利用大型基因组数据集进行眼部肿瘤相关基因的遗传分析：人群中选择约束和变异体表达的见解。

Genetic analysis of ocular tumour-associated genes using large genomic datasets: insights into selection constraints and variant representation in the population.

机构信息

Institute of Ophthalmology, University College London, London, UK.

Retinal Genetics Service, Moorfields Eye Hospital NHS Foundation Trust, London, UK.

出版信息

BMJ Open Ophthalmol. 2024 Feb 21;9(1):e001565. doi: 10.1136/bmjophth-2023-001565.

DOI:10.1136/bmjophth-2023-001565

PMID:38388005

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10897839/

Abstract

BACKGROUND

Large genomic databases enable genetic evaluation in terms of haploinsufficiency and prevalence of missense and synonymous variants. We explored these parameters in ocular tumour-associated genes.

METHODS

A curated list of ocular tumour-associated genes was assessed using the genomic databases Genome Aggregation Database (gnomAD) and DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) and compared with breast and lung cancer-associated gene lists. Haploinsufficiency was determined based on specific criteria: probability of loss of function index ≥0.9 in gnomAD, upper CI O/E limit <0.35 for loss of function variants in gnomAD and/or a DECIPHER pHaplo ≥0.86. UniProt was used for further gene characterisation, and gene ontology Protein Analysis THrough Evolutionary Relationships was explored for common biological pathways. In addition, we identified genes with under-representation/over-representation of missense/synonymous variants.

RESULTS

Fifty-seven genes were identified in association with ocular and extraocular tumours.Regarding haploinsufficiency, 41% of genes met the criteria for negative selection, with 57% categorised as tumour-suppressing and 39% as oncogenic. Most genes were involved in regulatory processes. Regarding triplosensitivity, 33% of genes reached significance and 83% of these were haploinsufficient. Analysis of variants revealed under-representation of missense variants in 23% of genes and over-representation of synonymous variants in 5% of genes. Ocular tumour-associated genes exhibited higher scores for haploinsufficiency and triplosensitivity compared with breast and lung cancer-associated genes. Pathway analysis revealed significant enrichment in cellular proliferation, differentiation and division. Encoded proteins of ocular tumour-associated genes were generally longer than the median of the UniProt database.

CONCLUSION

Our findings highlight the importance of negative selection in ocular tumour genes, supporting cranial gene conservation. This study provides insights into ocular tumourigenesis and future research avenues.

摘要

背景

大型基因组数据库使我们能够根据单倍不足和错义及同义变异的流行情况进行遗传评估。我们在眼部肿瘤相关基因中探索了这些参数。

方法

使用基因组数据库基因组聚集数据库（gnomAD）和使用 Ensembl 资源的基因组变异和表型数据库（DECIPHER）对眼部肿瘤相关基因的精选列表进行评估，并与乳腺癌和肺癌相关基因列表进行比较。根据特定标准确定单倍不足：gnomAD 中功能丧失指数概率≥0.9，gnomAD 中功能丧失变异的上置信区间 O/E 限值<0.35，或 DECIPHER pHaplo≥0.86。UniProt 用于进一步的基因特征描述，探索基因本体蛋白质分析通过进化关系的常见生物学途径。此外，我们确定了错义/同义变异的代表性不足/过度的基因。

结果

鉴定出 57 个与眼部和眼外肿瘤相关的基因。关于单倍不足，41%的基因符合负选择标准，57%归类为肿瘤抑制基因，39%归类为致癌基因。大多数基因参与调节过程。关于三倍敏感性，33%的基因达到显著水平，其中 83%的基因单倍不足。变异分析显示，23%的基因中错义变异代表性不足，5%的基因中同义变异代表性过度。与乳腺癌和肺癌相关基因相比，眼部肿瘤相关基因的单倍不足和三倍敏感性评分更高。通路分析显示细胞增殖、分化和分裂显著富集。眼部肿瘤相关基因编码的蛋白质通常比 UniProt 数据库的中位数长。