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研究探讨X染色体对脑解剖结构的影响

   2021-09-03 medicalxpress130
核心提示:过去的神经科学研究表明,人们基因图谱的共同差异可以解释人们大脑解剖结构的很大一部分差异。更具体地说,他们发现神经解剖变异部分是由遗传变异解释的。科学家们假设 X 染色体对大脑具有特别重要的影响,因为已知

过去的神经科学研究表明,人们基因图谱的共同差异可以解释人们大脑解剖结构的很大一部分差异。更具体地说,他们发现神经解剖变异部分是由遗传变异解释的。


科学家们假设 X 染色体对大脑具有特别重要的影响,因为已知它与许多基因的表达有关。此外,已发现几种类型的智力障碍与 X 染色体上的基因突变有关。

美国国家心理健康研究所校内研究项目和贝塞斯达国家健康与心理健康研究所的研究人员最近开展了一项研究,调查 X 染色体对人脑解剖结构的作用。他们的研究结果发表在Nature Neuroscience 上的一篇论文中,强调了 X 染色体在人类神经发育中的关键作用。

“所有现有的研究遗传学对大脑解剖学的作用的研究都排除了 X 染色体,它约占我们基因组的 5%,”进行这项研究的研究人员之一 Armin Raznahan 告诉 Medical Xpress。“我们认为解决这一差距很重要,因为除了完成缺失分析的基本需要之外,还有很多现有的迹象表明 X 染色体可能实际上具有解释大脑解剖结构变异的特殊能力。”

Raznahan 和他的同事决定研究 X 染色体在神经解剖学发育中的作用的第一个原因是,与其他染色体相比,已知 X 染色体基因在大脑中表达更多。此外,在过去的一系列针对遗传疾病的研究中,该团队发现携带异常数量的 X 染色体会对人类的大脑解剖结构产生显着影响。

“之前将常见的遗传变异与脑解剖结构的变异联系起来的研究表明,每条染色体与其相对长度成比例地对这种关系做出贡献:较长的染色体占大脑解剖结构变异的更大部分,这可以由基因组来解释,”Raznahan说过。“所以,作为一个玩具的例子,如果一个常见的遗传变异解释了总脑容量变异的30%,那么代表基因组 10% 的染色体将解释总脑容量变异的 3%。”


X 染色体约占总基因组的 5%。考虑到这一点,Raznahan 和他的同事计算了 X 染色体可以解释的解剖变异的比例。他们发现,鉴于其已知的大小和它所代表的人类基因组的百分比,他们计算出的比例与预期的比例有显着差异。

Raznahan 和他的同事使用来自英国生物银行的数据进行了计算。英国生物银行是一项著名的过去研究工作,旨在收集数千人的脑部扫描和基因数据。

“我们研究的主要结论是,X 染色体在解释大脑解剖结构差异的能力方面确实“超越了它的重量”,而且这种现象似乎集中在对复杂思维、决策很重要的特定大脑系统中。制作和行动,”拉兹纳汉说。“就实际意义而言,我们认为这一发现告诉我们,我们确实需要结束将 X 染色体排除在大脑和相关特征(如认知和行为)的遗传分析之外。”

这组研究人员收集的研究结果极大地丰富了目前对 X 染色体在人类神经发育中的作用的理解。将来,他们可以为新的全基因组关联研究提供信息,这些研究将 X 染色体考虑在内。

“我们的研究为未来的研究提出了很多问题,”拉兹纳汉说。“例如,如果 X 染色体因其影响大脑解剖结构的能力而富集,那么它对扫描仪中测量的大脑功能或思维或行为的差异的影响又如何?这种丰富的影响是如何实现的以及细胞过程是什么,在哪些细胞中,X 对哪些发育阶段表现出特殊影响?”

由于 X 染色体本身是一个广泛的研究课题,未来的研究可以探索许多不同的研究方向。除其他外,Raznahan 和他的同事希望更多地了解它对大脑的影响如何分布在它所携带的基因和基因调节器中。

原文:


Study explores the influence of the X-chromosome on brain anatomy

Past neuroscience research suggests that common differences in people's genetic profiles can explain a significant proportion of variations in people's brain anatomy. In more specific terms, they found that neuroanatomical variation is partly explained by genetic variation.

Scientists have hypothesized that the X-chromosome has a particularly crucial influence on the brain, as it is known to be associated with the expression of many genes. In addition, several types of intellectual disabilities have been found to be related with mutations of genes on the X chromosome.

Researchers at the National Insitute of Mental Health Intramural Research Program and the National Institutes of Health and Mental Health in Bethesda have recently carried out a study investigating the role of the X-chromosome on human brain anatomy. Their findings, published in a paper in Nature Neuroscience, highlight the key role of the X-chromosome in human neurodevelopment.

"All existing studies investigating the role of genetics on brain anatomy excluded the X-chromosome, which accounts for about 5% of our genomes," Armin Raznahan, one of the researchers who carried out the study, told Medical Xpress. "We thought it would be important to address this gap because—beyond the basic need to complete the missing analysis—there were lot of existing hints that the X-chromosome might actually have a special capacity to explain variation in brain anatomy."

The first reason why Raznahan and his colleagues decided to investigate the role of the X-chromosome in neuroanatomical development is that compared to other chromosomes, X-chromosome genes are known to be more expressed in the brain. In addition, in a series of past studies focusing on genetic disorders, the team found that carrying an unusual number of X-chromosomes can have a prominent impact on the brain anatomy of humans.

"Prior research relating common genetic variation to variation in brain anatomy had shown that each chromosome contributes to this relationship in proportion to its relative length: longer chromosomes account for a larger chunk of the variation in brain anatomy that is explained by the genome," Raznahan said. "So, as a toy example, if a common genetic variation explains 30% of variation in total brain volume, then a chromosome which represents 10% of the genome would explain 3% of variation in total brain volume."

The X-chromosome consists of approximately 5% of the total genome. Taking this into consideration, Raznahan and his colleagues calculated the proportion of anatomical variation that could be explained by the X-chromosome. They found that given its known size and the percentage of the human genome it represents, the proportion they calculated differed significantly from the expected proportion.

Raznahan and his colleagues performed their calculations using data from the UK Biobank. The UK Biobank is a renowned past research effort aimed at collecting of both brain scans and genetic data from thousands of individuals.

"The main take-aways from our studies are that the X-chromosome does indeed 'punch above its weight' in its capacity to explain differences in brain anatomy and that this phenomenon seems to be concentrated in particular brain systems important for complex thinking, decision making and action," Raznahan said. "In terms of practical implications—we think this finding tells us that we really do need to put an end to exclusion of the X-chromosome from genetic analyses of the brain and related traits such as cognition and behavior."

The findings gathered by this team of researchers significantly enrich the current understanding of the X-chromosome's role in human neurodevelopment. In the future, they could inform new genome-wide association studies that take the X-chromosome into account.

"Our study poses lots of questions for future research," Raznahan said. "For example—if the X-chromosome is enriched for its capacity to influence brain anatomy, what about its influence on brain function as measured in the scanner or as differences in thinking or behavior? Also how is this enriched influence achieved and what cellular processes, in which cells as what stages of development is the X showing a special influence on?"

As the X-chromosome itself is a broad topic of research, future research could explore numerous different research directions. Among other things, Raznahan and his colleagues hope to find out more about how its influence on the brain is distributed across the genes and gene regulators it carries.


 
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