Evolutionary constraint genes implicated in autism spectrum disorder across 2,054 nonhuman primate genomes
Evolutionary constraint genes implicated in autism spectrum disorder across 2,054 nonhuman primate genomes
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DOI：
10.1101/2023.11.08.566198
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发表时间：
2023-11
期刊：
影响因子：
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通讯作者：
Yukiko Kikuchi;Mohammed Uddin;J. Veltman;Sara Wells;M. Woodbury-Smith
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作者：
Yukiko Kikuchi;Mohammed Uddin;J. Veltman;Sara Wells;M. Woodbury-Smith
背景在阐明自闭症谱系障碍(ASD)的遗传基础方面取得了重大进展。从公共卫生的角度来看，这种儿童期起病的慢性认知、沟通和行为障碍属于最严重的疾病之一，因此希望新的发现将导致更好的治疗选择。然而，在我们对基因组学、神经生物学和科学发现中的临床表型之间的联系的理解上仍有很大的差距。因此，需要新的模式来弥补这些差距。恒河猴(Macaca Mulatta)被广泛用于临床前神经生物学研究，因为它在生物学和行为方面与人类有着惊人的相似之处，这是其他实验动物无法捕捉到的。方法利用由2,054个猕猴基因组组成的猕猴基因和表型(MGAP)资源(v2.0)，研究已知人类神经发育基因的进化制约模式。计算所有注释常染色体基因(N=18,168)的剩余变异不耐受分数(RVIS)，并使用基因集丰富分析(GSEA)来检查ASD基因和相关神经发育基因之间的约束模式。结果在人类和猕猴中，常染色体基因的约束模式是相关的，并且ASD相关基因在猕猴中表现出显著的约束(p=9.4×10-27)。在猕猴中，许多关键的ASD基因被观察到含有预测的破坏性突变。然而，在人类中对突变高度耐受的少数关键ASD基因(CACNA1D、CNTNAP2、MBD5、AUTS2和NRXN1)在猕猴中没有显示出类似的不耐受证据。在智力残疾(p=1.1 x 10-46)、癫痫(p=2.1 x 10-33)和精神分裂症(p=4.2 x 10-45)相关基因上也观察到了限制，对于重叠的神经发育基因集(p=4.0 x 10-10)限制，在其基因类型被研究的猕猴中缺乏行为表型，这意味着我们无法进一步调查基因变异是否在非人类灵长类动物中具有类似的表型后果。结论猕猴ASD基因存在病理性突变，且这些基因存在与人类相似的限制因素，为进一步研究非人灵长类的基因-表型关系提供了有力的理论依据。这突出了确定与临床症状相关的表型行为、阐明自闭症的神经生物学基础以及开发用于翻译研究的灵长类模型以推进精确医学和治疗干预方法的重要性。
Background Significant progress has been made in elucidating the genetic underpinning of Autism Spectrum Disorder (ASD). This childhood-onset chronic disorder of cognition, communication and behaviour ranks among the most severe from a public health perspective, and it is therefore hoped that new discoveries will lead to better therapeutic options. However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals. Methods We used the macaque Genotype and Phenotype (mGAP) resource (v2.0) consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes. Results We demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-implicated genes exhibit significant constraint in macaques (p = 9.4 x 10-27). Among macaques, many key ASD genes were observed to harbour predicted damaging mutations. A small number of key ASD genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D, CNTNAP2, MBD5, AUTS2 and NRXN1). Constraint was also observed across genes implicated in intellectual disability (p = 1.1 x 10-46), epilepsy (p = 2.1 x 10-33) and schizophrenia (p = 4.2 x 10-45), and for an overlapping neurodevelopmental gene set (p = 4.0 x 10-10) Limitations The lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates. Conclusion The presence of pathological mutations in ASD genes among macaques, and the evidence of similar constraints in these genes to humans, provide a strong rationale for further investigation of genotype-phenotype relationships in nonhuman primates. This highlights the importance of identifying phenotypic behaviours associated with clinical symptoms, elucidating the neurobiological underpinnings of ASD, and developing primate models for translational research to advance approaches for precision medicine and therapeutic interventions.