《科學》雜誌官網近日消息稱，一項探索非編碼DNA的新研究發現，調節基因活性區域的改變也可能導致自閉症，令人驚訝的是，這些變化傾向於從非自閉症的父親那裏繼承而來。
過去十年中，研究人員已經發現了數百種可能影響大腦發育，從而增加自閉症風險的基因變異，但這些變異主要來自直接編碼蛋白質的DNA中。此外，科學家一直試圖在患者個體基因組中發現如何自發產生突變，而非從父母中尋找遺傳突變。
論文作者、加利福尼亞大學遺傳學家喬納森·賽博特說：“基因組中隻有2%由蛋白質編碼基因組成，那些被稱為‘垃圾’DNA的非編碼部分，迄今在自閉症研究中一直被忽視。”
賽博特團隊對能調節基因表達的非編碼DNA部分特別感興趣，他們研究了來自829個家庭的全基因組序列，包括自閉症個體、其沒有患自閉症的兄弟姐妹和他們的父母。
評估個體非編碼區DNA堿基變化帶來的影響非常困難，因此，研究團隊選擇了所謂的大序列DNA結構變體作為考察對象。每個人在其基因組中僅有數千個結構變異，這樣就縮小了分析範圍，僅需要檢查一小部分基因結構變體即可。
他們查找了一般人群變異少於預期的區域，包括在腦發育過程中負責調節基因活性並啟動基因轉錄的位點，然後，通過檢查父母對自閉症和非自閉症兒童的影響模式，檢查這些區域的結構變體是否與自閉症有關。
研究人員發現，父親傳遞了超過50%的變體，這表明自閉症兒童可能遺傳了父親而不是母親的風險變異。為驗證這個結果，賽博特團隊隨後測試了另外1771個家庭的樣本，再次驗證了上述結論。
對此，斯波坎華盛頓州立大學的神經科學家和計算生物學家露西卡·佩西歐托認為：“這是一篇非常好的文章，雖然有挑戰性，但讓我們思考自閉症遺傳學的不同成因，這是對該領域的巨大貢獻。”
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
