同基因特异性的替代多基解将非编码遗传变异与阿尔茨海默病风险联系起来
bioRxiv : the preprint server for biology
|February 23, 2026
概括
遗传变异调节人脑中的替代多基 (APA),影响神经发育和神经退行性疾病. FMRP蛋白被认为是这个过程的关键调节者.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- 替代多基化 (APA) 在神经系统中产生了转录多样性.
- 遗传变异在调节人类大脑3' UTR使用中的作用尚不清楚.
- 基因特异性APA (asAPA) 及其对神经系统疾病的影响需要进一步研究.
研究的目的:
- 为了描述asAPA在人类大脑中的特征.
- 研究asAPA在神经发育和神经退行性疾病中的作用.
- 为了确定监管机制和asAPA的功能后果.
主要方法:
- 分析了来自293名阿尔茨海默氏病 (AD) 和对照患者的1,047个RNA-seq数据集.
- 识别asAPA事件和单核酸多态 (SNP).
- 功能变异的优先考虑和RNA结合蛋白质基因的丰富分析.
主要成果:
- 确定了4,462个与3,432个SNP相关的APA事件,其中富含RNA结合蛋白基因,特别是FMRP.
- 在脆弱X综合征大脑中观察到广泛的3' UTR缩短,涉及FMRP调节APA.
- 发现asAPA SNPs和GWAS风险位置之间存在显著的重叠,用于自闭症谱系障碍 (ASD),ADHD和AD.
- 在AD大脑中确定了77个asAPA基因,具有特定条件的等位基因偏差转移,包括像CAMK2G这样的突触基因.
结论:
- asAPA代表了人类大脑中一个显著的cis-regulatory变异层.
- FMRP是asAPA的关键调节者,影响3' UTR长度.
- asAPA在神经发育和神经退行性疾病中提供了遗传风险因素和神经元功能障碍之间的机制联系.
更多相关视频
09:38Generalized Psychophysiological Interaction PPI Analysis of Memory Related Connectivity in Individuals at Genetic Risk for Alzheimer's Disease
Published on: November 14, 2017
15.8K
07:26High-resolution Melting PCR for Complement Receptor 1 Length Polymorphism Genotyping: An Innovative Tool for Alzheimer's Disease Gene Susceptibility Assessment
Published on: July 18, 2017
12.3K
相关概念视频
Alternative RNA Splicing
25.4K
Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
25.4K
RNA Splicing
60.8K
Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
60.8K
Genome-wide Association Studies-GWAS
15.9K
Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
GWAS does not require the identification of the target gene involved in...
GWAS does not require the identification of the target gene involved in...
15.9K
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
30
Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
30
Human Genetics
1.7K
Human genetics provides a profound framework for understanding the interplay between genetic predispositions and human psychology. At the heart of this discipline lies the study of how genes influence physical traits, behaviors, and susceptibility to diseases. Each person carries a unique genetic code that subtly or significantly shapes their psychological and behavioral landscape.
The complex relationship between genetics and psychology is observable through common biological components such...
The complex relationship between genetics and psychology is observable through common biological components such...
1.7K
Pharmacogenomics: Identification of New Drug Targets
29
Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...
29
