Apoe Expression

INTRODUCTION. The difference in APOEϵ4 risk for Alzheimer disease (AD) between different populations is associated with APOEϵ4 local ancestry (LA). We examined LA SNPs with significant frequency differences between African and European/Japanese APOEϵ4 haplotypes for areas of differential regulation. METHODS. We performed two enhancer Massively Parallel Reporter Assay (MPRA) approaches, supplemented with single fragment reporter assays. We utilized Capture C analyses to support interactions with the APOE promoter. RESULTS. The TOMM40 intron 2 and 3 region showed increased enhancer activity in the European/Japanese versus African LA haplotypes in astrocytes and microglia. This region overlaps with APOE promoter interactions as assessed by Capture C analysis. Single variant analyses pinpoints rs2075650/rs157581, and rs59007384 as functionally different on these haplotypes. DISCUSSION. Both differential regulatory function and Capture C data support an intronic region in TOMM40 as contributing to the differential APOE expression between African and European/Japanese LA.

scholarly journals A systematic comparison reveals substantial differences in chromosomal versus episomal encoding of enhancer activity

2016 ◽  
Author(s):  
Fumitaka Inoue ◽  
Martin Kircher ◽  
Beth Martin ◽  
Gregory M. Cooper ◽  
Daniela M. Witten ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Sequence Information ◽  
Regulatory Sequences ◽  
Enhancer Activity ◽  
Functional Activities ◽  
Reporter Assays ◽  
Bona Fide ◽  
Massively Parallel Reporter Assay

AbstractCandidate enhancers can be identified on the basis of chromatin modifications, the binding of chromatin modifiers and transcription factors and cofactors, or chromatin accessibility. However, validating such candidates as bona fide enhancers requires functional characterization, typically achieved through reporter assays that test whether a sequence can drive expression of a transcriptional reporter via a minimal promoter. A longstanding concern is that reporter assays are mainly implemented on episomes, which are thought to lack physiological chromatin. However, the magnitude and determinants of differences incis-regulation for regulatory sequences residing in episomes versus chromosomes remain almost completely unknown. To address this question in a systematic manner, we developed and applied a novel lentivirus-based massively parallel reporter assay (lentiMPRA) to directly compare the functional activities of 2,236 candidate liver enhancers in an episomal versus a chromosomally integrated context. We find that the activities of chromosomally integrated sequences are substantially different from the activities of the identical sequences assayed on episomes, and furthermore are correlated with different subsets of ENCODE annotations. The results of chromosomally-based reporter assays are also more reproducible and more strongly predictable by both ENCODE annotations and sequence-based models. With a linear model that combines chromatin annotations and sequence information, we achieve a Pearson’s R2of 0.347 for predicting the results of chromosomally integrated reporter assays. This level of prediction is better than with either chromatin annotations or sequence information alone and also outperforms predictive models of episomal assays. Our results have broad implications for howcis-regulatory elements are identified, prioritized and functionally validated.

THE GROWTH OF IQ AMONG ESTONIAN SCHOOLCHILDREN FROM AGES 7 TO 19

2004 ◽  
Vol 36 (6) ◽  
pp. 735-740 ◽  
Author(s):  
HELLE PULLMANN ◽  
JÜRI ALLIK ◽  
RICHARD LYNN
Keyword(s):  
Secondary School ◽  
School Children ◽  
Growth Pattern ◽  
Representative Sample ◽  
Sampling Error ◽  
First Grade ◽  
Maturation Process ◽  
Different Populations ◽  
The Mean ◽  
The Difference

The Standard Progressive Matrices test was standardized in Estonia on a representative sample of 4874 schoolchildren aged from 7 to 19 years. When the IQ of Estonian children was expressed in relation to British and Icelandic norms, both demonstrated a similar sigmoid relationship. The youngest Estonian group scored higher than the British and Icelandic norms: after first grade, the score fell below 100 and remained lower until age 12, and after that age it increased above the mean level of these two comparison countries. The difference between the junior school children and the secondary school children may be due to schooling, sampling error or different trajectories of intellectual maturation in different populations. Systematic differences in the growth pattern suggest that the development of intellectual capacities proceeds at different rates and the maturation process can take longer in some populations than in others.

Early manifestations and first-contact incidence of schizophrenia in different cultures: A preliminary report on the initial evaluation phase of the WHO Collaborative Study on Determinants of Outcome of Severe Mental Disorders

1986 ◽  
Vol 16 (4) ◽  
pp. 909-928 ◽  
Author(s):  
N. Sartorius ◽  
A. Jablensky ◽  
A. Korten ◽  
G. Ernberg ◽  
M. Anker ◽  
...  
Keyword(s):  
Collaborative Study ◽  
Strong Support ◽  
Developed Countries ◽  
Incidence Rates ◽  
Symptom Profiles ◽  
Evaluation Phase ◽  
Different Populations ◽  
The Difference ◽  
Different Cultures ◽  
First Contact

SynopsisIn a context of a WHO collaborative study, 12 research centres in 10 countries monitored geographically defined populations over 2 years to identify individuals making a first-in-lifetime contact with any type of ‘helping agency’ because of symptoms of psychotic illness. A total of 1379 persons who met specified inclusion criteria for schizophrenia and other related non-affective disorders were examined extensively, using standardized instruments, on entry into the study and on two consecutive follow-ups at annual intervals. Patients in different cultures, meeting the ICD and CATEGO criteria for schizophrenia, were remarkably similar in their symptom profiles and 49% of them presented the central schizophrenic conditions as defined by CATEGO class S+. However, the 2-year pattern of course was considerably more favourable in patients in developing countries compared with patients in developed countries, and the difference could not be fully explained by the higher frequency of acute onsets among the former. Age- and sex-specific incidence rates and estimates of disease expectancy were determined for a ‘broad’ diagnostic group of schizophrenic illness and for CATEGO S+ cases. While the former showed significant differences among the centres, the differences in the rates for S+ cases were non-significant or marginal. The results provide strong support for the notion that schizophrenic illnesses occur with comparable frequency in different populations and support earlier findings that the prognosis is better in less industrialized societies.

Abstract 18374: Targeted Sequencing and Massively Parallel Reporter Assay Identify the Functional Variation Underlying the 4q25 Locus for Atrial Fibrillation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Nathan R Tucker ◽  
Jiangchuan Ye ◽  
Honghuang Lin ◽  
Michael A McLellan ◽  
Emelia J Benjamin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Association Studies ◽  
Targeted Sequencing ◽  
Massively Parallel ◽  
Genome Wide Association Studies ◽  
Sequencing Analysis ◽  
Reporter Assay ◽  
Enhancer Activity ◽  
Functional Variants ◽  
Massively Parallel Reporter Assay

Introduction: Genome-wide association studies have identified 14 independent loci for atrial fibrillation (AF). The 4q25 locus upstream of the left-right asymmetry gene PITX2 is, by far, the strongest association signal for AF. However, as with most GWAS loci, the functional variants are noncoding, presumed to be regulatory, and remain unknown. We therefore sought to rapidly identify the functional variants at an AF locus by combining high throughput sequencing and massively parallel reporter assays. Methods and Results: We sequenced a ~750kb region encompassing the PITX2 locus in 462 individuals with early-onset AF from the MGH AF Study and 464 referents from the Framingham Heart Study. The SNP most significantly associated with AF in our sequenced sample was rs2129983, which is 140kb from PITX2 (OR=2.43, P =8.9X10 -16 ). rs2129983 is approximately 1.7kb from the most significantly associated SNP in a prior AF GWAS, rs6817105 (r 2 =0.52). From the targeted sequencing analysis, we identified 262 SNVs with a MAF >0.5% within a genomic region bounded by SNPs with an r2 greater than 0.4 with the top variant. To identify functional variants, we then utilized a massively parallel reporter assay (MPRA) in order to measure enhancer activity at each SNP across the entire AF locus. In both HL-1 and C2C12 myoblasts, MPRA identified many distinct SNP regions with differential enhancer activity. Using AF-association status as a standard, we were able to identify a series of variants that have both differential activity in either cell line tested and also a high level of association (rs17042076, rs4469143). Mechanistically, these functional SNPs are predicted to alter transcription factor binding. Conclusions: We have comprehensively identified the AF-associated variation at 4q25 and determined which of these variants are functional through differential enhancer activity. Here, in addition to identifying the causative variation for AF at 4q25, we provide a generalizable pathway for translating this work to other loci, a method that could expedite the identification of causative genetic variants at other disease loci.

Diagnosis and classification criteria

2018 ◽  
Author(s):  
Laura C. Coates ◽  
William J. Taylor
Keyword(s):  
Signs And Symptoms ◽  
Classification Criteria ◽  
Design Function ◽  
Diagnosis And Classification ◽  
Axial Disease ◽  
Different Populations ◽  
The Difference ◽  
And Performance ◽  
Over Time

This chapter covers diagnosis and classification of psoriatic arthritis (PsA). Firstly the difference between diagnosis and classification criteria in terms of their design, function, and performance is discussed. The diagnostic clues of PsA are summarized: risk factors for development of arthritis amongst patients with psoriasis, signs, and symptoms of articular, entheseal and axial disease, and relevant investigations. Older classification criteria for PsA are discussed along with later modifications. The development of the CASPAR criteria is described and subsequent studies assessing the accuracy of the CASPAR criteria in different populations are then summarized. How PsA fits within the broader family of spondyloarthritides (SpA) and the performance of CASPAR compared to SpA criteria is outlined. Different subtypes of PsA, as well as the evolution of individual patients through subtypes over time, are described. Finally future proposals to develop the ‘stem’ of CASPAR to define ‘inflammatory articular, entheseal or axial disease’ are summarized.

scholarly journals Meta‐analysis of massively parallel reporter assays enables prediction of regulatory function across cell types

2019 ◽  
Vol 40 (9) ◽  
pp. 1299-1313 ◽  
Author(s):  
Anat Kreimer ◽  
Zhongxia Yan ◽  
Nadav Ahituv ◽  
Nir Yosef
Keyword(s):  
Meta Analysis ◽  
Cell Types ◽  
Massively Parallel ◽  
Regulatory Function ◽  
Reporter Assays

scholarly journals HLA B-27 Subtypes in Turkish Patients with Spondyloarthropathy and Healthy Controls

2004 ◽  
Vol 20 (6) ◽  
pp. 309-312 ◽  
Author(s):  
Fatma Savran Oguz ◽  
Lale Ocal ◽  
Ali Sarper Diler ◽  
Hilmi Ozkul ◽  
Faruk Asicioglu ◽  
...  
Keyword(s):  
Turkish Population ◽  
Study Group ◽  
Healthy Controls ◽  
Hla B27 ◽  
Caucasian Patients ◽  
Male Patients ◽  
Different Populations ◽  
The Difference ◽  
Turkish Patients ◽  
Predominant Allele

The frequency and the distribution of HLA-B27 subtypes in spondylarthropathy (SpA) patients and controls were investigated in a sample Turkish population. B27 subtyping was performed by PCR-SSP method in two groups: 49 unrelated HLA-B27 positive Turkish patients with the diagnosis of SpA according to the European Spondyloarthropathy Study Group Criteria, and 55 HLA-B27 positive healthy controls. The frequency of HLA-B∗27 was 2.6% in the Turkish population, and B∗2705 was the predominant allele among patients with SpA. The difference was mainly between male patients and male controls The proportion of B∗2705 among B27-positive patients and controls was significantly different (P = 0.02). Our study supports other reports from different populations which showed that B∗2705 and B∗2702 were more frequent in Caucasian patients with SpA.

scholarly journals Systematic dissection of genomic features determining transcription factor binding and enhancer function

2017 ◽  
Vol 114 (7) ◽  
pp. E1291-E1300 ◽  
Author(s):  
Sharon R. Grossman ◽  
Xiaolan Zhang ◽  
Li Wang ◽  
Jesse Engreitz ◽  
Alexandre Melnikov ◽  
...  
Keyword(s):  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Binding Assays ◽  
Genomic Locus ◽  
Enhancer Activity ◽  
Genomic Features ◽  
Motif Site ◽  
Reporter Assays ◽  
Enhancer Function

Enhancers regulate gene expression through the binding of sequence-specific transcription factors (TFs) to cognate motifs. Various features influence TF binding and enhancer function—including the chromatin state of the genomic locus, the affinities of the binding site, the activity of the bound TFs, and interactions among TFs. However, the precise nature and relative contributions of these features remain unclear. Here, we used massively parallel reporter assays (MPRAs) involving 32,115 natural and synthetic enhancers, together with high-throughput in vivo binding assays, to systematically dissect the contribution of each of these features to the binding and activity of genomic regulatory elements that contain motifs for PPARγ, a TF that serves as a key regulator of adipogenesis. We show that distinct sets of features govern PPARγ binding vs. enhancer activity. PPARγ binding is largely governed by the affinity of the specific motif site and higher-order features of the larger genomic locus, such as chromatin accessibility. In contrast, the enhancer activity of PPARγ binding sites depends on varying contributions from dozens of TFs in the immediate vicinity, including interactions between combinations of these TFs. Different pairs of motifs follow different interaction rules, including subadditive, additive, and superadditive interactions among specific classes of TFs, with both spatially constrained and flexible grammars. Our results provide a paradigm for the systematic characterization of the genomic features underlying regulatory elements, applicable to the design of synthetic regulatory elements or the interpretation of human genetic variation.

scholarly journals A Human Accelerated Region is a Leydig cell GLI2 Enhancer that Affects Male-Typical Behavior

2021 ◽  
Author(s):  
Andrew R. Norman ◽  
Ann H. Ryu ◽  
Kirsty Jamieson ◽  
Sean Thomas ◽  
Yin Shen ◽  
...  
Keyword(s):  
Cell Line ◽  
Reproductive Biology ◽  
Leydig Cells ◽  
Massively Parallel ◽  
Reporter Assay ◽  
Enhancer Activity ◽  
Human Male ◽  
Enhancer Function ◽  
Massively Parallel Reporter Assay ◽  
Human Accelerated Regions

ABSTRACTHuman accelerated regions (HARs) are sequences that have evolved at an accelerated rate in the human lineage. Some HARs are developmental enhancers. We used a massively parallel reporter assay (MPRA) to identify HARs with enhancer activity in a mammalian testis cell line. A subset of HARs exhibited differential activity between the human and chimpanzee orthologs, representing candidates for underlying unique human male reproductive biology. We further characterized one of these candidate testis enhancers, 2xHAR.238. CRISPR/Cas9-mediated deletion in a testis cell line and mice revealed that 2xHAR.238 enhances expression of Gli2, encoding a Hedgehog pathway effector, in testis Leydig cells. 4C-seq revealed that 2xHAR.238 contacts the Gli2 promoter, consistent with enhancer function. In adult male mice, deletion of 2xHAR.238 disrupted mouse male-typical behavior and male interest in female odor. Combined, our work identifies a HAR that promotes the expression of Gli2 in Leydig cells and may have contributed to the evolution of human male reproductive biology.

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