{"id":54020,"date":"2025-07-31T07:00:50","date_gmt":"2025-07-31T14:00:50","guid":{"rendered":"https:\/\/www.salk.edu\/?post_type=disclosure&p=54020"},"modified":"2025-07-31T16:04:05","modified_gmt":"2025-07-31T23:04:05","slug":"new-ai-tool-illuminates-dark-side-of-the-human-genome","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/zh\/news-release\/new-ai-tool-illuminates-dark-side-of-the-human-genome\/","title":{"rendered":"\u65b0\u7684\u4eba\u5de5\u667a\u80fd\u5de5\u5177\u63ed\u793a\u4e86\u4eba\u7c7b\u57fa\u56e0\u7ec4\u7684\u201c\u9ed1\u6697\u9762\u201d"},"content":{"rendered":"

LA JOLLA\u2014Proteins sustain life as we know it, serving many important structural and functional roles throughout the body. But these large molecules have cast a long shadow over a smaller subclass of proteins called microproteins. Microproteins have been lost in the 99% of DNA disregarded as \u201cnoncoding\u201d\u2014hiding in vast, dark stretches of unexplored genetic code. But despite being small and elusive, their impact may be just as big as larger proteins.<\/p>\n

\"Brendan<\/a>
Brendan Miller (left) and Alan Saghatelian (right) stand in their lab, while ShortStop runs on the desktop beside them.
Click here<\/a> for a high-resolution image.
Credit: Salk Institute<\/figcaption><\/figure>\n

Salk Institute scientists are now exploring the mysterious dark side of the genome in search of microproteins. With their new tool ShortStop, researchers can probe genetic databases and identify DNA stretches in the genome that likely code for microproteins. Importantly, ShortStop also predicts which microproteins are most likely to be biologically relevant, saving time and money in the search for microproteins involved in health and disease.<\/p>\n

ShortStop shines a new light on existing datasets, spotlighting microproteins formerly impossible to find. In fact, the Salk team has already used the tool to analyze a lung cancer dataset to find 210 entirely new microprotein candidates\u2014with one standout validated microprotein\u2014that may make good therapeutic targets in the future.<\/p>\n

The findings were published in BMC Methods <\/em><\/a>on July 31, 2025.<\/p>\n

\u201cMost of the proteins in our body are well known, but recent discoveries suggest we\u2019ve been missing thousands of small, hidden proteins\u2014called microproteins\u2014coded by overlooked regions of our genome,\u201d says senior author Alan Saghatelian<\/a>, professor and holder of the Dr. Frederik Paulsen Chair at Salk. \u201cFor a long time, scientists only really studied the regions of DNA that coded for large proteins and dismissed the rest as \u2018junk DNA,\u2019 but we\u2019re now learning that these other regions are actually very important, and the microproteins they produce could play critical roles in regulating health and disease.\u201d<\/p>\n

More about microproteins<\/strong><\/p>\n

It is difficult to detect and catalog microproteins, owing mostly to their size. Compared to standard proteins that can range from hundreds to thousands of amino acids long, microproteins typically contain fewer than 150 amino acids, making them harder to detect using standard protein analysis methods. Therefore, instead of searching for the microproteins themselves, scientists search large, publicly available datasets for the DNA sequences that make them.<\/p>\n

Scientists have now learned that certain stretches of DNA called small open reading frames (smORFs) can contain the instructions for making microproteins. Current experimental methods have already cataloged thousands of smORFs, but these tools remain time-consuming and expensive. Furthermore, their inability to separate potentially functional microproteins from nonfunctional microproteins has stalled their discovery and characterization.<\/p>\n

How ShortStop works<\/strong><\/p>\n

Not all smORFs translate to biologically meaningful microproteins. Existing methods can\u2019t discriminate between functional and nonfunctional microprotein-generating smORFs. This means that scientists must independently test each microprotein to determine whether it is functional or not.<\/p>\n

\"Cells<\/a>
Cells express a novel ShortStop-predicted microprotein (green), with cell nuclei stained blue. The pattern suggests microproteins are localized either in endosomes, which are organelles responsible for sorting and transporting cellular cargo, or in lysosomes, which are organelles that collect and remove cellular waste.
Click here<\/a> for a high-resolution image.
Credit: Salk Institute<\/figcaption><\/figure>\n

ShortStop radically alters this workflow, optimizing smORF discovery by sorting microproteins into functional and nonfunctional categories. The key to ShortStop\u2019s two-class sorting is how it\u2019s trained as a machine learning system. Its training relies on a negative control dataset of computer-generated random smORFs. ShortStop compares found smORFs against these decoys to quickly decide whether a new smORF is likely to be functional or nonfunctional.<\/p>\n

ShortStop cannot definitively say whether a smORF will code for a biologically relevant microprotein, but this two-class system narrows down the experimental pool immensely. Now researchers can spend less time manually sorting through datasets and failing at the bench.<\/p>\n

When the researchers applied ShortStop to a previously published smORF dataset, they identified 8% as likely functional microproteins, prioritizing them for targeted follow-up. This accelerates microprotein characterization by filtering out sequences unlikely to have biological relevance. ShortStop could also identify microproteins that were overlooked by other methods, including one that was validated by being detected in human cells and tissues.<\/p>\n

\u201cWhat makes ShortStop especially powerful is that it works with common data types, like RNA sequencing datasets, which many labs already use,\u201d says first author Brendan Miller, a postdoctoral researcher in Saghatelian\u2019s lab. \u201cThis means we can now search for microproteins across healthy and diseased tissues at scale, which will reveal new insights into human biology and unlock new paths for diagnosing and treating diseases, such as cancer and Alzheimer\u2019s disease.\u201d<\/p>\n

ShortStop spots microprotein associated with lung cancer<\/strong><\/p>\n

The researchers have already used ShortStop to identify a microprotein that was upregulated in lung cancer tumors. They analyzed genetic data from human lung tumors and adjacent normal tissue to create a list of potential functional smORFs. Among the smORFs ShortStop found, one stood out\u2014it was expressed more in tumor tissue than normal tissue, suggesting it may serve as a biomarker or functional microprotein for lung cancer.<\/p>\n

The identification of this lung cancer-related microprotein demonstrates the value of ShortStop and machine learning to prioritize candidates for future research and therapeutic development.<\/p>\n

\u201cThere\u2019s so much data that already exists that we can now process with ShortStop to find novel microproteins associated with health and disease, stretching from Alzheimer\u2019s to obesity and beyond,\u201d says Saghatelian. \u201cMy team is really good at making methods, and with data from other Salk faculty, we can integrate these methods and accelerate the science.\u201d<\/p>\n

Other authors include Eduardo Vieira de Souza, Victor Pai, Joan Vaughan, Calvin Lau, and Jolene Diedrich of Salk, as well as Hosung Kim of UC Los Angeles.<\/p>\n

The work was supported by the National Institutes of Health (P30CA014195, R01GM102491) and Clayton Medical Research Foundation.<\/p>","protected":false},"featured_media":54077,"template":"","faculty":[111],"disease-research":[448,332],"class_list":["post-54020","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-alan-saghatelian","disease-research-artificial-intelligence","disease-research-computational-biology"],"acf":[],"yoast_head":"\nNew AI tool illuminates \u201cdark side\u201d of the human genome - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/zh\/news-release\/new-ai-tool-illuminates-dark-side-of-the-human-genome\/\" \/>\n<meta property=\"og:locale\" content=\"zh_CN\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"New AI tool illuminates \u201cdark side\u201d of the human genome - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014Proteins sustain life as we know it, serving many important structural and functional roles throughout the body. 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