利用蛋白质语言模型识别复杂的特征关联与以前无法访问的功能罕见变异类别的复杂特征关联
Seon-Kyeong Jang1, Zitian Wang2, Richard Border3
1Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Cell genomics
|November 20, 2025
概括
蛋白质语言模型 (PLMs) 增强了复杂特征中基因发现的变异效应预测. 这种方法识别了更多的遗传关联,并突出了异形特异性影响,改善了对外体数据的罕见变异解释.
科学领域:
- 遗传学 遗传学 是一个
- 计算生物学 计算生物学
- 生物信息学是一种生物信息学.
背景情况:
- 蛋白质语言模型 (PLM) 正在推进变异效应预测.
- 在复杂特征的基因发现中,PLM的实用性尚未得到很好的定义.
- 标准负荷测试在识别复杂特征的遗传关联方面存在局限性.
研究的目的:
- 为了利用PLM衍生的变异效应预测,在复杂的特征中增强基因发现.
- 研究非正典转录在基因特征关联中的作用.
- 识别和描述进化可信变体 (EPV) 和它们与人类特征的关联.
主要方法:
- 开发了一种基于基序列的回归测试,使用PLM预测作为效果大小代理.
- 进行了异形级别分析,以比较正规和非正规的转录.
- 确定了进化可信变异 (EPV) 作为误解变异,其PLM概率高于野生类型的等位基因.
主要成果:
- 新的回归测试与标准负担测试相比,发现了大约46%的基因特征关联.
- 发现了26个基因特征对,在非正典转录中具有更强的关联,表明异型特异性影响.
- 鉴定了EPV (0.45%的误解变体) 与同义变体相比具有更高的等位基因频率,与包括LDL和骨矿物质密度在内的9个特征相关.
结论:
- PLM显著提高了复杂疾病的基因特征关联的发现.
- 异形特异性分析揭示了对基因功能和调节的新生物学见解.
- EPVs代表了一个潜在的选择类型的变体,对人类健康和进化有影响.
相关概念视频
01:11Genome-wide Association Studies-GWAS
15.2K
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...
15.2K
01:33Pleiotropy
43.1K
Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
43.1K
01:18Polygenic Traits
68.8K
When more than one gene is responsible for a given phenotype, the trait is considered polygenic. Human height is a polygenic trait. Studies have uncovered hundreds of loci that influence height, and there are believed to be many more. Due to the high number of genes involved, as well as environmental and nutritional factors, height varies significantly within a given population. The distribution of height forms a bell-shaped curve, with relatively few individuals in the population at the...
68.8K
01:05Single Nucleotide Polymorphisms-SNPs
17.9K
A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
17.9K
01:49Multiple Allele Traits
37.9K
The Concept of Multiple Allelism
37.9K
02:26Protein Networks
4.5K
An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
4.5K