In a paper published on August 8, 2019 in Cell, researchers identify small proteins belonging to more than 4,000 new biological families. Over 30% of these proteins are predicted to be involved in cell-to-cell communications between microbes and their hosts, and housekeeping functions. However, a majority of these small proteins have no know function or domain, according to researchers.

So why have these proteins been overlooked? A biological blind spot Because many of the proteins identified in the study are fewer than 50 amino acids in length, they can fold into unique shapes that are unnoticed in traditional analysis methods. In the past, scientists have lacked the computational and research tools that would enable them to detect these proteins.

“The bacterial genome is like a book with long strings of letters, only some of which encode the information necessary to make proteins,” said Bhatt, the senior author. “Traditionally, we identify the presence of protein-coding genes within this book by searching for combinations of letters that indicate the ‘start’ and ‘stop’ signals that sandwich genes. This works well for larger proteins. But the smaller the protein, the more likely that this technique yields large numbers of false positives that muddy the results.”

The ability to detect and classify these previously unknown structures could allow scientists to determine new biological building blocks. The Stanford researchers sought to identify small open reading frames (sORFs) to infer their potential relevance to the human microbiome using a reference-free approach with shotgun metagenomic sequencing data analysis. Researchers confirmed the genes encoded true proteins by showing they are transcribed into RNA and shuttled to the ribosome for translation. If scientists can recreate the structure and function of these proteins in the laboratory, they can be used to help advance scientific understanding of how the microbiome affects health and open a new area of focus in drug discovery.

Shotgun sequencing: a method for sequencing random DNA strands. DNA is broken up randomly into numerous small segments, which are sequenced using chain termination Sanger method or next generation sequencing to obtain reads. The metagenomic approach to shotgun sequencing allows researchers to determine the species/strain of the DNA comes from.

This work suggests that “small proteins can be synthesized rapidly and could be used by the bacteria as biological switches to toggle between functional states or to trigger specific reactions in other cells,” Bhatt said. “They are also easier to study and manipulate than larger proteins, which could facilitate drug development. We anticipate this to be a valuable new area of biology for study.”

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