后GWAS时代基因组功能变异的高通量鉴定方法及其在农业动物中的应用

doi:10.16288/j.yczz.25-319

遗传 ›› 2026, Vol. 48 ›› Issue (5): 451-470.doi: 10.16288/j.yczz.25-319

后GWAS时代基因组功能变异的高通量鉴定方法及其在农业动物中的应用

尹心怡¹^,²^,³(), 王守志¹^,²^,³()

¹ 农业农村部鸡遗传育种重点实验室，哈尔滨 150030
² 黑龙江省普通高等学校动物遗传育种与繁殖重点实验室，哈尔滨 150030
³ 东北农业大学动物科学技术学院，哈尔滨 150030

收稿日期:2025-12-04 修回日期:2026-01-18 出版日期:2026-05-20 发布日期:2026-03-04
通讯作者: 王守志，博士，教授，博士生导师，研究方向: 动物遗传育种与繁殖。E-mail: shouzhiwang@neau.edu.cn
作者简介:尹心怡，硕士研究生，专业方向：动物遗传育种与繁殖。E-mail: 18637783198@163.com
基金资助:
国家自然科学基金项目(32372867);国家农业科技重大项目(NK20221001);国家现代农业产业技术体系(CARS-41)

High-throughput identification methods of genomic functional variation in post-GWAS era and their application in agricultural animals

Xinyi Yin¹^,²^,³(), Shouzhi Wang¹^,²^,³()

¹ Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, China
² Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, China
³ College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China

Received:2025-12-04 Revised:2026-01-18 Published:2026-05-20 Online:2026-03-04
Supported by:
National Natural Science Foundation of China(32372867);National Major Agricultural Science and Technology Project(NK20221001);China Agriculture Research System of MOF and MARA(CARS-41)

摘要/Abstract

摘要：

全基因组关联分析(genome-wide association study，GWAS)已鉴定出大量与人类疾病和动植物经济性状显著关联的遗传变异。然而，由于多数变异位于基因组的非编码区域，使得从众多变异位点中准确识别具有生物学功能的变异仍面临巨大挑战。进入后GWAS时代，以高通量报告基因分析、CRISPR/Cas9基因编辑技术及表观遗传学分析为代表的高通量解析方法，已成为系统揭示基因组中功能变异的有力工具。这些方法不仅能够有效识别功能性变异，还可以揭示其调控基因表达的机制，从而阐明影响性状或疾病形成的分子基础。本文系统综述了当前用于基因组功能性变异的高通量鉴定方法，总结了其在主要农业动物中的应用进展，并对其未来研究前景进行展望，以期为后续相关领域研究提供参考。

关键词: 农业动物, GWAS, 功能性变异, 基因表达调控

Abstract:

Genome-wide association study (GWAS) has identified a large number of genetic variations that are significantly associated with human diseases and animal and plant economic traits. However, the majority of these variants are located in non-coding regions of the genome, which makes it challenging to accurately pinpoint functional variants of biological significance from a vast number of candidate loci. In the post-GWAS era, high-throughput analytical approaches, such as high-throughput reporter gene analysis, CRISPR/Cas9-based gene editing technologies, and epigenetic analyses, have become powerful tools for systematically uncovering functional variants in the genome. These methods not only enable efficient identification of functional variants but also help elucidate the mechanisms through which they regulate gene expression, thereby clarifying the molecular basis underlying trait formation or disease pathogenesis. In this review, we systematically summarize current high-throughput strategies for identifying functional genomic variants, highlight their applications and recent advances in major agricultural animal species, and outline future research directions, with the aim of providing a reference for subsequent studies in related fields.

Key words: agricultural animals, GWAS, functional variant, gene expression regulation

尹心怡, 王守志. 后GWAS时代基因组功能变异的高通量鉴定方法及其在农业动物中的应用[J]. 遗传, 2026, 48(5): 451-470.

Xinyi Yin, Shouzhi Wang. High-throughput identification methods of genomic functional variation in post-GWAS era and their application in agricultural animals[J]. Hereditas(Beijing), 2026, 48(5): 451-470.

图/表 5

图1

表1

鉴定功能性SNP的高通量方法及其衍生技术"

类别	方法	作用	技术名称	核心原理	应用	优点	不足	参考文献
核酸	高通量报告基因分析	筛选和鉴定顺式调控元件	经典MPRA*	将携带独特条形码的目标序列插入MPRA载体，从而驱动报告基因及其条形码的转录表达	全基因组筛选非编码区功能元件，分析功能变异对表型的作用	高通量检测大量序列，精准量化调控活性	与体内生理状态存在差异	[25]
			SysMPRA	通过腺病毒载体将MPRA文库递送到各种组织中进行检测增强子活性	体内顺式调控元件活性分析	接近体内真实生理状况	数据分析难度大	[32]
			经典STARR-seq	将目标序列插入到STARR-seq载体，直接驱动自身转录	全基因组鉴定增强子与沉默子活性	检测内源性转录活性	存在假阳性结果	[37]
			ChIP-STARR-seq	结合ChIP富集特定染色质状态的DNA片段，将其克隆到STARR-seq载体从而驱动转录	靶向富集转录因子结合的调控元件	提升筛选效率	依赖特异性抗体	[43]
			Ss-STARR-seq	基于STARR-seq载体将目标序列置于强启动子下游驱动自身转录	在全基因组范围内系统性鉴定沉默子	直接定量沉默子抑制活性	存在假阳性或假阴性结果	[47]
			HDI-STARR-seq	通过高压注射(HDI)体内递送 STARR-seq质粒进行检测增强子活性	复杂环境检测调控元件活性	区分活性差异细微的增强子	实验门槛高	[49]
			UMI-STARR-seq	基于STARR-seq载体引入UMI标签以消除PCR偏倚并量化转录本	用于精确定量增强子活性	减少PCR扩增偏差	实验成本高，难度大	[50]
	CRISPR/ Cas9基因编辑技术	解析基因表达调控机制	CRISPRi	dCas9融合阻遏结构域并靶向基因启动子区域，从而抑制基因的表达	阻断转录起始实现基因沉默	无切割，可逆性调控	对基因结构有依赖性	[53]
			CRISPRi-FlowFISH	CRISPRi靶向抑制并结合FlowFISH在单细胞分辨率下检测靶基因表达	研究增强子-启动子调控	增强子-基因关联准确性高	实验成本高，实验复杂	[55]
			CRISPRa	dCas9融合激活结构域并靶向基因调控区，从而激活基因表达	激活转录因子，增强基因转录活性	特异性激活目标基因	激活效率有限	[57]
			enCRISPRa	利用MS2-gRNA与多个激活因子复合物融合，协同增强靶基因的转录	实现增强子区域的精准靶向	激活效果更显著	载体构建复杂	[59]
			Perturb-seq	结合特异性gRNA条形码标记，通过scRNA-seq分析基因的转录组变化	解析基因功能、遗传互作及调控网络	高分辨率的单细胞基因组分析	成本高且范围有限	[63]
核酸与蛋白质互作	核酸-蛋白互作方法	研究DNA和蛋白质相互作用	REEL-seq	基于EMSA电泳分离回收蛋白结合的DNA片段并测序	体外检测蛋白质-DNA互作	高分辨率，高灵敏度	无法反映体内真实环境	[65]
			ChIP-seq	通过甲醛交联固定染色质结构，利用特异性抗体富集结合片段并测序	精确检测蛋白质结合区域	反映体内真实互作，应用广泛	依赖抗体，实验流程长	[67]
			scChIP-seq	基于ChIP-seq通过液滴微流控与分子条形码技术进行建库测序	单细胞水平检测蛋白质-DNA互作	解析单个细胞染色质特征	技术复杂，信噪比差	[71]
核酸与蛋白质互作	核酸-蛋白互作方法	研究DNA和蛋白质相互作用	CUT&Run	通过抗体引导MNase酶原位切割DNA片段并测序	获取蛋白质因子的高分辨率结合图谱	原位切割，细胞需求低	导致DNA损失	[73]
			CUT&Tag	通过抗体引导Tn5转座酶原位切割并同时连接测序接头进行测序	精准定位转录因子结合位点	信噪比高，效率高	Tn5转座酶存在序列偏好性	[74]
			scCUT&Tag	基于CUT&Tag通过液滴微流控条形码标记技术，实现目标蛋白与DNA结合位点的测序	单细胞分辨率绘制组蛋白修饰	解析单细胞异质性	技术复杂度高	[76]
			Spatial-CUT&Tag	通过在组织切片上进行原位Tn5转座酶切割，利用特异条形码磁珠捕获DNA片段进行测序	特定细胞类型在组织中的空间定位	整合空间分辨率与表观遗传信息	技术难度大	[79]
			DAP-seq	将纯化蛋白与基因组DNA体外孵育富集并测序	检测体外蛋白质-DNA互作	无需抗体参与，高通量	蛋白质数量不足	[80]
染色质构象	染色质可及性分析	鉴定开放染色质区域	FAIRE-seq	利用酚-氯仿抽提去除核小体富集裸露DNA片段进行测序	鉴定染色质开放区域	无需酶切	低丰度开放区域灵敏度低	[84]
			DNase-seq	通过DNase I酶切开放区域的DNA并测序	定位活性调控元件	分辨率、灵敏度高	依赖酶切条件	[85]
			MNase-seq	利用MNase酶切核小体间DNA并测序	分析核小体定位	分辨率高	酶切有偏好	[86]
			ATAC-seq	通过Tn5转座酶切割并标记开放染色质DNA进行建库测序	鉴定全基因组可及性区域	细胞用量少且高通量	易受线粒体DNA污染	[87]
			scATAC-seq	基于ATAC-seq并结合细胞特异性条形码的磁珠捕获进行建库测序	单细胞水平检测染色质可及性	解析细胞类型异质性	信噪比低	[90]
	三维染色质构象捕获技术	解析染色质三维空间构象及调控互作	Hi-C	通过邻近连接非连续DNA片段并利用生物素磁珠富集连接产物并测序	全基因组检测染色质远距离互作	覆盖范围广	分辨率较低	[92]
			PCHi-C	基于Hi-C利用启动子特异性探针捕获启动子区域进行富集测序	启动子相互作用的频率	分辨率高	覆盖范围有限	[93]
			HiChIP	基于Hi-C结合ChIP特异性富集DNA片段进行Tn5建库测序	不同细胞类型中启动子-增强子互作	特异性高	依赖抗体	[95]
			ChIA-PET	利用ChIP富集DNA片段在两端加上特殊的连接子并测序连接产物	检测特定蛋白质介导的染色质互作	靶向性强，分辨率高	细胞需求量大	[96]
			PLAC-seq	基于Hi-C结合ChIP特异性富集目标蛋白结合的DNA片段进行测序	捕获长程染色质相互作用	细胞需求量低	覆盖不足	[97]
			scHi-C	基于Hi-C结合单细胞分离与特异性条形码标记进行测序	捕获单细胞水平的染色质三维结构	揭示细胞间三维基因组差异	测序深度要求高	[101]

表1

图2

图3

表2

高通量方法在农业动物功能性变异鉴定中的研究进展"

物种	高通量方法	应用	参考文献
猪	STARR-seq	鉴定猪肺泡巨噬细胞中的增强子，解析猪疫病抗性机制	[102]
	STARR-seq	鉴定猪肾上皮细胞系和睾丸细胞系的活性增强子及其在生长发育中的作用	[103]
	CRISPR/Cas9	引入PVD 20 H和GP 19del两种突变后会促进肌肉质量增长	[104]
	CRISPRi	鉴定到rs694899689作为调控猪NUDT3表达和背膘厚度的eQTL，敲低NUDT3会调节肌肉中的核苷酸代谢和脂肪沉积	[105]
	CUT&Tag	鉴定猪产前和产后阶段骨骼肌中增强子相关的组蛋白修饰标记，探究对骨骼发育的影响	[106]
	CUT&Tag	鉴定猪脑和脂肪组织中抗寒性状相关顺式调控元件，研究耐寒适应机制	[107]
	Hi-C	构建猪白色与米色脂肪细胞的三维基因组图谱，鉴定出促进脂肪细胞分化的活性增强子	[108]
家禽	CRISPRa	激活IRF7和PPARG相关的增强子区域，表现出内源基因表达下调	[109]
	CRISPRa	激活鸡胸肌中与核苷酸相关非编码GWAS SNPs所在基因组区域，调节肌肉基因表达并影响肉质。	[110]
	ATAC-seq	鉴定到鸭CLN8基因启动子区的SNP通过改变与C/EBPα结合，调节禽类的脂肪生成	[111]
	CUT&Tag	鉴定到超级增强子的组蛋白修饰标记，并评估其在鸡脂肪组织中的潜在作用	[112]
	CUT&Run	鉴定到鸡颗粒细胞中DHCR7启动子雌激素响应区域的组蛋白修饰标记，促进其转录激活和卵泡成熟	[113]
	Hi-C	构建全面的染色质三维调控网络图，系统识别并解析了影响鸡腹部脂肪沉积性状的遗传调控机制	[114]
牛	CRISPR/Cas9	牛胚胎成纤维细胞中IGF2基因中ZBED6结合位点突变后，促进肌肉细胞的增殖能力	[115]
牛	ATAC-seq	鉴定牛肌肉组织基因组的功能元件，揭示肌肉发育的调控机制	[117]
羊	CRISPR/Cas9	阿勒泰羊PDGFD基因中与尾脂性状相关的SNP位点进行编辑后，其体外胚胎的囊胚率出现显著降低	[116]
	CUT&Tag	检测奶山羊乳腺细胞的H3K27ac组蛋白修饰，鉴定到超级增强子与转录因子STAT5结合调控泌乳基因表达	[118]
	CHIP-seq	鉴定到苏湖肉羊SNP分子标记影响生长发育相关基因的表达	[119]

表2

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后GWAS时代基因组功能变异的高通量鉴定方法及其在农业动物中的应用

High-throughput identification methods of genomic functional variation in post-GWAS era and their application in agricultural animals

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