《科学》杂志官网近日消息称，一项探索非编码DNA的新研究发现，调节基因活性区域的改变也可能导致自闭症，令人惊讶的是，这些变化倾向于从非自闭症的父亲那里继承而来。
过去十年中，研究人员已经发现了数百种可能影响大脑发育，从而增加自闭症风险的基因变异，但这些变异主要来自直接编码蛋白质的DNA中。此外，科学家一直试图在患者个体基因组中发现如何自发产生突变，而非从父母中寻找遗传突变。
论文作者、加利福尼亚大学遗传学家乔纳森·赛博特说：“基因组中只有2%由蛋白质编码基因组成，那些被称为‘垃圾’DNA的非编码部分，迄今在自闭症研究中一直被忽视。”
赛博特团队对能调节基因表达的非编码DNA部分特别感兴趣，他们研究了来自829个家庭的全基因组序列，包括自闭症个体、其没有患自闭症的兄弟姐妹和他们的父母。
评估个体非编码区DNA碱基变化带来的影响非常困难，因此，研究团队选择了所谓的大序列DNA结构变体作为考察对象。每个人在其基因组中仅有数千个结构变异，这样就缩小了分析范围，仅需要检查一小部分基因结构变体即可。
他们查找了一般人群变异少于预期的区域，包括在脑发育过程中负责调节基因活性并启动基因转录的位点，然后，通过检查父母对自闭症和非自闭症儿童的影响模式，检查这些区域的结构变体是否与自闭症有关。
研究人员发现，父亲传递了超过50%的变体，这表明自闭症儿童可能遗传了父亲而不是母亲的风险变异。为验证这个结果，赛博特团队随后测试了另外1771个家庭的样本，再次验证了上述结论。
对此，斯波坎华盛顿州立大学的神经科学家和计算生物学家露西卡·佩西欧托认为：“这是一篇非常好的文章，虽然有挑战性，但让我们思考自闭症遗传学的不同成因，这是对该领域的巨大贡献。”
Autistic children may inherit DNA mutations from their fathers
There is no one gene that, when mutated, causes autism. But over the past decade, researchers have identified hundreds of gene variations that seem to affect brain development in ways that increase the risk of autism. However, these scientists mainly searched for variants in the DNA that directly encodes the building blocks of proteins. Now, a new study probing so-called noncoding DNA has found that alterations in regions that regulate gene activity may also contribute to autism. And surprisingly, these variations tended to be inherited from fathers who aren’t autistic.
“This is a really good article—it’s somewhat provocative and it makes us think about [autism genetics in a] different way,” says Lucia Peixoto, a neuroscientist and computational biologist at Washington State University in Spokane, who was not involved in the research. “I think it’s a great contribution to the field.”
Research into the genetic risk for autism has mainly focused on how mutations that arise spontaneously in an individual’s genome—rather than being inherited from a parent—disrupt protein-coding regions and lead to the condition. That’s because these sporadic mutations have relatively large effects and studies have shown that such mutations, although individually rare, together contribute to about 25% to 30% of cases, says Jonathan Sebat, a geneticist at the University of California, San Diego. But only about 2% of the genome consists of protein-coding areas. Sebat says the large noncoding portion of our DNA—often previously referred to as “junk DNA”—has so far been ignored in autism research.
Sebat’s team was especially interested in the parts of noncoding DNA that regulate gene expression. They looked at whole-genome sequences from 829 families that included autistic individuals, their nonautistic siblings, and their parents. Assessing the influence of individual DNA base changes is particularly difficult in noncoding regions, so they instead identified bigger alterations, so-called structural variants, in which large sequences of DNA are inverted, duplicated, or deleted.
Each individual has thousands of structural variants in their genome, so the researchers narrowed down their analysis to examine just a handful of regulatory regions where genetic variation seemed most likely to cause disruption. They chose these by finding regions where the general population has less variation than expected, suggesting that genetic changes there could be detrimental. These included sites involved in regulating gene activity during brain development and initiating the transcription of genes.
The scientists then examined whether structural variants in these regions were associated with autism by examining the pattern of transmission from parents to their autistic and nonautistic children. Researchers have assumed that mothers are more likely to pass on autism-promoting gene variants. That’s because the rate of autism in women is much lower than that in men, and it is thought that women can carry the same genetic risk factors without having any signs of autism. But when a mother passes these genes to her sons, they are not protected in the same way and thus will be affected.
The team found that mothers passed only half of their structural variants on to their autistic children—a frequency that would be expected by chance alone—suggesting that variants inherited from mothers were not associated with autism. But surprisingly, fathers did pass on substantially more than 50% of their variants. This suggests that autistic children might have inherited risk variants in regulatory regions from their fathers but not their mothers, the researchers report today in Science.
To check that this result held up, Sebat’s team then tested a second, larger sample of 1771 families. Once again, autistic children received more structural variants from their fathers but not mothers—though the size of the effect wasn’t quite as large in this second sample.
“This is completely opposite to … what we had previously assumed,” Sebat says. Peixoto finds the paternal bias surprising as well, although she already suspected that the inherited component of autism would be more apparent in noncoding regions. Compared with mutations in protein-coding regions, variants in regulatory regions usually have “smaller but additive effects. And when you have a smaller effect, you are much more likely to pass [it] along from generation to generation.”
Based on these results, Sebat proposes a more complex model of how autism arises, in which mothers pass on mutations affecting coding regions, which have large effects that women are protected from, while fathers pass on variants affecting noncoding regions; their effects are much more moderate and may only cause symptoms when combined with risk variants from mothers.
Dalila Pinto, a molecular geneticist at the Icahn School of Medicine at Mount Sinai in New York City, says the study provides “very insightful preliminary findings.” She said she will be interested to see whether the results are replicated in even larger genome databases—and whether additional variants will be identified. Peixoto agrees: Although the research is still at an early stage, she says, it “open[s] a door in a different direction.”
http://www.sciencemag.org/news/2018/04/autistic-children-may-inherit-dna-mutations-their-fathers
